A Study of Carfilzomib, Lenalidomide, Dexamethasone and Daratumumab for Patients With Relapsed/Refractory Myeloma With Salvage Autologous Hematopoietic Cell Transplantation

Sponsor

Memorial Sloan Kettering Cancer Center (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT03556332

Collaborator

Janssen Pharmaceuticals (Industry)

Enrollment

Locations

Arm

Anticipated Duration (Months)

3.4

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to test any good and bad effects of giving a combination of study drugs before and after autologous stem cell transplant.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Carfilzomib Drug: Lenalidomide Drug: Dexamethasone Drug: Daratumumab Procedure: autologous hematopoietic cell transplantation	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

41 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Intervention Model Description:

Single arm, Simon two-stage phase II trial of combination therapySingle arm, Simon two-stage phase II trial of combination therapy

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase 2 Trial of Intensive Chemo-immunotherapy With Carfilzomib, Lenalidomide, Dexamethasone and Daratumumab for Relapsed/Refractory Myeloma in the Context of Salvage Autologous Hematopoietic Cell Transplantation

Actual Study Start Date :

Jul 2, 2018

Anticipated Primary Completion Date :

Jul 1, 2023

Anticipated Study Completion Date :

Jul 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Carfilzomib, Lenalidomide, Dexamethasone and Daratumumab & HCT After receiving four 28-day cycles of Dara-CRd, eligible patients will then undergo HCT with high dose melphalan conditioning. Sixty to ninety days after HCT, patients will receive another 4 cycles of Dara-CRd.	Drug: Carfilzomib Dara-CRd Induction Cycle 1 ONLY: Carfilzomib 20 mg/m2 per dose, days 1 and 2; Carfilzomib 27 mg/m2 per dose, days 8, 9, 15, and 16 Cycles 2-4: Carfilzomib 27 mg/m2 per dose, days 1, 2, 8, 9, 15, and 16 Dara-CRd Consolidation (60-90 days post HCT) Cycles 5-8: Carfilzomib 27 mg/m2 per dose, days 1, 2, 8, 9, 15, and 16 Drug: Lenalidomide Dara-CRd Induction Cycles 1-4: Lenalidomide 25 mg/day, days 1-21 every 28 days Dara-CRd Consolidation (60-90 days post HCT) Cycles 5-8: Lenalidomide 25 mg/day, days 1-21 every 28 days Drug: Dexamethasone Dara-CRd Induction Cycles 1-4: Dexamethasone 20 mg/dose, days 1, 2, 8, 9, 15, 16, 22, 23 Dara-CRd Consolidation (60-90 days post HCT) Cycles 5-8: Dexamethasone 20 mg/dose, days 1, 2, 8, 9, 15, 16, 22, 23 Drug: Daratumumab Dara-CRd Induction Cycles 1 and 2: Daratumumab 16 mg/kg weekly (days 1,8, 15, 22) Dara-CRd Consolidation (60-90 days post HCT) Cycles 3 and 4: Daratumumab 16 mg/kg every other week, days 1 and 15. Cycles 5-6:Daratumumab 16 mg/kg every other week, days 1 and 15. Schedule together with Carfilzomib and use scheduled dexamethasone as premed. Cycles 7-8: Daratumumab 16 mg/kg days 1 of each cycle. Procedure: autologous hematopoietic cell transplantation High Dose Melphalan and Autologous Hematopoietic Cell Transplantation Patients will receive Melphalan 200 mg/m2 per institutional guidelines, or if over 70 years of age or creatinine >2mg/dL, they will receive 140 mg/m2.

Arm

Intervention/Treatment

Experimental: Carfilzomib, Lenalidomide, Dexamethasone and Daratumumab & HCT

After receiving four 28-day cycles of Dara-CRd, eligible patients will then undergo HCT with high dose melphalan conditioning. Sixty to ninety days after HCT, patients will receive another 4 cycles of Dara-CRd.

Drug: Carfilzomib

Dara-CRd Induction Cycle 1 ONLY: Carfilzomib 20 mg/m2 per dose, days 1 and 2; Carfilzomib 27 mg/m2 per dose, days 8, 9, 15, and 16 Cycles 2-4: Carfilzomib 27 mg/m2 per dose, days 1, 2, 8, 9, 15, and 16 Dara-CRd Consolidation (60-90 days post HCT) Cycles 5-8: Carfilzomib 27 mg/m2 per dose, days 1, 2, 8, 9, 15, and 16

Drug: Lenalidomide

Dara-CRd Induction Cycles 1-4: Lenalidomide 25 mg/day, days 1-21 every 28 days Dara-CRd Consolidation (60-90 days post HCT) Cycles 5-8: Lenalidomide 25 mg/day, days 1-21 every 28 days

Drug: Dexamethasone

Dara-CRd Induction Cycles 1-4: Dexamethasone 20 mg/dose, days 1, 2, 8, 9, 15, 16, 22, 23 Dara-CRd Consolidation (60-90 days post HCT) Cycles 5-8: Dexamethasone 20 mg/dose, days 1, 2, 8, 9, 15, 16, 22, 23

Drug: Daratumumab

Dara-CRd Induction Cycles 1 and 2: Daratumumab 16 mg/kg weekly (days 1,8, 15, 22) Dara-CRd Consolidation (60-90 days post HCT) Cycles 3 and 4: Daratumumab 16 mg/kg every other week, days 1 and 15. Cycles 5-6:Daratumumab 16 mg/kg every other week, days 1 and 15. Schedule together with Carfilzomib and use scheduled dexamethasone as premed. Cycles 7-8: Daratumumab 16 mg/kg days 1 of each cycle.

Procedure: autologous hematopoietic cell transplantation

High Dose Melphalan and Autologous Hematopoietic Cell Transplantation Patients will receive Melphalan 200 mg/m2 per institutional guidelines, or if over 70 years of age or creatinine >2mg/dL, they will receive 140 mg/m2.

Outcome Measures

Primary Outcome Measures

number of patients with complete remission (CR) rate [3 years]
Traditional Response Criteria from International Myeloma Working Group Criteria for Multiple Myeloma

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patient must be capable, willing, and able to provide written, informed consent.
Age ≥ 18-years-old and <= 75-years-old.
Histologic confirmation of multiple myeloma by the enrolling institution
Symptomatic myeloma that has progressed/relapsed after 1 to 3 prior lines of therapy
Patients who have received <=1 cycle of therapy after most recent progression/relapse are eligible to enroll on study
Treatment of hypercalcemia or spinal cord compression or aggressively progressing myeloma with current or prior corticosteroids is permitted
Bisphosphonates are permitted
Concurrent or prior treatment with corticosteroids for indications other than multiple myeloma is permitted
Prior treatment with radiotherapy is permitted
Patients with measurable disease who received up to one cycle of any therapy within 60 days with a washout period of 4 weeks from last dose (on a trial or outside a trial) are eligible
Maintenance single agent imid (ie. lenalidomide or pomalidomide) or monoclonal antibody (ie. daratumumab) do not require the 4-week washout period
More than 2 x 10^6 autologous CD34+ cells/kg cryopreserved. The graft may not be CD34+ selected or otherwise manipulated to remove tumor or other cells. The graft can be collected at the transplanting institution or by a referring center.
Planning to receive autologous HCT per institutional standards as part of standard of care. Eligibility for autologous HCT should be based on institutional guidelines.
However, at minimum all patients must meet the following criteria:
KPS greater than 70
Cardiac left ventricular ejection fraction of greater than 40%
Calculated creatinine clearance of greater than 40 cc/min
AST and ALT of less than 2 x upper limit of normal
Direct bilirubin of less than 2 x upper limit of normal
Total bilirubin of less than 2 x upper limit of normal. If Total bilirubin is abnormal. Direct bilirubin of less than 2 x upper limit of normal
Measurable disease as defined by any of the following International Myeloma Working Group Criteria
Monoclonal serum peak of greater than 0.5 gms per deciliter
Measurable urine peak as defined by urine protein electrophoresis of greater than 100 mg per 24 hours
Serum FLC assay: involved FLC level ≥10 mg/dL provided serum FLC ratio is abnormal
Hemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior to enrollment (subjects may be receiving red blood cell [RBC] transfusions in accordance with institutional guidelines)
Platelet count ≥ 50 × 109/L (≥ 30 × 109/L if myeloma involvement in the bone marrow is

50%) within 14 days prior to initial treatment (subjects may be receiving platelet transfusions in accordance with institutional guidelines) .

