Trial Outcomes & Findings for Onalespib, Dabrafenib, and Trametinib in Treating Patients With BRAF-Mutant Melanoma or Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery (NCT NCT02097225)

NCT ID: NCT02097225

Last Updated: 2024-10-16

Results Overview

Maximum tolerated dose is defined as the highest dose level at which 0 or 1 of six patients has experienced a dose limiting toxicity (DLT) within 28 days after start of treatment. Toxicities will be graded according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0. Participant enrollment occurred from July 2015 to June 2018, spanning Dose Levels 1-4. * Dose Level 1 (starting dose): * Dabrafenib = 150 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 2: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 180 mg/m2 * Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 * Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2

Recruitment status

TERMINATED

Study phase

PHASE1

Target enrollment

22 participants

Primary outcome timeframe

28 days after start of treatment

Results posted on

2024-10-16

Participant Flow

Participant milestones

Participant milestones
Measure	Dose Level 1: Dabrafenib = 150 mg, Trametinib = 1 mg, Onalespib = 180 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 1 (starting dose): * Dabrafenib = 150 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 2: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 180 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO
Dose Level 1 STARTED	3	0	0	0
Dose Level 1 COMPLETED	3	0	0	0
Dose Level 1 NOT COMPLETED	0	0	0	0
Dose Level 2 STARTED	0	4	0	0
Dose Level 2 COMPLETED	0	4	0	0
Dose Level 2 NOT COMPLETED	0	0	0	0
Dose Level 3 STARTED	0	0	6	0
Dose Level 3 COMPLETED	0	0	6	0
Dose Level 3 NOT COMPLETED	0	0	0	0
Dose Level 4 STARTED	0	0	0	9
Dose Level 4 COMPLETED	0	0	0	8
Dose Level 4 NOT COMPLETED	0	0	0	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Dose Level -1: Dabrafenib = 75 mg, Trametinib = 1 mg, Onalespib = 180 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). Fallback dose level -1 is initiated if more than 1 of 6 subjects in dose level 1 (starting dose) develop DLTs. \* Dose Level -1 (fallback dose): * Dabrafenib = 75 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 1: Dabrafenib = 150 mg, Trametinib = 1 mg, Onalespib = 180 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 1 (starting dose): * Dabrafenib = 150 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 2: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 180 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO
Dose Level 4 Adverse Event	0	0	0	0	1

Baseline Characteristics

Onalespib, Dabrafenib, and Trametinib in Treating Patients With BRAF-Mutant Melanoma or Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Dose Level -1: Dabrafenib = 75 mg, Trametinib = 1 mg, Onalespib = 180 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). Fallback dose level -1 is initiated if more than 1 of 6 subjects in dose level 1 (starting dose) develop DLTs. \* Dose Level -1 (fallback dose): * Dabrafenib = 75 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 1: Dabrafenib = 150 mg, Trametinib = 1 mg, Onalespib = 180 mg/m2 n=3 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 1 (starting dose): * Dabrafenib = 150 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2 n=4 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 2: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 180 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2 n=6 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2 n=9 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Total n=22 Participants Total of all reporting groups
Age, Continuous	—	51.0 years n=107 Participants	66.5 years n=206 Participants	54.0 years n=7 Participants	58.0 years n=31 Participants	57.5 years n=30 Participants
Sex: Female, Male Female	0 Participants n=99 Participants	1 Participants n=107 Participants	3 Participants n=206 Participants	4 Participants n=7 Participants	5 Participants n=31 Participants	13 Participants n=30 Participants
Sex: Female, Male Male	0 Participants n=99 Participants	2 Participants n=107 Participants	1 Participants n=206 Participants	2 Participants n=7 Participants	4 Participants n=31 Participants	9 Participants n=30 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants	0 Participants n=31 Participants	0 Participants n=30 Participants
Race (NIH/OMB) Asian	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants	0 Participants n=31 Participants	0 Participants n=30 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants	0 Participants n=31 Participants	0 Participants n=30 Participants
Race (NIH/OMB) Black or African American	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants	0 Participants n=31 Participants	0 Participants n=30 Participants
Race (NIH/OMB) White	0 Participants n=99 Participants	3 Participants n=107 Participants	4 Participants n=206 Participants	6 Participants n=7 Participants	8 Participants n=31 Participants	21 Participants n=30 Participants
Race (NIH/OMB) More than one race	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants	0 Participants n=31 Participants	0 Participants n=30 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants	1 Participants n=31 Participants	1 Participants n=30 Participants
Performance Status Score 0	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants	3 Participants n=7 Participants	4 Participants n=31 Participants	7 Participants n=30 Participants
Performance Status Score 1	0 Participants n=99 Participants	3 Participants n=107 Participants	4 Participants n=206 Participants	3 Participants n=7 Participants	5 Participants n=31 Participants	15 Participants n=30 Participants
Months since diagnosis at time of study enrollment	—	7.8 months n=107 Participants	19.2 months n=206 Participants	68.8 months n=7 Participants	18.9 months n=31 Participants	19.7 months n=30 Participants
Disease Histology Adenocarcinoma of colon	—	2 Participants n=107 Participants	4 Participants n=206 Participants	2 Participants n=7 Participants	4 Participants n=31 Participants	12 Participants n=30 Participants
Disease Histology Metastatic melanoma	—	1 Participants n=107 Participants	0 Participants n=206 Participants	2 Participants n=7 Participants	3 Participants n=31 Participants	6 Participants n=30 Participants
Disease Histology Adenocarcinoma of lung	—	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants	1 Participants n=31 Participants	1 Participants n=30 Participants
Disease Histology Epithelioid sarcoma	—	0 Participants n=107 Participants	0 Participants n=206 Participants	1 Participants n=7 Participants	0 Participants n=31 Participants	1 Participants n=30 Participants
Disease Histology Anaplastic thyroid carcinoma	—	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants	1 Participants n=31 Participants	1 Participants n=30 Participants
Disease Histology Adenocarcinoma, Not otherwise specified	—	0 Participants n=107 Participants	0 Participants n=206 Participants	1 Participants n=7 Participants	0 Participants n=31 Participants	1 Participants n=30 Participants
Prior Therapy Received Chemotherapy, not otherwise specified	—	0 Participants n=107 Participants	0 Participants n=206 Participants	1 Participants n=7 Participants	1 Participants n=31 Participants	2 Participants n=30 Participants
Prior Therapy Received Chemotherapy, multiple agents systemic	—	3 Participants n=107 Participants	4 Participants n=206 Participants	4 Participants n=7 Participants	8 Participants n=31 Participants	19 Participants n=30 Participants
Prior Therapy Received Chemotherapy, single agent systemic	—	1 Participants n=107 Participants	1 Participants n=206 Participants	2 Participants n=7 Participants	3 Participants n=31 Participants	7 Participants n=30 Participants
Prior Therapy Received Chemotherapy, non-cytotoxic	—	0 Participants n=107 Participants	0 Participants n=206 Participants	1 Participants n=7 Participants	0 Participants n=31 Participants	1 Participants n=30 Participants
Prior Therapy Received Immunotherapy	—	1 Participants n=107 Participants	1 Participants n=206 Participants	3 Participants n=7 Participants	3 Participants n=31 Participants	8 Participants n=30 Participants
Prior Therapy Received Limited Radiation Therapy	—	1 Participants n=107 Participants	0 Participants n=206 Participants	1 Participants n=7 Participants	3 Participants n=31 Participants	5 Participants n=30 Participants
Prior Therapy Received Radiation Therapy, not otherwise specified	—	1 Participants n=107 Participants	0 Participants n=206 Participants	1 Participants n=7 Participants	1 Participants n=31 Participants	3 Participants n=30 Participants
Prior Therapy Received Surgery	—	3 Participants n=107 Participants	4 Participants n=206 Participants	6 Participants n=7 Participants	9 Participants n=31 Participants	22 Participants n=30 Participants
Prior Therapy Received Vaccine therapy	—	0 Participants n=107 Participants	0 Participants n=206 Participants	1 Participants n=7 Participants	0 Participants n=31 Participants	1 Participants n=30 Participants
Prior Therapy Received Prior therapy, not otherwise specified	—	0 Participants n=107 Participants	0 Participants n=206 Participants	0 Participants n=7 Participants	1 Participants n=31 Participants	1 Participants n=30 Participants

PRIMARY outcome

Timeframe: 28 days after start of treatment

Outcome measures

Outcome measures
Measure	Treatment (Dabrafenib, Trametinib, Onalespib) n=21 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Four dose levels, plus a fallback dose, are summarized in the table below. Dose escalation begins at dose level 1 (starting dose). * Dose Level -1: * Dabrafenib = 75 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 1 (starting dose): * Dabrafenib = 150 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 2: * Dabrafenib = 75 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 * Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 2: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 180 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO
Maximum Tolerated Dose of Dabrafenib	150 mg	—	—	—

PRIMARY outcome

Timeframe: 28 days after start of treatment

Outcome measures

Outcome measures
Measure	Treatment (Dabrafenib, Trametinib, Onalespib) n=18 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Four dose levels, plus a fallback dose, are summarized in the table below. Dose escalation begins at dose level 1 (starting dose). * Dose Level -1: * Dabrafenib = 75 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 1 (starting dose): * Dabrafenib = 150 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 2: * Dabrafenib = 75 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 * Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 2: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 180 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO
Maximum Tolerated Dose of Trametinib	2 mg	—	—	—

PRIMARY outcome

Timeframe: 28 days after start of treatment

Outcome measures

Outcome measures
Measure	Treatment (Dabrafenib, Trametinib, Onalespib) n=8 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Four dose levels, plus a fallback dose, are summarized in the table below. Dose escalation begins at dose level 1 (starting dose). * Dose Level -1: * Dabrafenib = 75 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 1 (starting dose): * Dabrafenib = 150 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 2: * Dabrafenib = 75 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 * Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 2: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 180 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2 Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO
Maximum Tolerated Dose of Onalespib	260 mg/m2	—	—	—

PRIMARY outcome

Timeframe: 28 days after start of treatment (1 cycle)

Dose limiting toxicities (DLTs) are at least possibly related to study treatment and graded according to the Common Toxicity Criteria for Adverse Events (CTCAE) v5.0: * any grade 4 toxicity * grade 3 (or grade 2 intolerable) non-hematologic toxicity (including fatigue lasting \>1 week or that requires hospitalization) * grade 3 or higher hematologic toxicity with complications (e.g., thrombocytopenia with bleeding, neutropenia with fever) * toxicity that lead to missing a dose of onalespib or \>25% of dabrafenib/trametinib in the first cycle The following grade 3 toxicities are not considered DLTs: * cutaneous squamous cell carcinoma or keratoacanthoma * nausea, vomiting, or diarrhea persisting \</= 72 hours with maximum supportive care * electrolyte events that resolve with replacement within 24 hours * any grade lymphopenia * lab abnormalities that return to baseline within 7 days: elevated bilirubin, AST, ALT, cholesterol, amylase, lipase, creatinine, hypertriglyceridemia

Outcome measures

Outcome measures
Measure	Treatment (Dabrafenib, Trametinib, Onalespib) n=3 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Four dose levels, plus a fallback dose, are summarized in the table below. Dose escalation begins at dose level 1 (starting dose). * Dose Level -1: * Dabrafenib = 75 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 1 (starting dose): * Dabrafenib = 150 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 2: * Dabrafenib = 75 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 * Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2 n=4 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 2: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 180 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2 n=6 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2 n=8 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO
Number of Dose Limiting Toxicities While Determining Maximum Tolerated Dose Grade 3 toxicity	0 dose limiting toxicities	0 dose limiting toxicities	5 dose limiting toxicities	1 dose limiting toxicities
Number of Dose Limiting Toxicities While Determining Maximum Tolerated Dose Grade 4 toxicity	0 dose limiting toxicities	0 dose limiting toxicities	0 dose limiting toxicities	0 dose limiting toxicities

SECONDARY outcome

Timeframe: up to 9 months

Objective response rate is defined as the number of participants with complete response or partial response as their best response to therapy assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1. * Complete response (CR) = Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. * Partial response (PR) = At least a 30% decrease in the sum of longest diameters of target lesions, taking as reference the baseline sum diameters.

Outcome measures

Outcome measures
Measure	Treatment (Dabrafenib, Trametinib, Onalespib) n=3 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Four dose levels, plus a fallback dose, are summarized in the table below. Dose escalation begins at dose level 1 (starting dose). * Dose Level -1: * Dabrafenib = 75 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 1 (starting dose): * Dabrafenib = 150 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 2: * Dabrafenib = 75 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 * Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2 n=4 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 2: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 180 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2 n=6 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2 n=8 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO
Objective Response Rate Partial response (PR)	0 Participants	0 Participants	2 Participants	0 Participants
Objective Response Rate Complete response (CR)	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: up to 9 months

Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of progressive disease assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1, or death, whichever occurs first. Progressive disease (PD) = At least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the baseline sum of diameters. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progressions.

