Clinical trial NCT00633594: Rituximab, Lenalidomide, and Bortezomib in Mantle Cell Lymphoma
Official title: Phase I/II Study Evaluating Rituximab, Lenalidomide, and Bortezomib in the First-Line or Second-Line Treatment of Patients With Mantle Cell Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Mantle Cell Lymphoma
Keywords: Mantle Cell Lymphoma
Rituximab
Lenalidomide
Bortezomib
Phase 1/2
Lead sponsor: SCRI Development Innovations, LLC
Sponsor class: OTHER
Collaborators: name: Millennium Pharmaceuticals, Inc.
name: Celgene
First posted: 2008-03-12
Enrollment: 39
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a Phase I/II multicenter, open-label, dose-escalation study of rituximab, bortezomib, and lenalidomide in the first-line or second-line treatment of patients with Mantle Cell Lymphoma (MCL).

Detailed description: The combination of lenalidomide with bortezomib has not been studied in patients with MCL, but feasibility and tolerability has been demonstrated in patients with multiple myeloma. Thus, almost every 2-drug combination of rituximab, lenalidomide, and bortezomib has been tested, or is being tested. We hypothesize that all three drugs are important in MCL, and therefore propose to combine all 3 agents (rituximab, bortezomib, and lenalidomide) in a schedule that is convenient to lymphoma patients.

Approximately 18 patients may be enrolled in the Phase I portion of the study. Approximately 45 patients are planned for enrollment in Phase II.

Eligibility criteria: Inclusion Criteria:

1. All study participants must be registered into the Mandatory Revlimid Risk Evaluation and Mitigation Strategies (REMS) Program, and be willing and able to comply with the requirements of the REMS program.
2. Histology: biopsy-proven mantle cell lymphoma (MCL).
3. Prior therapy: both newly diagnosed patients and relapsed or refractory patients who have received one prior therapy are eligible. Patients who have previously received high-dose chemotherapy with peripheral stem cell support are eligible.
4. Presence of at least one lymph node evaluable or mass measurable for response.
5. Platelets ≥ 75,000/µL and absolute neutrophil count (ANC) ≥ 1,000/µL within 14 days of study registration (unless the treating physician deems the neutropenia is related to bone marrow involvement, then an ANC of \> 750/mm3 is allowed).
6. Renal function assessed by calculated creatinine clearance between ≥ 30 ml/min and ˂60ml/min by the Cockcroft-Gault method within 14 days of study registration
7. Total bilirubin ≤ 1.5x upper limit of normal (ULN), aspartate transaminase (AST) (SGOT) and alanine transaminase (ALT) (SGOT) ≤ 3 x ULN
8. Eastern Cooperative Oncology Group (ECOG) performance of 0, 1, or 2.
9. Recovery from any previous treatment therapy.
10. Females of childbearing potential (FCBP) must adhere to the scheduled pregnancy testing required in the Revlimid REMS® program, must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10-14 days prior and again within 24 hours of starting lenalidomide for Cycle 1 (prescriptions must be filled within 7 days as required by Revlimid REMS Program) 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.
11. All study participants must be registered into the mandatory Revlimid REMS® program, and be willing and able to comply with the requirements of Revlimid REMS® program.
12. Ability to understand and willingness to voluntarily sign a written informed consent document before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.

Exclusion Criteria:

1. Patient has \>1.5 x ULN total bilirubin.
2. Peripheral neuropathy ≥ CTCAE grade 2.
3. Relapsed or refractory patients who have received more than one prior therapy.
4. Pregnant or breastfeeding females. (Lactating females must agree not to breastfeed while taking lenalidomide.)
5. Female patients who have a positive serum pregnancy test during the screening period, or a positive urine pregnancy test on Day 1 before first dose of study drug, if applicable.
6. Thrombolic or embolic events (such as a cerebrovascular accident, including transient ischemic attacks) within the past 6 months.
7. Pulmonary hemorrhage/bleeding event ≥ CTCAE grade 2 within 28 days of the first dose of study drug.
8. Any other hemorrhage/bleeding event ≥ CTCAE grade 3 ≤ 28 days of the first dose of study drug
9. Known brain metastasis. Patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasis.
10. Central nervous system (CNS) involvement by lymphoma at time of enrollment.
11. Other medical conditions or psychiatric illness that would potentially interfere with patient participation in this trial.
12. A second malignancy, other than basal cell carcinoma of the skin or in situ carcinoma of the cervix, unless the tumor was treated with curative intent at least 2 years previously.
13. Previous evidence of hypersensitivity to bortezomib, boron, mannitol, thalidomide, (and development of erythema nodosum if characterized by a desquamating rash), or rituximab (true anaphylaxis, not a rituximab-infusion reaction).
14. Known human immunodeficiency virus (HIV) infection or chronic hepatitis A, B, or C. Patients who are HIV positive or who are positive for chronic hepatitis A, B, or C will be excluded due to increased risk for bone marrow suppression and other toxicities.
15. Active, clinically serious infection \> CTCAE grade 2. Patients may be eligible upon resolution of the infection.
16. Evidence or history of bleeding diathesis or coagulopathy.
17. Major surgery, open biopsy, or significant traumatic injury within 28 days of the first dose of study drug.
18. Use of any other standard chemotherapy, radiation therapy, or experimental drug for the treatment of MCL within 28 days of starting treatment.
19. Any condition that impairs a patient's ability to swallow whole pills. Impairment of gastrointestinal function (GI) or GI disease that may significantly alter the absorption of lenalidomide (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
20. Patients with grade 3/4 cardiac problems, as defined by the New York Heart Association (NYHA) criteria or any of the following:

