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Phase I/II Carfilzomib Plus Lenalidomide and Rituximab in the Treatment of Relapsed/Refractory Mantle Cell Lymphoma

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ClinicalTrials.gov Identifier: NCT01729104
Recruitment Status : Terminated (Low response)
First Posted : November 20, 2012
Last Update Posted : May 23, 2019
Sponsor:
Collaborators:
Celgene
Onyx Therapeutics, Inc.
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

The goal of Part 1 of this clinical research study is to find the highest tolerable dose of carfilzomib that can be given in combination with lenalidomide and rituximab to patients with relapsed or refractory B-cell non-hodgkin lymphoma.

The goal of Part 2 of this study is to learn if the drug combination can help to control B-cell non-hodgkin lymphoma.

The safety of this drug combination will be studied in both parts.

Carfilzomib is designed to keep cancer cells from repairing themselves. If the cancer cells cannot repair themselves, this may cause them to die.

Lenalidomide is designed to change the body's immune system. It may also interfere with the development of tiny blood vessels that help support tumor growth. This may decrease the growth of cancer cells.

Rituximab is designed to attach to cancer cells and damage them, which may cause the cancer cells to die. It is also designed to cause the immune system to attack cancer cells.


Condition or disease Intervention/treatment Phase
Lymphoma Drug: Carfilzomib Drug: Lenalidomide Drug: Rituximab Phase 1 Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 18 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of Carfilzomib Plus Lenalidomide and Rituximab in the Treatment of Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma
Actual Study Start Date : April 25, 2013
Actual Primary Completion Date : October 3, 2018
Actual Study Completion Date : October 3, 2018


Arm Intervention/treatment
Experimental: Phase I: Carfilzomib + Lenalidomide + Rituximab
Phase I: Four primary dose levels of carfilzomib plus lenalidomide (carfilzomib 20 mg/27 mg + lenalidomide 20 mg, carfilzomib 20 mg/36 mg + lenalidomide 20 mg, carfilzomib 20mg/45 mg + lenalidomide 20 mg, carfilzomib 20 mg/56 mg + lenalidomide 20 mg,) evaluated with a fixed dose of rituximab (375 mg/m2 weekly for 4 weeks). Alternate dose levels using 15 mg of lenalidomide in combination with carfilzomib and rituximab evaluated if MTD is exceeded with 20 mg of lenalidomide.
Drug: Carfilzomib

Phase I Starting Dose: 20 mg/m2 by vein on Days 1, 2, 8, 9, 15, and 16 of Cycles 1-12. Cycles 13 and beyond, dose given on Days 1, 2, 15, and 16.

Phase II Starting Dose: MTD from Phase I.


Drug: Lenalidomide
Phase I and Phase II: 20 mg by vein on Days 1-21 of each cycle.
Other Names:
  • CC-5013
  • Revlimid

Drug: Rituximab
Phase I and II: 375 mg/m2 by vein on Days 1, 8, 15, and 22 of Cycle 1 and 2. For Cycles 3 - 12, given on Day 1. For Cycles 13 and beyond, given on Day 1 every other cycle for up to 24 months.
Other Name: Rituxan

Experimental: Phase II: Mantle Cell Lymphoma Group

Phase II: Patients enrolled at recommended dose level (MTD) of Carfilzomib established in Phase I of the study.

Phase II Lenalidomide Dose: 20 mg by vein on Days 1-21 of each cycle.

Phase II Rituximab Dose: 375 mg/m2 by vein on Days 1, 8, 15, and 22 of Cycle 1 and 2. For Cycles 3 - 12, given on Day 1. For Cycles 13 and beyond, given on Day 1 every other cycle for up to 24 months.

Drug: Carfilzomib

Phase I Starting Dose: 20 mg/m2 by vein on Days 1, 2, 8, 9, 15, and 16 of Cycles 1-12. Cycles 13 and beyond, dose given on Days 1, 2, 15, and 16.

Phase II Starting Dose: MTD from Phase I.


Drug: Lenalidomide
Phase I and Phase II: 20 mg by vein on Days 1-21 of each cycle.
Other Names:
  • CC-5013
  • Revlimid

Drug: Rituximab
Phase I and II: 375 mg/m2 by vein on Days 1, 8, 15, and 22 of Cycle 1 and 2. For Cycles 3 - 12, given on Day 1. For Cycles 13 and beyond, given on Day 1 every other cycle for up to 24 months.
Other Name: Rituxan

Experimental: Phase II: Follicular, Marginal Zone, DLBCL Group

Group consists of : Patients with follicular lymphoma (FL) grade 1 - 3, marginal zone lymphoma (MZL), or non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL).

Phase II: Patients enrolled at recommended dose level (MTD) of Carfilzomib established in Phase I of the study.

Phase II Lenalidomide Dose: 20 mg by vein on Days 1-21 of each cycle.

Phase II Rituximab Dose: 375 mg/m2 by vein on Days 1, 8, 15, and 22 of Cycle 1 and 2. For Cycles 3 - 12, given on Day 1. For Cycles 13 and beyond, given on Day 1 every other cycle for up to 24 months.

Drug: Carfilzomib

Phase I Starting Dose: 20 mg/m2 by vein on Days 1, 2, 8, 9, 15, and 16 of Cycles 1-12. Cycles 13 and beyond, dose given on Days 1, 2, 15, and 16.

Phase II Starting Dose: MTD from Phase I.


Drug: Lenalidomide
Phase I and Phase II: 20 mg by vein on Days 1-21 of each cycle.
Other Names:
  • CC-5013
  • Revlimid

Drug: Rituximab
Phase I and II: 375 mg/m2 by vein on Days 1, 8, 15, and 22 of Cycle 1 and 2. For Cycles 3 - 12, given on Day 1. For Cycles 13 and beyond, given on Day 1 every other cycle for up to 24 months.
Other Name: Rituxan




Primary Outcome Measures :
  1. Maximum Tolerated Dose (MTD) of Carfilzomib and Lenalidomide in Combination With Rituximab [ Time Frame: 28 days ]
    MTD defined as highest dose level in which 6 patients have been treated with less than 2 instances of dose limiting toxicity (DLT). Dose limiting toxicity (DLT) assessed during first course of each cohort (28 days), and refers to a medically significant event which meets one of the criteria using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.


Secondary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: 4 months ]
    Objective response rate defined as complete or partial response after 2 cycles of therapy maintained for one month. Response definitions for measurable disease from the International Workshop Standardized Response Criteria for non-Hodgkin's Lymphoma will be used.



Information from the National Library of Medicine

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

Inclusion Criteria:

  1. Patients must have previously treated relapsed and/or refractory MCL, follicular lymphoma grade 1-3, marginal zone lymphoma, or non-germinal center B-cell diffuse large B-cell lymphoma with 1 - 4 prior lines of therapy. (prior anthracycline, rituximab or stem cell transplant (auto or allo) are acceptable).
  2. Understand and voluntarily sign an institutional review board (IRB)-approved informed consent form.
  3. Age >/= 18 years at the time of signing the informed consent.
  4. Patients must have bi-dimensional measurable disease (bone marrow only involvement is acceptable).
  5. Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less
  6. Serum bilirubin <1.5 mg/dl and Cr Clearance >/= 60 mL/min, platelet count >75,000/mm^3 and absolute neutrophil count (ANC) > 1,000/mm^3, aspartate aminotransferase (AST)/ serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/ serum glutamic pyruvic transaminase (SGPT) < 3 x upper limit of normal or < 5 x upper limit of normal if hepatic metastases are present.
  7. Disease free of prior malignancies of equal to or greater than 3 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast, or other malignancies in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated, with a life expectancy > 3 years.
  8. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days as required by RevAssist) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. See Appendix E: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods.
  9. Patients must be willing to receive transfusions of blood products.
  10. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation [patients intolerant to acetylsalicylic acid (ASA) may use warfarin or low molecular weight heparin].
  11. Patients may have received prior Ibrutinib, lenalidomide, rituximab, and/or bortezomib either alone or in combination.
  12. All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®.

Exclusion Criteria:

  1. Any serious medical condition including but not limited to, uncontrolled hypertension, uncontrolled congestive heart failure, uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, COPD, LVEF less than 40, renal failure, active infection, active hemorrhage, laboratory abnormality, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form. Patients with history of cardiac arrhythmias should have cardiac evaluation and clearance.
  2. Pregnant or lactating females.
  3. Use of any standard/experimental anti-lymphoma drug therapy, including steroids, within 3 weeks of initiation of the study or use of any experimental non-drug therapy (e.g., donor leukocyte/mononuclear cell infusions) within 56 days of initiation of the study drug treatment. Prior allogeneic stem cell transplant (SCT) within 16 weeks or autologous SCT within 8 weeks of initiation of therapy.
  4. Known hypersensitivity to thalidomide, lenalidomide or rituximab; including the development of erythema nodosum if characterized by a desquamating rash while taking thalidomide.
  5. Known HIV infection. Patients with active hepatitis B infection (not including patients with prior hepatitis B vaccination; or positive serum Hepatitis B antibody). Known hepatitis C infection is allowed as long as there is no active disease and is cleared by GI consultation.
  6. All patients with history of central nervous system lymphoma.
  7. Patients with peripheral blood involvement with white blood count (WBC) > 20,000 or those considered to be at high risk for tumor lysis syndrome (TLS) by high tumor burden are EXCLUDED for the Phase I component of the study.
  8. Significant neuropathy (Grades 3 - 4, or Grade 2 with pain) within 14 days prior to enrollment
  9. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib).
  10. 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 to ascites requiring paracentesis.
  11. Patients with active pulmonary embolism or deep vein thrombosis (diagnosed within 30 days of study enrollment).
  12. Patients with severe bradycardia (heart rate <40 bpm, hypotension, light-headedness, syncope).
  13. Patients with NYHA Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities, including but not limited to atrial fibrillation, AV block, QT prolongation, sick sinus syndrome, ventricular tachycardia, as these patients may be at greater risk for cardiac complications, per carfilzomib labeling.

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): NCT01729104


Locations
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United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Celgene
Onyx Therapeutics, Inc.
Investigators
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Principal Investigator: Hun J. Lee, MD M.D. Anderson Cancer Center

Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT01729104     History of Changes
Other Study ID Numbers: 2012-0188
NCI-2013-00117 ( Registry Identifier: NCI CTRP )
First Posted: November 20, 2012    Key Record Dates
Last Update Posted: May 23, 2019
Last Verified: May 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 M.D. Anderson Cancer Center:
Mantle cell lymphoma
Lenalidomide
CC-5013
Revlimid
Lymphoma
MCL
Relapsed
Refractory
Carfilzomib
Rituximab
Rituxan
Additional relevant MeSH terms:
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Lenalidomide
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Rituximab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors