Trial Outcomes & Findings for Safety/Efficacy Study of LDE225 (Sonidegib) Plus Bortezomib in Patients With Relapsed or Relapsed/Refractory Multiple Myeloma (NCT NCT02254551)

Last Updated: 2017-02-16

Results Overview

During the safety lead-in, a standard 3+3 dose escalation design was used to establish the MTD for LDE225 in combination with bortezomib. The MTD would be determined by the highest dose at which ≤1 of 6 patients experiences a dose-limiting toxicity (DLT) during one cycle (21 days) of therapy. If 2 of 6 patients within a dose level experienced a DLT, that dose level would be defined as exceeding MTD and no further dose escalation would occur. The previous dose level would be considered the MTD.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

7 participants

Primary outcome timeframe

every 3 weeks up to 48 weeks

Results posted on

2017-02-16

Participant Flow

The primary objective of this study was to investigate safety, tolerability and determine the maximum tolerated dose (MTD) of LDE225 to administer along with a fixed dose of bortezomib. Between March 2015 and September 2015, 7 patients were enrolled in the safety lead-in part of the study at 4 investigational sites in the U.S.

7 patients received at least 1 cycle (21 days) of treatment on dose level 1.

Participant milestones

Participant milestones
Measure	LDE225 Plus Bortezomib Safety Lead-In: To determine the maximum tolerated dose (MTD), LDE225 will be administered orally at three dose levels: 400mg, 600mg, and 800mg. Bortezomib will be administered by subcutaneous injection (SQ) at a fixed dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21 day cycle. Expansion: Patients will receive LDE225 orally once daily for 21 days at the MTD. Bortezomib will be administered SQ at a fixed dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21 day cycle. Maintenance Therapy: Patients who complete 16 cycles of therapy with stable disease or better will be eligible for single agent maintenance therapy of LDE225 at the MTD orally for up to 2 years or until progressive disease or unacceptable toxicity.
Dose Escalation STARTED	7
Dose Escalation Cohort 1: LDE225 400mg	7
Dose Escalation Cohort 2: LDE225 600mg	0
Dose Escalation Cohort 3: LDE225 800mg	0
Dose Escalation COMPLETED	4
Dose Escalation NOT COMPLETED	3
Expansion STARTED	0
Expansion COMPLETED	0
Expansion NOT COMPLETED	0
Maintenance STARTED	0
Maintenance COMPLETED	0
Maintenance NOT COMPLETED	0

Reasons for withdrawal

Reasons for withdrawal
Measure	LDE225 Plus Bortezomib Safety Lead-In: To determine the maximum tolerated dose (MTD), LDE225 will be administered orally at three dose levels: 400mg, 600mg, and 800mg. Bortezomib will be administered by subcutaneous injection (SQ) at a fixed dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21 day cycle. Expansion: Patients will receive LDE225 orally once daily for 21 days at the MTD. Bortezomib will be administered SQ at a fixed dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21 day cycle. Maintenance Therapy: Patients who complete 16 cycles of therapy with stable disease or better will be eligible for single agent maintenance therapy of LDE225 at the MTD orally for up to 2 years or until progressive disease or unacceptable toxicity.
Dose Escalation Physician Decision	1
Dose Escalation Dose-limiting toxicity	2

Baseline Characteristics

Safety/Efficacy Study of LDE225 (Sonidegib) Plus Bortezomib in Patients With Relapsed or Relapsed/Refractory Multiple Myeloma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	LDE225 Plus Bortezomib n=7 Participants Safety Lead-In: To determine the maximum tolerated dose (MTD), LDE225 will be administered orally at three dose levels: 400mg, 600mg, and 800mg. Bortezomib will be administered by subcutaneous injection (SQ) at a fixed dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21 day cycle. Expansion: Patients will receive LDE225 orally once daily for 21 days at the MTD. Bortezomib will be administered SQ at a fixed dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21 day cycle. Maintenance Therapy: Patients who complete 16 cycles of therapy with stable disease or better will be eligible for single agent maintenance therapy of LDE225 at the MTD orally for up to 2 years or until progressive disease or unacceptable toxicity.
Age, Continuous	79 years n=39 Participants
Gender Female	6 Participants n=39 Participants
Gender Male	1 Participants n=39 Participants
Race/Ethnicity, Customized Caucasian	5 Participants n=39 Participants
Race/Ethnicity, Customized Black or African AMerican	1 Participants n=39 Participants
Race/Ethnicity, Customized Unknown	1 Participants n=39 Participants
Region of Enrollment United States	7 participants n=39 Participants

PRIMARY outcome

Timeframe: every 3 weeks up to 48 weeks

Outcome measures

Outcome measures
Measure	LDE225 Plus Bortezomib n=7 Participants Safety Lead-In: To determine the maximum tolerated dose (MTD), LDE225 will be administered orally at three dose levels: 400mg, 600mg, and 800mg. Bortezomib will be administered by subcutaneous injection (SQ) at a fixed dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21 day cycle. Expansion: Patients will receive LDE225 orally once daily for 21 days at the MTD. Bortezomib will be administered SQ at a fixed dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21 day cycle. Maintenance Therapy: Patients who complete 16 cycles of therapy with stable disease or better will be eligible for single agent maintenance therapy of LDE225 at the MTD orally for up to 2 years or until progressive disease or unacceptable toxicity
Maximum Tolerated Dose (MTD) of LDE225 Plus Bortezomib	NA (NUMBER) The MTD was not reached. Due to lack of efficacy and toxicity seen during dose level 1, additional dose levels were not examined and the study was terminated.