    * History of uncontrolled or symptomatic angina
    * History of arrhythmias requiring medications, or clinically significant, with the exception of asymptomatic atrial fibrillation requiring anticoagulation
    * Myocardial infarction \< 6 months from study entry
    * Uncontrolled or symptomatic congestive heart failure
    * Ejection fraction below the institutional normal limit
    * Electrocardiographic evidence of acute ischemia or active conduction system
    * Any other cardiac condition that, in the opinion of the treatment physician, would make this protocol unreasonably hazardous for the patient
    * Prior to study entry, any ECG abnormality at screening has to be documented by the investigator as not medically relevant.
21. Uncontrolled hypertension (systolic blood pressure \[BP\] \> 180 or diastolic BP \> 100mm Hg) or uncontrolled cardiac arrhythmias.
22. Any prior use of lenalidomide.

Primary outcomes:
measure: Maximum Tolerated Dose of Lenalidomide Combined With Bortezomib and Rituximab in Phase I Participants
timeFrame: Collected from day of first dose to the end of the first treatment cycle, up to 21 days
measure: Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II
timeFrame: Collected from day of first dose to 30 days after the last dose of study medication, a maximum of 18 weeks and 30 days after last study treatment
Secondary outcomes:
measure: Overall Response Rate (ORR) of Phase I and Phase II Participants
timeFrame: Every 6 weeks until treatment discontinuation then every 3 months thereafter, projected average 24 months
measure: Overall Response Rate (ORR) of Previously Treated and Previously Untreated Participants
timeFrame: Every 6 weeks until treatment discontinuation then every 3 months thereafter, projected average 24 months
measure: Time to Best Response of Phase I and Phase II Participants
timeFrame: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years
measure: Time to Best Response of Previously Treated and Previously Untreated Participants
timeFrame: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years
measure: Duration of Response (DoR) of Phase I and Phase II Participants
timeFrame: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years or until documented disease progression
measure: Duration of Response (DoR) of Previously Treated and Previously Untreated Participants
timeFrame: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years or until documented disease progression
measure: Progression Free Survival (PFS) of Phase I and Phase II Participants
timeFrame: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years, then every 6 months after documented disease progression
measure: Progression Free Survival (PFS) of Previously Treated and Previously Untreated Participants
timeFrame: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years, then every 6 months after documented disease progression
measure: Overall Survival of Phase I and Phase II Participants
timeFrame: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years, then every 6 months after documented disease progression
measure: Overall Survival of Previously Treated and Previously Untreated Participants
timeFrame: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years, then every 6 months after documented disease progression
Other outcomes:
Locations:
city: Terre Haute
country: United States
facility: Providence Medical Group
state: Indiana
city: Terre Haute
country: United States
facility: RHHP/ Hope Cancer Center
state: Indiana
city: Chesterfield
country: United States
facility: St. Louis Cancer Care
state: Missouri
city: Morristown
country: United States
facility: Hematology-Oncology Associates of Northern NJ
state: New Jersey
city: Cincinnati
country: United States
facility: Oncology Hematology Care Inc.
state: Ohio
city: Chattanooga
country: United States
facility: Chattanooga Oncology Hematology Associates
state: Tennessee
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
Study officials:
affiliation: SCRI Development Innovations, LLC
name: Ian W Flinn, M.D.
role: STUDY_CHAIR
References:
