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

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ClinicalTrials.gov Identifier: NCT03556332
Recruitment Status : Recruiting
First Posted : June 14, 2018
Last Update Posted : August 15, 2019
Sponsor:
Collaborator:
Janssen Pharmaceuticals
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 46 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Single 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 : July 2, 2018
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : June 2021


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.




Primary Outcome Measures :
  1. number of patients with complete remission (CR) rate [ Time Frame: 3 years ]
    Traditional Response Criteria from International Myeloma Working Group Criteria for Multiple Myeloma



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  • 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
  • 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
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03556332


Contacts
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Contact: Gunjan Shah, MD 212-639-8356 shahg@mskcc.org
Contact: Sergio Giralt, MD 212-639-3859

Locations
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United States, Alabama
University of Alabama Comprehensive Cancer Center Not yet recruiting
Birmingham, Alabama, United States, 35294
Contact: Luciano Costa, MD    205-975-3371      
United States, New Jersey
Memorial Sloan Kettering Basking Ridge Recruiting
Basking Ridge, New Jersey, United States, 07920
Contact: Gunjan Shah, MD    212-639-8356      
Hackensack University Medical Center Cancer Center Not yet recruiting
Hackensack, New Jersey, United States, 07601
Contact: Noa Biran, MD    551-996-5900      
Memoral Sloan Kettering Monmouth Recruiting
Middletown, New Jersey, United States, 07748
Contact: Gunjan Shah, MD    212-639-8356      
Memorial Sloan Kettering Bergen Recruiting
Montvale, New Jersey, United States, 07645
Contact: Gunjan Shah, MD    212-639-8356      
United States, New York
Memorial Sloan Kettering Commack Recruiting
Commack, New York, United States, 11725
Contact: Gunjan Shah, MD    212-639-8356      
Memorial Sloan Kettering Westchester Recruiting
Harrison, New York, United States, 10604
Contact: Gunjan Shah, MD    212-639-8356      
Northwell Health Not yet recruiting
Manhasset, New York, United States, 11030
Contact: Ruthee-lu Bayer, MD    516-734-8973      
New York University Not yet recruiting
New York, New York, United States, 10010
Contact: Samer Al-Homsi, MD    646-501-4848      
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Gunjan Shah, MD, MS    212-639-8356      
Principal Investigator: Gunjan Shah, MD,MS         
Memorial Sloan Kettering Rockville Centre Recruiting
Rockville Centre, New York, United States, 11570
Contact: Gunjan Shah, MD    212-639-8356      
Memorial Sloan Kettering Nassau Recruiting
Uniondale, New York, United States, 11553
Contact: Gunjan Shah, MD    212-639-8356      
United States, North Carolina
Wake Forest University Recruiting
Winston-Salem, North Carolina, United States, 27109
Contact: Cesar Rodriguez, MD    336-713-5440      
United States, Wisconsin
Medical College of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Saurabh Chhabra, MD, MS    414-805-0505      
Sponsors and Collaborators
Memorial Sloan Kettering Cancer Center
Janssen Pharmaceuticals
Investigators
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Principal Investigator: Gunjan Shah, MD Memorial Sloan Kettering Cancer Center

Additional Information:
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Responsible Party: Memorial Sloan Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT03556332     History of Changes
Other Study ID Numbers: 17-493
First Posted: June 14, 2018    Key Record Dates
Last Update Posted: August 15, 2019
Last Verified: August 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Memorial Sloan Kettering Cancer Center:
Carfilzomib
Lenalidomide
Dexamethasone
Daratumumab
salvage autologous hematopoietic cell transplantation
17-493

Additional relevant MeSH terms:
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Multiple Myeloma
Neoplasms, Plasma Cell
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone
Dexamethasone acetate
Lenalidomide
Daratumumab
BB 1101
Antibodies, Monoclonal
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal