Multiple Myeloma
Conditions
Keywords
Plasma Cell Neoplasms, Blood Malignancy
Brief summary
The primary objective of Phase I is to establish the maximum tolerated dose (MTD) of ruxolitinib in combination with carfilzomib and dexamethasone. The primary objective of phase II is to evaluate progression-free survival (PFS) at 4 months in multiple myeloma subjects who receive the combination treatment carfilzomib, dexamethasone, and ruxolitinib.
Detailed description
This is an open-label, Phase I/II study of carfilzomib, ruxolitinib, and low-dose dexamethasone for carfilzomib-refractory multiple myeloma. Phase I is designed to evaluate overall maximum tolerated dose (MTD) of ruxolitinib in combination with carfilzomib and dexamethasone in the following cohorts: Cohort 1) 5mg ruxolitinib, Cohort 2) 10mg ruxolitinib, Cohort 3) 15mg ruxolitinib. Phase II is designed to evaluate 4-month progression-free survival (PFS) in the following cohorts: Cohort A) non-responders to Phase I regimen, Cohort B) responders to Phase I regimen. Up to 18 evaluable subjects will be enrolled in Phase I over approximately 12 months. An additional 30 evaluable subjects will be enrolled in Phase II over 24 months.
Interventions
DRUGCarfilzomib
Irreversible proteasome inhibitor
DRUGRuxolitinib
Oral JAK inhibitor
DRUGDexamethasone
glucocorticoid
Sponsors
Incyte Corporation
Multiple Myeloma Research Consortium
Amgen
Wake Forest University Health Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Subjects must meet all of the following criteria: 1. Documented history of relapsed and/or refractory multiple myeloma with \> 2 lines of therapy. One of the prior lines of therapy must have been a carfilzomib containing regimen with evidence of relapse or progression within the last 60 days of the carfilzomib containing regimen with a carfilzomib dose of at least 27 mg/m2. Carfilzomib containing regimen at the standard dose of 20/27 mg/m2 is acceptable. 2. Measurable disease, as defined by at least one of the following: 1. Serum monoclonal protein level ≥0.5 g/dL for IgG, IgA, or IgM disease 2. Urinary M-protein excretion of ≥200 mg over a 24-hour period 3. Involved free light chain level ≥10 mg/dL, along with an abnormal free light chain ratio 3. Adequate bone marrow reserves, as defined by the following: 1. Absolute neutrophil count (ANC) ≥1000 cells/mm3 within 1 week of the initiation of treatment 2. Platelet count of ≥75 ,000 cells/mm3 for subjects who have bone marrow plasmacytosis of \<50%, or ≥50,000 cells/mm3 for subjects who have bone marrow plasmacytosis of \>50% 4. Adequate hepatic function, as defined by the following: 1. Total bilirubin ≤ 2 times the upper limit of the institutional normal values 2. Total AST and ALT ≤ 3 times the upper limit of the institutional normal values 5. Adequate renal function, as defined by the following: creatinine clearance (CrCl) ≥ 30 mL/min., as measured by a 24-hour urine collection, or estimated by the Cockcroft and Gault formula. 6. Adequate cardiac function defined as LVEF ≥ 40% by MUGA, echocardiogram or cardiac MRI. 7. Be 18-75 years of age 8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 9. FOCBP and male subjects who are sexually active with FOCBP must agree to use two highly effective (as determined per the Investigator) methods of contraception during the study and for 30 days (female subjects) or for 90 days (male subjects) following the last dose of study treatment including a male condom. 10. Ability to understand and the willingness to sign a written informed consent document. 11. Recovered from all reversible acute toxic effects of prior therapy (other than alopecia) to ≤ Grade 1 or baseline.
Exclusion criteria
Subjects must not meet any of the following criteria: 1. Non-secretory multiple myeloma 2. Known amyloidosis 3. Known POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) 4. Clinically significant illness including, but not limited to the following: active systemic infection, uncontrolled hypertension (as defined by BP \> 160/90), New York Heart Association Class III and IV heart failure, unstable angina pectoris, myocardial infarction within the past 6 months of consent, uncontrolled cardiac arrhythmia, or any other condition (including laboratory abnormalities) that, in the opinion of the Investigator, places the subject at unacceptable risk for adverse outcome if he/she were to participate in the study 5. Prior cerebrovascular accident with persistent neurologic deficit. 6. Psychiatric illness/social situations that would limit compliance with study treatment and requirements 7. Pregnant or breast feeding. Females of childbearing potential (FOCBP) must have a negative serum pregnancy test within the 7 days prior to study drug administration and a negative urine pregnancy test within the 3 days prior to the first study drug administration. 8. Known human immunodeficiency virus (HIV) infection 9. Active hepatitis B and/or hepatitis C infection 10. Currently active second malignancy, other than non-melanoma skin cancer and carcinoma in situ of the cervix, should not be enrolled. Subjects are not considered to have a currently active malignancy if they have completed therapy for a prior malignancy, are disease free from prior malignancies for \>5 years, and are considered by their physician to be at less than 30% risk of relapse. In addition, subjects with basal cell carcinoma of the skin, superficial carcinoma of the bladder, carcinoma of the prostate with a current PSA value of \<0.5 ng/mL, or cervical intraepithelial neoplasia will be eligible. Finally, subjects who are on hormonal therapy for a history of either prostate cancer or breast cancer may enroll, provided that there has been no evidence of disease progression during the previous three years. 11. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib). 12. Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis or ascites requiring paracentesis. 13. Known intolerance to carfilzomib. 14. Co-administration with strong CYP3A4 inhibitors (such as, but not limited to, boceprevir, clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole) as well as fluconazole (a dual inhibitor of CYP3A4 and CYP2C9).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicity (DLT) | 28 days | DLTs will be determined for each subject as a binary variable indicating whether or not the subject experienced a DLT during Cycle 1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate | Approximately 180 days after treatment start (disease assessment occurred after every 28-day cycle) | Clinical benefit will be determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of minimal response (MR) or better as determined by the IMWG criteria |
| Disease Control Rate | Approximately 180 days after treatment start (disease assessment occurred after every 28-day cycle) | Disease control will be determined for each subject as a binary variable indicating whether or not the subject achieved a disease response or stable disease for greater than or equal to 8 weeks |
| Progression-free Survival (PFS) | approx. 5 years | PFS is defined as the duration of time from the initiation of study treatment with ruxolitinib to first occurrence of either progressive disease or death without progressive disease. |
| Objective Response Rate (ORR) | Approximately 180 days after treatment start (disease assessment occurred after every 28-day cycle) | Objective response will be determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of PR or better as per the IMWG criteria |
| Overall Survival | approx. 5 years | Overall survival is defined as the duration from initiation of ruxolitinib treatment to the date of death from any cause. |
| Time to Progression | approx. 5 years | Time to progression (TTP) is defined as the duration of time from the initiation of study treatment with ruxolitinib to first occurrence of either progressive disease or death. |
| Duration of Response | approx. 5 years | Duration of response will be defined as the time from first objective status assessment of response to the time of first documented disease progression or death. |
| Time to Best Response | Approximately 180 days after treatment start (disease assessment occurred after every 28-day cycle) | Time to best response will be defined as the time from initiation of ruxolitinib treatment to the time of best objective status assessment of response. |
Countries
United States
Participant flow
Pre-assignment details
The 10 participants who completed the Phase I component of the trial did not continue to the Phase II component of the trial. This is because the Phase II component of the trial did not open.
Participants by arm
| Arm | Count |
|---|---|
| Phase II Cohort A) non-responders to Phase I regimen, Cohort B) responders to Phase I regimen
Carfilzomib: Irreversible proteasome inhibitor
Ruxolitinib: Oral JAK inhibitor
Dexamethasone: glucocorticoid | 0 |
| Phase I 5mg Ruxolitinib Cohort 1) 5mg ruxolitinib
Carfilzomib: Irreversible proteasome inhibitor
Ruxolitinib: Oral JAK inhibitor
Dexamethasone: glucocorticoid | 5 |
| Phase I 10mg Ruxolitinib Cohort 2) 10mg ruxolitinib
Carfilzomib: Irreversible proteasome inhibitor
Ruxolitinib: Oral JAK inhibitor
Dexamethasone: glucocorticoid | 4 |
| Phase I 15 mg Ruxolitibin Cohort 3) 15mg ruxolitinib
Carfilzomib: Irreversible proteasome inhibitor
Ruxolitinib: Oral JAK inhibitor
