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

Sponsor

University of Chicago (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02659293

Collaborator

(none)

180

Enrollment

Locations

Arms

126.2

Anticipated Duration (Months)

Patients Per Site

0.5

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Lenalidomide Drug: Carfilzomib Drug: Dexamethasone Drug: Lenalidomide (Control)	Phase 3

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 Design

Study Type:

Interventional

Actual Enrollment :

180 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase 3 Randomized Trial of Carfilzomib, Lenalidomide, Dexamethasone Versus Lenalidomide Alone After Stem-cell Transplant for Multiple Myeloma

Actual Study Start Date :

Apr 26, 2016

Anticipated Primary Completion Date :

Nov 1, 2024

Anticipated Study Completion Date :

Nov 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Lenalidomide (Control) Treatment with lenalidomide only	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 Names: Revlimid
Experimental: Experimental Combination Regimen Experimental arm using a combination of Carfilzomib, Lenalidomide and Dexamethasone	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 Names: 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 Names: 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

Arm

Intervention/Treatment

Active Comparator: Lenalidomide (Control)

Treatment with lenalidomide only

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 Names:

Revlimid

Experimental: Experimental Combination Regimen

Experimental arm using a combination of Carfilzomib, Lenalidomide and Dexamethasone

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 Names:

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 Names:

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

Outcome Measures

Primary Outcome Measures

Progression free survival rates in participants receiving drug combination [4 years]
Measurement of time to disease worsening as measured by International Myeloma Working Group (IMWG) response criteria.

Secondary Outcome Measures

Rate of minimal residual negative disease (MRD) in participants receiving drug combination [3 years]
Calculation of number of participants with MRD-negative disease.
Response rate in participants receiving drug combination [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 [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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.
Patients must be within 12 months of initiation of induction therapy and must have had not more than 2 prior induction regimens.
Bone marrow specimen will be required at study entry; available DNA sample will be used for calibration step for MRD evaluation by gene sequencing.
Males and females ≥ 18 years of age
ECOG performance status of 0-1
Adequate hepatic function, with bilirubin ≤ 1.5 x ULN and aspirate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x ULN
ANC ≥ 1.0 x 109/L, hemoglobin ≥ 8 g/dL, platelet count ≥ 75 x 109/L.
Calculated creatinine clearance (by Cockcroft-Gault) ≥ 50 ml/min or serum creatinine below 2 mg/dL
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).
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.

UCM IRB CRd vs. R Version 1.0 Page 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.
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®.
Voluntary written informed consent

Exclusion Criteria:

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.
Patients who progressed after initial therapy.
Subjects whose therapy changed due to suboptimal response, intolerance, etc., remain eligible, provided they do not meet criteria for progression.
No more than two regimens for induction will be allowed excluding dexamethasone alone.
Evidence of progressive disease as per International Myeloma Working Group (IMWG) criteria
Patients who have already started or received post-transplant maintenance or consolidation regimen
Patients not able to tolerate lenalidomide or carfilzomib or dexamethasone
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
Plasma cell leukemia
Waldenström's macroglobulinemia or IgM myeloma
Peripheral neuropathy ≥ Grade 2 at screening
Diarrhea > Grade 1 in the absence of antidiarrheals
CNS involvement
Pregnant or lactating females
Radiotherapy within 14 days before randomization. Seven days may be considered if to single area.
Major surgery within 3 weeks prior to first dose
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
Prior or concurrent deep vein thrombosis or pulmonary embolism
Rate-corrected QT interval of electrocardiograph (QTc) > 470 msec on a 12-lead ECG during screening
Uncontrolled hypertension or diabetes
Acute infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose
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.
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
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Chicago	Chicago	Illinois	United States	60637
2	Wayne State University - Karmanos Cacner Institute	Detroit	Michigan	United States	48201
3	Polish Myeloma Consortium	Poznań		Poland