Trial Outcomes & Findings for Cabozantinib as a Targeted Strategy to Reverse Carfilzomib Resistance in Refractory Multiple Myeloma (NCT NCT03201250)

NCT ID: NCT03201250

Last Updated: 2023-09-08

Results Overview

The investigators will study three dose levels using the 3+3 algorithm. MTD will be assess with dose limiting toxicities (DLTs) based solely on adverse events that occur during cycle 1.

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

11 participants

Primary outcome timeframe

1 cycle (approximately 28 days)

Results posted on

2023-09-08

Participant Flow

The study was terminated prior to starting the Phase II portion of the study.

Participant milestones

Participant milestones
Measure	Level -1 = 20 mg Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Cabozantinib: Phase I: Level -1 = 20 mg Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)	Level 0 = 40 mg Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Cabozantinib: Phase I: Level 0 = 40 mg Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)
Overall Study STARTED	8	3
Overall Study COMPLETED	5	3
Overall Study NOT COMPLETED	3	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Level -1 = 20 mg Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Cabozantinib: Phase I: Level -1 = 20 mg Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)	Level 0 = 40 mg Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Cabozantinib: Phase I: Level 0 = 40 mg Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)	Level +1 = 60 mg Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Cabozantinib: Phase I: Level +1 = 60 mg Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)
Overall Study screen failures	3	0	0

Baseline Characteristics

Cabozantinib as a Targeted Strategy to Reverse Carfilzomib Resistance in Refractory Multiple Myeloma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Level -1 = 20 mg n=5 Participants Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Cabozantinib: Phase I: Level -1 = 20 mg Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)	Level 0 = 40 mg n=3 Participants Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Cabozantinib: Phase I: Level 0 = 40 mg Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)	Level +1 = 60 mg Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Cabozantinib: Phase I: Level +1 = 60 mg Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)	Total n=8 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=99 Participants	0 Participants n=107 Participants	—	0 Participants n=7 Participants
Age, Categorical Between 18 and 65 years	1 Participants n=99 Participants	2 Participants n=107 Participants	—	3 Participants n=7 Participants
Age, Categorical >=65 years	4 Participants n=99 Participants	1 Participants n=107 Participants	—	5 Participants n=7 Participants
Sex: Female, Male Female	2 Participants n=99 Participants	1 Participants n=107 Participants	—	3 Participants n=7 Participants
Sex: Female, Male Male	3 Participants n=99 Participants	2 Participants n=107 Participants	—	5 Participants n=7 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants	0 Participants n=107 Participants	—	0 Participants n=7 Participants
Race (NIH/OMB) Asian	1 Participants n=99 Participants	0 Participants n=107 Participants	—	1 Participants n=7 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	0 Participants n=107 Participants	—	0 Participants n=7 Participants
Race (NIH/OMB) Black or African American	0 Participants n=99 Participants	2 Participants n=107 Participants	—	2 Participants n=7 Participants
Race (NIH/OMB) White	4 Participants n=99 Participants	1 Participants n=107 Participants	—	5 Participants n=7 Participants
Race (NIH/OMB) More than one race	0 Participants n=99 Participants	0 Participants n=107 Participants	—	0 Participants n=7 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	0 Participants n=107 Participants	—	0 Participants n=7 Participants
Region of Enrollment United States	5 participants n=99 Participants	3 participants n=107 Participants	—	8 participants n=7 Participants

PRIMARY outcome

Timeframe: 1 cycle (approximately 28 days)

Population: Only subjects that were dosed are included in this analysis

The investigators will study three dose levels using the 3+3 algorithm. MTD will be assess with dose limiting toxicities (DLTs) based solely on adverse events that occur during cycle 1.

Outcome measures

Outcome measures
Measure	Treatment n=8 Participants Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Cabozantinib: Phase I: Level -1 = 20 mg or Level 0 = 40 mg or Level +1 = 60 mg, PO daily on days 1-28 Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)	Level 0 = 40 mg Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Cabozantinib: Phase I: Level 0 = 40 mg Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)	Level +1 = 60 mg Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Cabozantinib: Phase I: Level +1 = 60 mg Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)
Maximum Tolerated Dose (MTD) of Daily Cabozantinib Given	20 mg	—	—

PRIMARY outcome

Timeframe: 2 cycles (approximately 56 days)

Population: Two subjects were not included in this analysis as the protocol states that an individual must complete at least 2 cycles before a best response (ORR) could be established.