Dexamethasone: glucocorticoid | 3 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Participant currently on study and in follow up status. | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Phase II | Phase I 5mg Ruxolitinib | Phase I 10mg Ruxolitinib | Phase I 15 mg Ruxolitibin |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 0 Participants | 3 Participants | 2 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 0 Participants | 2 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 0 Participants | 4 Participants | 4 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 0 Participants | 3 Participants | 3 Participants | 3 Participants |
| Region of Enrollment United States | 12 participants | — | 5 participants | 4 participants | 3 participants |
| Sex: Female, Male Female | 3 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Male | 9 Participants | 0 Participants | 5 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 5 | 3 / 4 | 2 / 3 |
| other Total, other adverse events | 5 / 5 | 4 / 4 | 3 / 3 |
| serious Total, serious adverse events | 4 / 5 | 3 / 4 | 1 / 3 |
Outcome results
Primary
Dose Limiting Toxicity (DLT)
DLTs will be determined for each subject as a binary variable indicating whether or not the subject experienced a DLT during Cycle 1
Time frame: 28 days
Population: Participants who are DLT evaluable
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I 5 mg Ruxolitinib | Dose Limiting Toxicity (DLT) | 0 participants |
| Phase I 10 mg Ruxolitinib | Dose Limiting Toxicity (DLT) | 0 participants |
| Phase I 15 mg Ruxolitinib | Dose Limiting Toxicity (DLT) | 1 participants |
Secondary
Clinical Benefit Rate
Clinical benefit will be determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of minimal response (MR) or better as determined by the IMWG criteria
Time frame: Approximately 180 days after treatment start (disease assessment occurred after every 28-day cycle)
Population: Participants who initiate protocol-directed therapy and have measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I 5 mg Ruxolitinib | Clinical Benefit Rate | 1 participants |
| Phase I 10 mg Ruxolitinib | Clinical Benefit Rate | 2 participants |
| Phase I 15 mg Ruxolitinib | Clinical Benefit Rate | 1 participants |
Secondary
Disease Control Rate
Disease control will be determined for each subject as a binary variable indicating whether or not the subject achieved a disease response or stable disease for greater than or equal to 8 weeks
Time frame: Approximately 180 days after treatment start (disease assessment occurred after every 28-day cycle)
Population: Number of participants who achieved a disease response of stables disease or better and maintained the response for at least 8 weeks.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I 5 mg Ruxolitinib | Disease Control Rate | 3 participants |
| Phase I 10 mg Ruxolitinib | Disease Control Rate | 3 participants |
| Phase I 15 mg Ruxolitinib | Disease Control Rate | 1 participants |
Secondary
Duration of Response
Duration of response will be defined as the time from first objective status assessment of response to the time of first documented disease progression or death.
Time frame: approx. 5 years
Population: Duration of best response calculated only for participants who achieved a PR or better.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I 10 mg Ruxolitinib | Duration of Response | 4.8 months |
| Phase I 15 mg Ruxolitinib | Duration of Response | 8.5 months |
Secondary
Objective Response Rate (ORR)
Objective response will be determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of PR or better as per the IMWG criteria
Time frame: Approximately 180 days after treatment start (disease assessment occurred after every 28-day cycle)
Population: Participants who initiate protocol-directed therapy and have measurable disease at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I 5 mg Ruxolitinib | Objective Response Rate (ORR) | 0 participants |
| Phase I 10 mg Ruxolitinib | Objective Response Rate (ORR) | 2 participants |
| Phase I 15 mg Ruxolitinib | Objective Response Rate (ORR) | 1 participants |
Secondary
Overall Survival
Overall survival is defined as the duration from initiation of ruxolitinib treatment to the date of death from any cause.
Time frame: approx. 5 years
Population: All participants who initiate study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I 5 mg Ruxolitinib | Overall Survival | 16.1 months |
| Phase I 10 mg Ruxolitinib | Overall Survival | 11.2 months |
| Phase I 15 mg Ruxolitinib | Overall Survival | 10.6 months |
Secondary
Progression-free Survival (PFS)
PFS is defined as the duration of time from the initiation of study treatment with ruxolitinib to first occurrence of either progressive disease or death without progressive disease.
Time frame: approx. 5 years
Population: All participants who initiate study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I 5 mg Ruxolitinib | Progression-free Survival (PFS) | 3.0 months |
| Phase I 10 mg Ruxolitinib | Progression-free Survival (PFS) | 6.1 months |
| Phase I 15 mg Ruxolitinib | Progression-free Survival (PFS) | 10.6 months |
Secondary
Time to Best Response
Time to best response will be defined as the time from initiation of ruxolitinib treatment to the time of best objective status assessment of response.
Time frame: Approximately 180 days after treatment start (disease assessment occurred after every 28-day cycle)
Population: Time to best response calculated only for participants who achieved a PR or better.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I 10 mg Ruxolitinib | Time to Best Response | 3.2 months |
| Phase I 15 mg Ruxolitinib | Time to Best Response | 2.1 months |
Secondary
Time to Progression
Time to progression (TTP) is defined as the duration of time from the initiation of study treatment with ruxolitinib to first occurrence of either progressive disease or death.
Time frame: approx. 5 years
Population: All participants who initiate study treatment.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Phase I 5 mg Ruxolitinib | Time to Progression | 3.0 months |
| Phase I 10 mg Ruxolitinib | Time to Progression | 8.3 months |
| Phase I 15 mg Ruxolitinib | Time to Progression | 10.6 months |