Outcome measures

Outcome measures
Measure	Treatment (Dabrafenib, Trametinib, Onalespib) n=3 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Four dose levels, plus a fallback dose, are summarized in the table below. Dose escalation begins at dose level 1 (starting dose). * Dose Level -1: * Dabrafenib = 75 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 1 (starting dose): * Dabrafenib = 150 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 2: * Dabrafenib = 75 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 * Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2 n=4 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 2: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 180 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2 n=6 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2 n=8 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO
Progression-free Survival	1.6 months Interval 0.9 to 1.7	1.5 months Interval 0.6 to 3.6	3.9 months Interval 1.8 to 9.2	2.7 months Interval 1.5 to 3.8

SECONDARY outcome

Timeframe: 6 months

Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of progressive disease assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1, or death, whichever occurs first. PFS at 6 months will report the number of participants without progression at 6 months after starting treatment. Progressive disease (PD) = At least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the baseline sum of diameters. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progressions.

Outcome measures

Outcome measures
Measure	Treatment (Dabrafenib, Trametinib, Onalespib) n=3 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Four dose levels, plus a fallback dose, are summarized in the table below. Dose escalation begins at dose level 1 (starting dose). * Dose Level -1: * Dabrafenib = 75 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 1 (starting dose): * Dabrafenib = 150 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 2: * Dabrafenib = 75 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 * Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2 n=4 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 2: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 180 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2 n=6 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2 n=8 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO
Progression-free Survival at 6 Months	0 Participants	0 Participants	2 Participants	2 Participants

SECONDARY outcome

Timeframe: 1 year

Overall survival (OS) is defined as the time from start of treatment to death from any cause. OS at 1 year will report the number of participants alive at 1 year after starting treatment.

Outcome measures

Outcome measures
Measure	Treatment (Dabrafenib, Trametinib, Onalespib) n=3 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Four dose levels, plus a fallback dose, are summarized in the table below. Dose escalation begins at dose level 1 (starting dose). * Dose Level -1: * Dabrafenib = 75 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 1 (starting dose): * Dabrafenib = 150 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 2: * Dabrafenib = 75 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 * Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2 n=4 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 2: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 180 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2 n=6 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2 n=8 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO
Overall Survival at 1 Year	0 Participants	0 Participants	1 Participants	3 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 1 hour immediately after Cycle 1, Day 1 infusion

Population: There were 18 out of 21 total evaluable patients had blood samples analyzed on Cycle 1 Day 1.

Pharmacokinetics (PKs) represents the absorption, distribution, metabolism, and elimination of study drugs from the body. PKs for this study are reported a Area Under the Curve (AUC), which is estimated using the trapezoidal rule based on the average drug concentrations in blood samples, specifically blood plasma, at 1 hour immediately after study drug infusion. AUC gives insight into the extent of exposure to a drug and its clearance rate from the body.

Outcome measures

Outcome measures
Measure	Treatment (Dabrafenib, Trametinib, Onalespib) n=3 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Four dose levels, plus a fallback dose, are summarized in the table below. Dose escalation begins at dose level 1 (starting dose). * Dose Level -1: * Dabrafenib = 75 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 1 (starting dose): * Dabrafenib = 150 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 2: * Dabrafenib = 75 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 * Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 * Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2 n=3 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 2: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 180 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2 n=6 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2 n=6 Participants Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO
Pharmacokinetics of Dabrafenib, Trametinib, and Onalespib Combination	357 ng*hr/mL Interval 182.0 to 374.0	344 ng*hr/mL Interval 210.0 to 348.0	395 ng*hr/mL Interval 312.0 to 502.0	448 ng*hr/mL Interval 362.0 to 2310.0

