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Lenalidomide and Rituximab With or Without Idelalisib in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma

This study is currently recruiting participants.
Verified April 2013 by Alliance for Clinical Trials in Oncology
Sponsor:
Collaborators:
Celgene Corporation
Gilead Sciences
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier:
NCT01838434
First received: April 19, 2013
Last updated: July 9, 2013
Last verified: April 2013
  Purpose

This Phase I/II trial studies the safety and effectiveness of lenalidomide in combination with rituximab with or without idelalisib. Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Idelalisib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether lenalidomide and rituximab is more effective with or without idelalisib in treating mantle cell lymphoma.


Condition Intervention Phase
Relapsed/Refractory Mantle Cell Lymphoma
Drug: lenalidomide
Drug: idelalisib
Biological: rituximab
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/Randomized Phase II Trial of Idelalisib, Lenalidomide and Rituximab in Patients With Relapsed/Refractory Mantle Cell Lymphoma

Resource links provided by NLM:


Further study details as provided by Alliance for Clinical Trials in Oncology:

Primary Outcome Measures:
  • Maximum tolerated dose (MTD) of idelalisib and lenalidomide, determined according to incidence of dose-limiting toxicity (DLT) graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
  • Progression Free Survival (PFS) of the combination of lenalidomide and rituximab, with or without idelalisib (Phase II) [ Time Frame: Time between registration and disease progression or death, assessed up to 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Overall survival (OS) (Phase II) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
  • Overall response rate (partial or complete response) (Phase II) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 99
Study Start Date: July 2013
Estimated Primary Completion Date: August 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: lenalidomide and rituximab
Lenalidomide will be administered orally on days 1-21, repeated every 28 days for a maximum of 12 cycles (48 weeks). Rituximab will be administered intravenously and weekly for cycle 1 (i.e. cycle 1, day 1, day 8, day 15, day 22) and then on day 1 of cycles 4, 6, 8, and 10. (Phase II)
Drug: lenalidomide
given PO
Biological: rituximab
given IV
Experimental: lenalidomide, rituximab and idelalisib
Lenalidomide will be administered orally and daily on days 1-21, repeated every 28 days for a maximum of 12 cycles (48 weeks). Rituximab will be administered intravenously and weekly for cycle 1 (i.e. cycle 1, day 1, day 8, day 15, day 22) and then on day 1 cycles 4, 6, 8, and 10. Idelalisib will be orally administered for continuous 28-day cycles until progression, intolerance, or patient/physician discretion. (Phase II)
Drug: lenalidomide
given PO
Drug: idelalisib
given PO
Biological: rituximab
given IV

Detailed Description:

Outline: This is a phase I, dose-escalation study followed by a phase II study.

The phase I treatment plan includes the following:

  1. Lenalidomide will be tested at sequential dose levels in a standard 3+3 design.

    1. Dose Level 0 = 15mg/day for days 1-21 every 28 days
    2. Dose Level 1 = 20mg/day for days 1-21 every 28 days and
    3. Dose Level 2 = 25mg/day for days 1-21 every 28 days.

    Patients can continue lenalidomide for up to 48 weeks (12 cycles) of treatment.

  2. Idelalisib will be orally administered starting at Dose Level 1 (150 mg twice daily) for continuous 28-day cycles until progression, intolerence, or patient/physician discretion.
  3. Rituximab will be administered intravenously at 375 mg/m2 for cycle 1 (ie, cycle 1, day 1, day 8, day 15, day 22) and then on day 1 of cycles 4,6,8,10. There will be no dose reductions or escalations of rituximab.

Patients are randomized to 1 of 2 treatment arms in the Phase II treatment plan described in the "Arms" section. The primary and secondary objectives for this study are:

  1. Phase I Primary Objective: To determine the safety and tolerability of the combination of lenalidomide and rituximab with idelalisib in sequential dose cohorts.
  2. Phase II Primary Objective: To determine the progression-free survival (PFS) of the combination of lenalidomide and rituximab, with or without idelalisib in a randomized phase II design.
  3. Phase II Secondary Objectives:

    1. To determine the overall response rate (ORR), complete response rate (CR), and overall survival (OS) of the combination of lenalidomide and rituximab, with or without idelalisib in a randomized phase II design.
    2. To determine the prognostic and/or predictive significance of proliferation markers and cell cycle components in patients with relapsed/refractory mantle cell lymphoma (MCL) treated with idelalisib and lenalidomide.
    3. To determine whether phosphorylated protein kinase B (pAKT) expression levels are correlated with response to idelalisib plus lenalidomide.
    4. To determine whether notch homolog 1, translocation-association (NOTCH1) intracellular domain (ICD) immunohistochemistry (IHC) correlates with mutation and outcome in MCL patients treated with idelalisib and lenalidomide.
    5. To determine whether sex determining region Y-box 11 (SOX11) expression correlates with response in patients with relapsed/refractory MCL treated with idelalisib and lenalidomide.
    6. To correlate cereblon (CRBN) expression with response in patients with relapsed/refractory MCL treated with idelalisib and lenalidomide.
    7. To evaluate several plasma cytokines and correlate observed changes to objective response rates.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  1. Documentation of Disease:

