Trial of Carfilzomib, Lenalidomide, Dexamethasone Versus Lenalidomide Alone After Stem-cell Transplant for Multiple Myeloma

• ClinicalTrials.gov Identifier: NCT02659293
• Recruitment Status: Active, not recruiting
• First Posted: January 20, 2016
• Last Update Posted: April 28, 2023
• Sponsor: University of Chicago
• Information provided by (Responsible Party): University of Chicago

Tracking Information

• First Submitted Date: January 15, 2016
• First Posted Date: January 20, 2016
• Last Update Posted Date: April 28, 2023
• Actual Study Start Date: April 26, 2016
• Estimated Primary Completion Date: November 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 9, 2018)

Progression free survival rates in participants receiving drug combination [ Time Frame: 4 years ]

Measurement of time to disease worsening as measured by International Myeloma Working Group (IMWG) response criteria.

• Original Primary Outcome Measures (submitted: January 19, 2016): Time to progression or death [ Time Frame: From date of first treatment until maximum 6 year post randomization ]

Current Secondary Outcome Measures (submitted: March 9, 2018)

• Rate of minimal residual negative disease (MRD) in participants receiving drug combination [ Time Frame: 3 years ]
  Calculation of number of participants with MRD-negative disease.
• Response rate in participants receiving drug combination [ Time Frame: 3 years ]
  Number of participants with disease response (e.g. improvement) as measured by International Myeloma Working Group (IMWG) response criteria.
• Treatment-related side effects [ Time Frame: From date of screening until end of treatment ]
  Number of participants with grade 2 or greater treatment-related side effects as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.0

Original Secondary Outcome Measures (submitted: January 19, 2016)

• Rate of minimal residual negatibe disease (MRD) calculated using chi-square or Fisher's tests [ Time Frame: From date of screening up until 36 months on treatment ]
• Efficacy Rate of KRd arm versus lenalidomide arm [ Time Frame: From date of screening up until 36 months on treatment ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Trial of Carfilzomib, Lenalidomide, Dexamethasone Versus Lenalidomide Alone After Stem-cell Transplant for Multiple Myeloma
• Official Title: Phase 3 Randomized Trial of Carfilzomib, Lenalidomide, Dexamethasone Versus Lenalidomide Alone After Stem-cell Transplant for Multiple Myeloma
• Brief Summary: This is a Phase 3 randomized trial of carfilzomib, lenalidomide, dexamethasone versus lenalidomide alone after stem-cell transplant for multiple myeloma, eligible to subjects who completed autologous stem cell transplant for symptomatic myeloma who are considered for lenalidomide maintenance.

Detailed Description

Primary Objective:

• To compare progression free survival between Kyprolis (Carfilzomib), Revlimid (lenalidomide), Dexamethasone (KRd) arm and lenalidomide arm

Secondary Objectives

• To determine the rate of minimal residual negative disease (MRD) at 6 and 12 months after randomization
• To compare the efficacy (rate of partial response, very good partial response, complete response, and stringent complete response) of KRd vs. Lenalidomide alone after randomization

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Multiple Myeloma

Intervention

• Drug: Lenalidomide
  • Cycle 1: 15 mg days 1-21
  • Cycles 2-4: 25 mg days 1-21 if tolerated, otherwise continue at lower dose
  • Cycles 5 and beyond: best tolerated dose days 1-21
  Other Name: Revlimid
• Drug: Carfilzomib
  • Cycle 1: 20 mg/m2 Days 1, 2; 36 mg/m2 Days 8, 9, 15, 16. Alternatively, intermediate dose escalation (to 27mg/m2 on days 8,9 of cycle 1) will be al12,lowed at the treating physician's discretion.
  • Cycle 2-4: 36 mg/m2 if tolerated Days 1, 2, 8, 9, 15, 16
  • Cycles 5-8 (patients that are MRD- and have no risk factors at the end of cycle 6) and Cycle 5 - 36 (for MRD+ patients and high risk patients at the end of cycle 6): best tolerated dose Days 1, 2, 15, 16
  Other Name: Kyprolis
• Drug: Dexamethasone
  • Cycles 1 - 4: 20 mg PO or IV per dose Days 1, 8, 15, 22
  • Cycles 5+: 20 mg or best tolerated dose PO or IV per dose Days 1, 8, 15, 22
• Drug: Lenalidomide (Control)
  • Cycles 1-4: Days 1-28. Lenalidomide will begin at a dose of 10 mg PO daily (2 capsules per day). After three months, the dose will be increased, provided ANC ≥ 1,000/µL, platelet count ≥ 75,000/µL, and all nonhematologic toxicity is ≤ grade 1, to 15 mg PO daily (3 capsules per day).
  • Cycles 5 and beyond: best tolerated dose days 1-28
  Other Name: Revlimid