Adverse Events

Dose Level 1: Dabrafenib = 150 mg, Trametinib = 1 mg, Onalespib = 180 mg/m2

Serious events: 1 serious events

Other events: 3 other events

Deaths: 3 deaths

Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2

Serious events: 1 serious events

Other events: 4 other events

Deaths: 4 deaths

Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2

Serious events: 0 serious events

Other events: 6 other events

Deaths: 6 deaths

Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2

Serious events: 2 serious events

Other events: 8 other events

Deaths: 7 deaths

Serious adverse events

Serious adverse events
Measure	Dose Level 1: Dabrafenib = 150 mg, Trametinib = 1 mg, Onalespib = 180 mg/m2 n=3 participants at risk Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Four dose levels, plus a fallback dose, are summarized in the table below. Dose escalation begins at dose level 1 (starting dose). \Dose Level 1 (starting dose): Dabrafenib = 150 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2 n=4 participants at risk Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 2: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 180 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2 n=6 participants at risk Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2 n=8 participants at risk Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO
Investigations Investigations - Other, specify	33.3% 1/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	25.0% 1/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	25.0% 2/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Investigations Blood bilirubin increased	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	25.0% 1/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Vascular disorders Hypotension	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	12.5% 1/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Infections and infestations Sepsis	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	12.5% 1/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Infections and infestations Infections and infestations Other, specify	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	12.5% 1/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Metabolism and nutrition disorders Hypoglycemia	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	12.5% 1/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.

Other adverse events

Additional Information

Ryan Sullivan, MD

Massachusetts General Hospital

Phone: 617-643-3614

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	Dose Level 1: Dabrafenib = 150 mg, Trametinib = 1 mg, Onalespib = 180 mg/m2 n=3 participants at risk Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Four dose levels, plus a fallback dose, are summarized in the table below. Dose escalation begins at dose level 1 (starting dose). \Dose Level 1 (starting dose): Dabrafenib = 150 mg * Trametinib = 1 mg * Onalespib = 180 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 2: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 180 mg/m2 n=4 participants at risk Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 2: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 180 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 3: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 220 mg/m2 n=6 participants at risk Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 3: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 220 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO	Dose Level 4: Dabrafenib = 150 mg, Trametinib = 2 mg, Onalespib = 260 mg/m2 n=8 participants at risk Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28, and onalespib IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. There are four dose levels, plus a fallback dose. Dose escalation begins at dose level 1 (starting dose). \* Dose Level 4: * Dabrafenib = 150 mg * Trametinib = 2 mg * Onalespib = 260 mg/m2 Dabrafenib: Given PO Laboratory Biomarker Analysis: Correlative studies Onalespib: Given IV Pharmacological Study: Correlative studies Trametinib: Given PO
Vascular disorders Thromboembolic Event	33.3% 1/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	25.0% 1/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Gastrointestinal disorders Abdominal Pain	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	50.0% 2/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Gastrointestinal disorders Constipation	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	25.0% 1/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Respiratory, thoracic and mediastinal disorders Dyspnea	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	25.0% 1/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
General disorders Fatigue	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	33.3% 2/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	12.5% 1/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Gastrointestinal disorders Lower Gastrointestinal Hemorrhage	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	16.7% 1/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Metabolism and nutrition disorders Hyponatremia	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	50.0% 2/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	33.3% 2/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	12.5% 1/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Musculoskeletal and connective tissue disorders Generalized Muscle Weakness	33.3% 1/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Nervous system disorders Depressed level of consciousness	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	12.5% 1/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
General disorders Gait Disturbance	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	12.5% 1/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Musculoskeletal and connective tissue disorders Back Pain	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	12.5% 1/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	12.5% 1/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Gastrointestinal disorders Vomiting	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	12.5% 1/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Vascular disorders Hypotension	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	25.0% 1/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
General disorders Fever	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	12.5% 1/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Investigations Blood bilirubin increased	33.3% 1/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Nervous system disorders Neuralgia	33.3% 1/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
General disorders Pain, unspecified	33.3% 1/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Nervous system disorders Somnolence	33.3% 1/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Investigations Alkaline Phosphatase Increased	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	25.0% 1/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Gastrointestinal disorders Diarrhea	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	25.0% 1/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Blood and lymphatic system disorders Anemia	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	33.3% 2/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Investigations Neutrophil Count Decreased	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	16.7% 1/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Investigations Platelet count decreased	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	16.7% 1/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Investigations White Blood Cell Decreased	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	33.3% 2/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Metabolism and nutrition disorders Hypophosphatemia	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	33.3% 2/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	12.5% 1/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Investigations Alanine Aminotransferase Increased	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	12.5% 1/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Metabolism and nutrition disorders Hypocalcemia	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	12.5% 1/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Musculoskeletal and connective tissue disorders Muscle Weakness Lower Limb	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	12.5% 1/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Gastrointestinal disorders Colonic Obstruction	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	16.7% 1/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.
Vascular disorders Hypertension	0.00% 0/3 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/4 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	0.00% 0/6 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.	12.5% 1/8 • Up to approximately 4.5 years, starting from the day 1 of dosing throughout post-treatment follow-up.