    1. Histologically documented mantle cell lymphoma, with the following immunophenotypic characteristics: cluster of differentiation (CD)5+, (CD)23-, cyclin D1+; this may be from an initial diagnostic biopsy, or one obtained at time of relapse
    2. Institutional flow cytometry or immunohistochemistry must confirm CD5 antigen expression, lack of CD23 antigen expression, and expression of cyclin D1.
  2. Prior Treatment - Patients must have prior treatment with at least one regimen, which may have been single agent or multi-agent, and consisted of traditional cytotoxic agents and/or biologic agents. Patient must not have received prior idelalisib or lenalidomide therapy. Patient must have progressive disease or refractory disease following the initial regimen(s). Refractory disease will be defined as stable disease (SD) or progressive disease (PD) as best response to prior therapy, or complete response (CR) or partial response (PR) as initial response followed by disease progression within 6 months. Prior autologous, but not allogeneic, stem cell transplant is allowed. No corticosteroids within two weeks prior to study, except for maintenance therapy for a non-malignant disease. Maintenance therapy dose may not exceed 20 mg/day prednisone or equivalent.
  3. Eastern Cooperative Oncology Group (ECOG) Performance Status - Patients must have ECOG performance status of 0-2.
  4. Measurable Disease must be present either on imaging studies. Non-measurable disease alone is not acceptable. Any tumor mass > 1 cm by computed tomography (CT), magnetic resonance imaging (MRI), or conventional radiograph is acceptable. Lesions that are considered non-measurable include the following:

    1. Bone lesions (lesions, if present, should be noted)
    2. Ascites
    3. Pleural/pericardial effusion
    4. Lymphangitis cutis/pulmonis
    5. Bone marrow (involvement by non-Hodgkin lymphoma should be noted)
  5. Central Nervous System (CNS) Involvement - Patients must have no known CNS involvement by lymphoma.
  6. Human Immunodeficiency Virus (HIV) Infection - Patients with HIV infection are eligible, provided they meet the following:

    1. CD4+ cell count > 350/mm3
    2. Treatment sensitive HIV and, if on anti-HIV therapy, HIV viral load < 50 copies/mm3
    3. No history of Acquired Immune Deficiency Syndrome (AIDS)-defining conditions or other HIV related illness
    4. No concurrent zidovudine or stavudine because of overlapping toxicities with protocol therapy
    5. Patients with known HIV positivity must have CD4 assessment and viral load at baseline and every 6 months while on study.
  7. Pregnancy and Nursing Status - Patients must be non-pregnant and non-nursing. 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 prior to registration. Further, they 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 starting 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. A FCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy, or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time preceding 24 consecutive months).
  8. Deep Vein Thrombosis/Pulmonary Embolism (DVT/PE) - Patients with a recent history (within 3 months of study entry) of DVT/PE are not eligible. Patients with a distant history (greater than 3 months before study entry) of DVT/PE are eligible, but must receive either prophylactic aspirin or low molecular weight heparin, unless contraindicated.
  9. Congestive Heart Failure - Patients must have no New York Heart Association (NYHA) Class III or Class IV congestive heart failure at study entry.
  10. Myocardial Infarction - Patients must have no myocardial infarction within 6 months prior to study entry.
  11. Hepatitis - Patients must not have known positivity for hepatitis B, as evidenced by + HBsAg or +anti-HBc, and must not have known history of hepatitis C.
  12. Patients must be ≥ 18 years of age.
  13. Cytochrome P450 3A4 (CYP3A4) Strong Inducers and Inhibitors - Patients must not be on strong CYP3A4 inhibitors and/or inducers.

    1. The following strong inhibitors are prohibited: indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole,nefazodone
    2. The following strong inducers are prohibited: carbamazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's Wort, troglitazone
  14. Required Initial Laboratory Values:

    1. ANC ≥ 1,000/µL, ≥ 500/µL if marrow involvement
    2. Platelets ≥ 75,000/µL
    3. Creatinine ≤ 1.5 x ULN, and estimated creatinine clearance ≥ 60 mL/min (patients on dialysis not eligible), unless attributable to non-Hodgkin lymphoma
    4. Total bilirubin ≤ 2 x ULN, unless attributable to non-Hodgkin lymphoma or Gilbert's disease
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01838434

Locations
United States, Illinois
University of Chicago Recruiting
Chicago, Illinois, United States, 60637
Contact: Sonali Smith    773-702-9251      
Sponsors and Collaborators
Alliance for Clinical Trials in Oncology
Celgene Corporation
Gilead Sciences
Investigators
Study Chair: Sonali Smith, M.D. University of Chicago
  More Information

No publications provided

Responsible Party: Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier: NCT01838434     History of Changes
Other Study ID Numbers: A051201, NCI-2012-01734, U10CA031946
Study First Received: April 19, 2013
Last Updated: July 9, 2013
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Rituximab
Thalidomide
Lenalidomide
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents
Immunosuppressive Agents
Leprostatic Agents
Anti-Bacterial Agents
Anti-Infective Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors

ClinicalTrials.gov processed this record on April 17, 2014