citation: Bosch F, Lopez-Guillermo A, Campo E, Ribera JM, Conde E, Piris MA, Vallespi T, Woessner S, Montserrat E. Mantle cell lymphoma: presenting features, response to therapy, and prognostic factors. Cancer. 1998 Feb 1;82(3):567-75. doi: 10.1002/(sici)1097-0142(19980201)82:33.0.co;2-z.
citation: Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, Federico M, Diehl V; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007 Feb 10;25(5):579-86. doi: 10.1200/JCO.2006.09.2403. Epub 2007 Jan 22.
citation: Corral LG, Haslett PA, Muller GW, Chen R, Wong LM, Ocampo CJ, Patterson RT, Stirling DI, Kaplan G. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol. 1999 Jul 1;163(1):380-6.
citation: Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT, Lin B, Podar K, Gupta D, Chauhan D, Treon SP, Richardson PG, Schlossman RL, Morgan GJ, Muller GW, Stirling DI, Anderson KC. Thalidomide and immunomodulatory derivatives augment natural killer cell cytotoxicity in multiple myeloma. Blood. 2001 Jul 1;98(1):210-6. doi: 10.1182/blood.v98.1.210.
citation: Dredge K, Horsfall R, Robinson SP, Zhang LH, Lu L, Tang Y, Shirley MA, Muller G, Schafer P, Stirling D, Dalgleish AG, Bartlett JB. Orally administered lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro. Microvasc Res. 2005 Jan;69(1-2):56-63. doi: 10.1016/j.mvr.2005.01.002.
citation: Ghielmini M, Schmitz SF, Cogliatti S, Bertoni F, Waltzer U, Fey MF, Betticher DC, Schefer H, Pichert G, Stahel R, Ketterer N, Bargetzi M, Cerny T; Swiss Group for Clinical Cancer Research. Effect of single-agent rituximab given at the standard schedule or as prolonged treatment in patients with mantle cell lymphoma: a study of the Swiss Group for Clinical Cancer Research (SAKK). J Clin Oncol. 2005 Feb 1;23(4):705-11. doi: 10.1200/JCO.2005.04.164. Epub 2004 Dec 14.
citation: Howard OM, Gribben JG, Neuberg DS, Grossbard M, Poor C, Janicek MJ, Shipp MA. Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma: molecular complete responses are not predictive of progression-free survival. J Clin Oncol. 2002 Mar 1;20(5):1288-94. doi: 10.1200/JCO.2002.20.5.1288.
citation: Kaufman DS, Lewis RL, Hanson ET, Auerbach R, Plendl J, Thomson JA. Functional endothelial cells derived from rhesus monkey embryonic stem cells. Blood. 2004 Feb 15;103(4):1325-32. doi: 10.1182/blood-2003-03-0799. Epub 2003 Oct 16.
citation: Lenz G, Dreyling M, Hoster E, Wormann B, Duhrsen U, Metzner B, Eimermacher H, Neubauer A, Wandt H, Steinhauer H, Martin S, Heidemann E, Aldaoud A, Parwaresch R, Hasford J, Unterhalt M, Hiddemann W. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol. 2005 Mar 20;23(9):1984-92. doi: 10.1200/JCO.2005.08.133. Epub 2005 Jan 24.
citation: Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, Rekhtman G, Masliak Z, Robak T, Shubina A, Arnulf B, Kropff M, Cavet J, Esseltine DL, Feng H, Girgis S, van de Velde H, Deraedt W, Harousseau JL. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011 May;12(5):431-40. doi: 10.1016/S1470-2045(11)70081-X. Epub 2011 Apr 18.
citation: Romaguera JE, Fayad L, Rodriguez MA, Broglio KR, Hagemeister FB, Pro B, McLaughlin P, Younes A, Samaniego F, Goy A, Sarris AH, Dang NH, Wang M, Beasley V, Medeiros LJ, Katz RL, Gagneja H, Samuels BI, Smith TL, Cabanillas FF. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005 Oct 1;23(28):7013-23. doi: 10.1200/JCO.2005.01.1825. Epub 2005 Sep 6.
citation: Weisenburger DD, Sanger WG, Armitage JO, Purtilo DT. Intermediate lymphocytic lymphoma: immunophenotypic and cytogenetic findings. Blood. 1987 Jun;69(6):1617-21.
citation: Foran JM, Rohatiner AZ, Cunningham D, Popescu RA, Solal-Celigny P, Ghielmini M, Coiffier B, Johnson PW, Gisselbrecht C, Reyes F, Radford JA, Bessell EM, Souleau B, Benzohra A, Lister TA. European phase II study of rituximab (chimeric anti-CD20 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previously treated mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma. J Clin Oncol. 2000 Jan;18(2):317-24. doi: 10.1200/JCO.2000.18.2.317.
citation: Schafer PH, Gandhi AK, Loveland MA, Chen RS, Man HW, Schnetkamp PP, Wolbring G, Govinda S, Corral LG, Payvandi F, Muller GW, Stirling DI. Enhancement of cytokine production and AP-1 transcriptional activity in T cells by thalidomide-related immunomodulatory drugs. J Pharmacol Exp Ther. 2003 Jun;305(3):1222-32. doi: 10.1124/jpet.102.048496. Epub 2003 Mar 20.