PRIMARY outcome

Timeframe: every 3 weeks up to 48 weeks, then every 3 months thereafter up to 3 years from initiation of study treatment.

Population: This outcome measure was to be assessed during the expansion phase of the study. The study closed early and did not proceed to this phase of the study. There is no data to report for this outcome measure.

Time to progression (TTP) is measured from Day 1 of study drug administration to disease progression using International Myeloma Working Group (IMWG) Uniform Response Criteria.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Every 3 weeks up to 48 weeks

Population: Of 7 enrolled patients, 1 was deemed ineligible and was excluded from efficacy analyses. At a median follow-up of 6 weeks, 3 patients in Cohort 1 had progressive disease and 3 had stable disease. Study was terminated after reviewing data from this first lead-in cohort.

Number of patients with confirmed Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), Progressive Disease (PD) or Stable Disease (SD) according to International Myeloma Working Group (IMWG) Uniform Response Criteria. CR=5% or less plasma cells in bone marrow, disappearance of soft tissue plasmacytoma, negative immunofixation on serum and urine. VGPR=Serum and urine M-protein detectable by immunofixation but not by electrophoresis, disappearance of any soft tissue plasmacytomas that were present at baseline. PR= at least 50% reduction from baseline in serum M-protein and at least 90% reduction from baseline in 24hr urinary M-protein. PD=Increase of 25% or more from nadir in serum or urine proteins. SD= not meeting criteria for CR, VGPR, PR or PD.

Outcome measures

Outcome measures
Measure	LDE225 Plus Bortezomib n=6 Participants Safety Lead-In: To determine the maximum tolerated dose (MTD), LDE225 will be administered orally at three dose levels: 400mg, 600mg, and 800mg. Bortezomib will be administered by subcutaneous injection (SQ) at a fixed dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21 day cycle. Expansion: Patients will receive LDE225 orally once daily for 21 days at the MTD. Bortezomib will be administered SQ at a fixed dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21 day cycle. Maintenance Therapy: Patients who complete 16 cycles of therapy with stable disease or better will be eligible for single agent maintenance therapy of LDE225 at the MTD orally for up to 2 years or until progressive disease or unacceptable toxicity
Overall Response Progressive Disease	3 Participants
Overall Response Stable Disease	3 Participants

Adverse Events

Cohort 1: LDE225 400mg/m^2

Serious events: 2 serious events

Other events: 6 other events

Deaths: 0 deaths

Cohort 2: LDE225 600mg/m^2

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Cohort 3: LDE225 800mg/m^2

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Cohort 1: LDE225 400mg/m^2 n=7 participants at risk Cohort 1 will receive LDE225 orally on a daily basis, at 400mg/m\^2 every 21 days. Bortezomib will be administered by subcutaneous injection (SQ) at a fixed dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21 day cycle.	Cohort 2: LDE225 600mg/m^2 Cohort 2 will receive LDE225 orally on a daily basis, at 600 mg every 21 days. Bortezomib will be administered by subcutaneous injection (SQ) at a fixed dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21 day cycle.	Cohort 3: LDE225 800mg/m^2 Cohort 3 will receive LDE225 orally on a daily basis, at 800mg/m\^2 every 21 days. Bortezomib will be administered by subcutaneous injection (SQ) at a fixed dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of each 21 day cycle.
Infections and infestations Viral Gastroenteritis	14.3% 1/7 • Number of events 1 • Treatment-emergent adverse events were collected on Days 1 and 8 of every 21-day cycle for up to 48 weeks (plus 30 days for end of treatment visit). All patients who received at least one dose of LDE225 plus bortezomib.	— 0/0 • Treatment-emergent adverse events were collected on Days 1 and 8 of every 21-day cycle for up to 48 weeks (plus 30 days for end of treatment visit). All patients who received at least one dose of LDE225 plus bortezomib.	— 0/0 • Treatment-emergent adverse events were collected on Days 1 and 8 of every 21-day cycle for up to 48 weeks (plus 30 days for end of treatment visit). All patients who received at least one dose of LDE225 plus bortezomib.
Infections and infestations Sepsis	14.3% 1/7 • Number of events 1 • Treatment-emergent adverse events were collected on Days 1 and 8 of every 21-day cycle for up to 48 weeks (plus 30 days for end of treatment visit). All patients who received at least one dose of LDE225 plus bortezomib.	— 0/0 • Treatment-emergent adverse events were collected on Days 1 and 8 of every 21-day cycle for up to 48 weeks (plus 30 days for end of treatment visit). All patients who received at least one dose of LDE225 plus bortezomib.	— 0/0 • Treatment-emergent adverse events were collected on Days 1 and 8 of every 21-day cycle for up to 48 weeks (plus 30 days for end of treatment visit). All patients who received at least one dose of LDE225 plus bortezomib.

Other adverse events

Additional Information

Charles Davis, Sr Mgr Regulatory Strategy & Operations

Sarah Cannon Development Innovations

Phone: 615-524-4341

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The sponsor can review/embargo results communications prior to public release for a period that is \>60 days but ≤180 days from date submitted to sponsor, who may require changes to the communication in order to remove specifically identified confidential information (other than study data) and/or delay the proposed publication to enable the sponsor to seek patent protection for inventions. The PI may not publish its results until 18 mos. after the trial has been completed at all sites.
Publication restrictions are in place

Restriction type: OTHER