Per International Myeloma Working Group (IMWG) Uniform Response Criteria guidelines as assessed by laboratory blood tests: Complete Response (CR), negative immunofixation of serum and urine, disappearance of soft tissue plasmacytomas, \<5% plasma cells in bone marrow; Stringent Complete Response (sCR), same as CR plus normal serum free light chain (FLC) ratio and absence of clonal plasma cells; Very Good Partial Response (VGPR), serum and urine M-component still detectable by immunofixation or \>/= 90% reduction in serum M-component plus a urine M component of, 100mg per 24hrs; Partial Response (PR) ≥ 50% reduction of the serum M-protein and 24 hour urinary M-protein by ≥ 90%, or to \< 200 mg per 24 hours. If serum and urine M-protein are not measurable, a ≥ 50% decrease in the difference between involved and uninvolved FLC levels is required OR If FLC is also not informative, ≥ 50% reduction in bone marrow plasma. ORR includes following only: CR+sCR+VGPR+PR

Outcome measures

Outcome measures
Measure	Treatment n=3 Participants Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Cabozantinib: Phase I: Level -1 = 20 mg or Level 0 = 40 mg or Level +1 = 60 mg, PO daily on days 1-28 Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)	Level 0 = 40 mg n=3 Participants Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Cabozantinib: Phase I: Level 0 = 40 mg Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)	Level +1 = 60 mg Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Cabozantinib: Phase I: Level +1 = 60 mg Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)
Overall Response Rate (ORR)	1 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: variable, defined by individual response durability in individual patients who would stay on therapy until disease progression

Population: No subjects were dosed at 60 mg dose level.

Progressive Disease (PD) is defined per International Myeloma Working Group (IMWG) Uniform Response Criteria guidelines is an increase of 25% from the lowest response value in any one or more of the following: Serum M-component and/or Urine M-component and/or in patients without a measurable serum and urine M protein level: the difference between involved and uninvolved FLC levels must be \>10mg/dL, Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in the size of existing lesions or plasmacytomas, Development of hypercalcemia attributed solely to the plasma cell proliferative disorder

Outcome measures

Outcome measures
Measure	Treatment n=5 Participants Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Cabozantinib: Phase I: Level -1 = 20 mg or Level 0 = 40 mg or Level +1 = 60 mg, PO daily on days 1-28 Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)	Level 0 = 40 mg n=3 Participants Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Cabozantinib: Phase I: Level 0 = 40 mg Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)	Level +1 = 60 mg Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Cabozantinib: Phase I: Level +1 = 60 mg Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)
Response Durability Assessed by Progression Free Survival (PFS)	25 weeks Interval 12.0 to 68.0	19 weeks Interval 12.0 to 28.0	—

Adverse Events

Dose Level -1 = 20 mg

Serious events: 0 serious events

Other events: 3 other events

Deaths: 1 deaths

Dose Level 0 = 40 mg

Serious events: 2 serious events

Other events: 3 other events

Deaths: 0 deaths

Dose Level +1= 60 mg

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Dose Level -1 = 20 mg n=5 participants at risk Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Carfilzomib: carfilzomib will be administered intravenously over 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17 to 28). Each 28-day period is considered one treatment cycle. Dexamethasone: dexamethasone will be administered at 40 mg orally or intravenously on days 1, 8,15 and 22 of each 28-day cycle (for patient age ≥ 75, acceptable to be given as 20 mg orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, 23) Cabozantinib: Cabozantinib: Phase I: Level -1 = 20 mg PO daily on days 1-28 Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)	Dose Level 0 = 40 mg n=3 participants at risk Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Carfilzomib: carfilzomib will be administered intravenously over 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17 to 28). Each 28-day period is considered one treatment cycle. Dexamethasone: dexamethasone will be administered at 40 mg orally or intravenously on days 1, 8,15 and 22 of each 28-day cycle (for patient age ≥ 75, acceptable to be given as 20 mg orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, 23) Cabozantinib: Cabozantinib: Phase I: Level 0 = 40 mg PO daily on days 1-28 Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)	Dose Level +1= 60 mg Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Carfilzomib: carfilzomib will be administered intravenously over 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17 to 28). Each 28-day period is considered one treatment cycle. Dexamethasone: dexamethasone will be administered at 40 mg orally or intravenously on days 1, 8,15 and 22 of each 28-day cycle (for patient age ≥ 75, acceptable to be given as 20 mg orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, 23) Cabozantinib: Cabozantinib: Phase I: Level +1 = 60 mg, PO daily on days 1-28 Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)
Infections and infestations Other - Bacteremia infection	0.00% 0/5 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	33.3% 1/3 • Number of events 1 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	— 0/0 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.
Vascular disorders hypertension	0.00% 0/5 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	33.3% 1/3 • Number of events 1 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	— 0/0 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.
Renal and urinary disorders hematuria	0.00% 0/5 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	33.3% 1/3 • Number of events 1 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	— 0/0 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.
General disorders Non-cardiac chest pain	0.00% 0/5 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	33.3% 1/3 • Number of events 1 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	— 0/0 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.

Other adverse events

Other adverse events
Measure	Dose Level -1 = 20 mg n=5 participants at risk Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Carfilzomib: carfilzomib will be administered intravenously over 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17 to 28). Each 28-day period is considered one treatment cycle. Dexamethasone: dexamethasone will be administered at 40 mg orally or intravenously on days 1, 8,15 and 22 of each 28-day cycle (for patient age ≥ 75, acceptable to be given as 20 mg orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, 23) Cabozantinib: Cabozantinib: Phase I: Level -1 = 20 mg PO daily on days 1-28 Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)	Dose Level 0 = 40 mg n=3 participants at risk Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Carfilzomib: carfilzomib will be administered intravenously over 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17 to 28). Each 28-day period is considered one treatment cycle. Dexamethasone: dexamethasone will be administered at 40 mg orally or intravenously on days 1, 8,15 and 22 of each 28-day cycle (for patient age ≥ 75, acceptable to be given as 20 mg orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, 23) Cabozantinib: Cabozantinib: Phase I: Level 0 = 40 mg PO daily on days 1-28 Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)	Dose Level +1= 60 mg Combination of cabozantinib, carfilzomib and dexamethasone Cabozantinib: patients will receive cabozantinib orally once daily continuously during the four weeks of a 28-day cycle. Carfilzomib: carfilzomib will be administered intravenously over 10 minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17 to 28). Each 28-day period is considered one treatment cycle. Dexamethasone: dexamethasone will be administered at 40 mg orally or intravenously on days 1, 8,15 and 22 of each 28-day cycle (for patient age ≥ 75, acceptable to be given as 20 mg orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, 23) Cabozantinib: Cabozantinib: Phase I: Level +1 = 60 mg, PO daily on days 1-28 Carfilzomib: 27 mg/m2 IV over 10 min on days 1, 2, 8, 9, 15, 16 Dexamethasone: 40 mg PO/IV on days 1, 8,15 and 22 (for patient age ≥ 75, acceptable to be given as 20 mg PO/IV on days 1, 2, 8, 9, 15, 16, 22, 23)
Metabolism and nutrition disorders hyperglycemia	20.0% 1/5 • Number of events 1 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	0.00% 0/3 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	— 0/0 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.
Vascular disorders hypertension	40.0% 2/5 • Number of events 2 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	66.7% 2/3 • Number of events 2 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	— 0/0 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.
Blood and lymphatic system disorders anemia	0.00% 0/5 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	33.3% 1/3 • Number of events 1 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	— 0/0 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.
Investigations platelet count decreased	0.00% 0/5 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	33.3% 1/3 • Number of events 4 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	— 0/0 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.
Respiratory, thoracic and mediastinal disorders dyspnea	0.00% 0/5 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	33.3% 1/3 • Number of events 1 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	— 0/0 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.
Cardiac disorders cardiomyopathy	0.00% 0/5 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	33.3% 1/3 • Number of events 1 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	— 0/0 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.
Investigations alanine aminotransferase increased	0.00% 0/5 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	33.3% 1/3 • Number of events 2 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	— 0/0 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.
Investigations aspartate aminotransferase increased	0.00% 0/5 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	33.3% 1/3 • Number of events 2 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.	— 0/0 • All patients will be closely followed for toxicity from the time of informed consent until 30 days after last administration of study medication upto approximately 2 years. Since no subjects were enrolled into the 60 mg dose level for the study number of participants at risk for SAEs, All-Cause Mortality and Other AEs is zero for the dose level +1 = 60mg Arm/Group.

Additional Information

Muhamed Baljevic, MD

Vanderbilt University Medical Center

Phone: 615-936-8422

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place