Women of childbearing potential (WOCBP) † must agree to ongoing pregnancy testing and to practice contraception as described in section 9.3 and required by the Revlimid REMS program.

† A woman of childbearing potential is a sexually mature female who has not undergone a hysterectomy or bilateral oophorectomy or has not been naturally postmenopausal for at least 24 consecutive months (i.e. has had menses at any time in the preceding 24 consecutive months).

Male subjects must agree to practice contraception
All study participants must be registered into the mandatory Revlimid REMS program and be willing and able to comply with the requirements of the REMS program.

Exclusion Criteria:

Plasma cell leukemia (>20% circulating plasma cells) during screening studies
POEMS syndrome
Pregnant or lactating females. Because there is a potential risk for adverse events nursing infants secondary to treatment of the mother with carfilzomib in combination with lenalidomide. These potential risks may also apply to other agents used in this study.
Uncontrolled hypertension or diabetes
Active hepatitis B or C infection
Patients with HBV core antibody positive, but HBV PCR negative are eligible if they are on medication for suppression of HBV reactivation
Patients with HCV antibody positive, but PCR negative are eligible.
Serologically positive HIV (testing required during screening)
Significant cardiovascular disease with NYHA Class III or IV symptoms, EF<40% or hypertrophic cardiomyopathy, or restrictive cardiomyopathy, or myocardial infarction within 6 months prior to enrollment, or unstable angina, or unstable arrhythmia as determined by history and physical examination. Echocardiogram will be performed during screening evaluation.
Moderate or severe pulmonary hypertension defined as PASP >50 mm Hg
Chronic obstructive pulmonary disease (COPD) with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal. Note that FEV1 testing is required for participants suspected of having COPD and participants must be excluded if FEV1 is < 50% of predicted normal.
Moderate or severe persistent asthma within the past 2 years, or uncontrolled asthma of any classification. Note that participants who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed to participate.
Refractory GI disease that would prevent absorption of oral agents
Uncontrolled intercurrent illness including but not limited to active infection or psychiatric illness/social situations that would compromise compliance with study requirements
Significant neuropathy ≥Grade 3 or Grade 2 neuropathy with pain at baseline
Contraindication to any concomitant medication, including antivirals or anticoagulation.
Major surgery within 3 weeks prior to first dose
Prior Allogeneic HCT (prior autologous transplant is allowed regardless of response)
History of CNS involvement by myeloma
Disease progression as defined by IMW Criteria1 on the combination of carfilzomib, lenalidomide and dexamethasone (Patients with progression on lenalidomide maintenance after completion of carfilzomib, lenalidomide and dexamethasone combination therapy will be eligible).
Disease progression on daratumumab
Prior dose limiting toxicity from carfilzomib or lenalidomide.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama Comprehensive Cancer Center	Birmingham	Alabama	United States	35294
2	Memorial Sloan Kettering Basking Ridge (Limited Protocol Activities)	Basking Ridge	New Jersey	United States	07920
3	Memoral Sloan Kettering Monmouth (Limited Protocol Activities)	Middletown	New Jersey	United States	07748
4	Memorial Sloan Kettering Bergen (Limited Protocol Activities)	Montvale	New Jersey	United States	07645
5	Memorial Sloan Kettering Suffolk - Commack (Limited Protocol Activities)	Commack	New York	United States	11725
6	Memorial Sloan Kettering Westchester (Limited Protocol Activities)	Harrison	New York	United States	10604
7	Northwell Health	Manhasset	New York	United States	11030
8	New York University	New York	New York	United States	10010
9	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
10	Memorial Sloan Kettering Nassau (Limited Protocol Activities)	Uniondale	New York	United States	11553
11	Wake Forest University (Data Collection Only)	Winston-Salem	North Carolina	United States	27109
12	Medical College of Wisconsin (Data Collection Only)	Milwaukee	Wisconsin	United States	53226