Study Arms

• Active Comparator: Lenalidomide (Control)
  Treatment with lenalidomide only
  Intervention: Drug: Lenalidomide (Control)
• Experimental: Experimental Combination Regimen
  Experimental arm using a combination of Carfilzomib, Lenalidomide and Dexamethasone
  Interventions:

  • Drug: Lenalidomide
  • Drug: Carfilzomib
  • Drug: Dexamethasone

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: January 19, 2016): 180
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: November 2026
• Estimated Primary Completion Date: November 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Patients who completed single autologous stem cell transplant after completion of at most 2 induction regimens (excluding dexamethasone alone) and are in at least stable disease in the first 100 days after stem cell transplantation.
2. Patients must be within 12 months of initiation of induction therapy and must have had not more than 2 prior induction regimens.
3. Bone marrow specimen will be required at study entry; available DNA sample will be used for calibration step for MRD evaluation by gene sequencing.
4. Males and females ≥ 18 years of age
5. ECOG performance status of 0-1
6. Adequate hepatic function, with bilirubin ≤ 1.5 x ULN and aspirate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN
7. ANC ≥ 1.0 x 109/L, hemoglobin ≥ 8 g/dL, platelet count ≥ 75 x 109/L.
8. Calculated creatinine clearance (by Cockcroft-Gault) ≥ 50 ml/min or serum creatinine below 2 mg/dL
9. Females of childbearing potential (FCBP) must have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to initiating lenalidomide. The first pregnancy test must be performed within 10-14 days before and the second pregnancy test must be performed within 24 hours before lenalidomide is prescribed for Cycle 1 (prescriptions must be filled within 7 days).

10. FCBP must agree to use 2 reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting lenalidomide; 2) while participating in the study; and 3) for at least 28 days after discontinuation from the study.

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11. Male subjects must agree to use a latex condom during sexual contact with females of childbearing potential while participating in the study and for at least 28 days following discontinuation from the study even if he has undergone a successful vasectomy.
12. All study participants in the US must be consented to and registered into the mandatory Revlimid REMS® program and be willing and able to comply with the requirements of Revlimid REMS®.
13. Voluntary written informed consent

Exclusion Criteria:

1. Patients who have had more than 12 months of prior therapy. Patients outside of this window may be considered for inclusion on a case-by-case basis.

2. Patients who progressed after initial therapy.

   1. Subjects whose therapy changed due to suboptimal response, intolerance, etc., remain eligible, provided they do not meet criteria for progression.
   2. No more than two regimens for induction will be allowed excluding dexamethasone alone.
3. Evidence of progressive disease as per International Myeloma Working Group (IMWG) criteria
4. Patients who have already started or received post-transplant maintenance or consolidation regimen
5. Patients not able to tolerate lenalidomide or carfilzomib or dexamethasone
6. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
7. Plasma cell leukemia
8. Waldenström's macroglobulinemia or IgM myeloma
9. Peripheral neuropathy ≥ Grade 2 at screening
10. Diarrhea > Grade 1 in the absence of antidiarrheals
11. CNS involvement
12. Pregnant or lactating females
13. Radiotherapy within 14 days before randomization. Seven days may be considered if to single area.
14. Major surgery within 3 weeks prior to first dose
15. Myocardial infarction within 6 months prior to enrollment, NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
16. Prior or concurrent deep vein thrombosis or pulmonary embolism
17. Rate-corrected QT interval of electrocardiograph (QTc) > 470 msec on a 12-lead ECG during screening
18. Uncontrolled hypertension or diabetes
19. Acute infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose
20. Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are seropositive because of hepatitis B virus vaccine are eligible.
21. Non-hematologic malignancy or non-myeloma hematologic malignancy within the past 3 years except a) adequately treated basal cell, squamous cell skin cancer, thyroid cancer, carcinoma in situ of the cervix, or prostate cancer < Gleason Grade 6 with stable prostate specific antigen levels or cancer considered cured by surgical resection alone
22. Any clinically significant medical disease or condition that, in the Treating Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Poland, United States

Administrative Information

• NCT Number: NCT02659293
• Other Study ID Numbers: IRB15-1286
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: University of Chicago
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Chicago
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Andrzej Jakubowiak, MD, PhD; University of Chicago

• PRS Account: University of Chicago
• Verification Date: April 2023