Rituximab, Lenalidomide, and Bortezomib in Mantle Cell Lymphoma

NCT00633594 | Completed Phase 1 Results

• 1 other identifier: SCRI LYM 58
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 7

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).

Conditions

Mantle Cell Lymphoma

Keywords

Mantle Cell Lymphoma; Rituximab; Lenalidomide; Bortezomib; Phase 1/2

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose of Lenalidomide Combined With Bortezomib and Rituximab in Phase I Participants

  Determination of the maximum tolerated dose (MTD) of lenalidomide combined with bortezomib and rituximab, defined as the highest dose at which ≤1 of 6 patients experiences a dose-limiting toxicity according to the NCI CTCAE v. 4.03. MTD of Lenalidomide was tested, included with 1.3 mg/m2 subcutaneous (D1, 4, 8, 11) bortezomib, 375 mg/m2 (D1, 8, 15 of Cycle 1, D1 on subsequent cycles) rituximab. Three dose limiting toxicities were reported in two patients (grade 4 neutropenia and grade 3 neuropathy, grade 3 rash)

  Collected from day of first dose to the end of the first treatment cycle, up to 21 days

• Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II

  A count of affected participants with non-serious adverse events (regardless of relationship to study treatments) occurring in \>= 15% of treated patients enrolled in the Phase II section of the study. Lenalidomide DL-1 dose (10 mg orally, once daily (PO QD)) Day 1-14 followed by 7 days of rest, Rituximab 375 mg/m2 IV Days 1, 8, and 15 of Cycle 1; Cycles 2-6: 375 mg/m2 IV Day 1, Bortezomib 1.3 mg/m2 subcutaneous Days 1, 4, 8, and 11 for Cycles 1-6

  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 (10)

• Overall Response Rate (ORR) of Phase I and Phase II Participants

  Every 6 weeks until treatment discontinuation then every 3 months thereafter, projected average 24 months

• Overall Response Rate (ORR) of Previously Treated and Previously Untreated Participants

  Every 6 weeks until treatment discontinuation then every 3 months thereafter, projected average 24 months

• Time to Best Response of Phase I and Phase II Participants

  Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years

• Time to Best Response of Previously Treated and Previously Untreated Participants

  Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years

• Duration of Response (DoR) of Phase I and Phase II Participants

  Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years or until documented disease progression

Study Arms (1)

rituximab/bortezomib/lenalidomide

EXPERIMENTAL

Patients in Phase I \& II to receive treatment with rituximab, bortezomib and lenalidomide in 21-day cycles up to 6 cycles. Phase I: Cohorts of 3 patients will be enrolled at escalating dose levels to determine the maximum tolerated dose (MTD). Doses may be de-escalated if necessary. Phase II: patients will be treated with the MTD determined in Phase I.

Drug: Rituximab; Drug: Bortezomib; Drug: Lenalidomide

Interventions

Rituximab DRUG

DL 1, DL 2, and DL 3: 375 mg/m2 IV Days 1, 8, and 15; Cycles 2-6: 375 mg/m2 IV Day 1 Same for DL-1.

Also known as: Rituxan, MabThera

rituximab/bortezomib/lenalidomide

Bortezomib DRUG

DL 1, DL 2, and DL 3: 1.3 mg/m2 IV Days 1, 4, 8, and 11 Same for DL-1.

Also known as: Velcade

rituximab/bortezomib/lenalidomide

Lenalidomide DRUG

DL 1: 15 mg PO daily Days 1-14 followed by 7 days of rest DL 2: 20 mg PO daily Days 1-14 followed by 7 days of rest DL 3: 25 mg PO daily Days 1-14 followed by 7 days of rest DL-1: 10 mg PO daily Days 1-14 followed by 7 days of rest

Also known as: Revlimid

rituximab/bortezomib/lenalidomide

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Histology: biopsy-proven mantle cell lymphoma (MCL).
• 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.
• Presence of at least one lymph node evaluable or mass measurable for response.
• 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).
• 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
• Total bilirubin ≤ 1.5x upper limit of normal (ULN), aspartate transaminase (AST) (SGOT) and alanine transaminase (ALT) (SGOT) ≤ 3 x ULN
• Eastern Cooperative Oncology Group (ECOG) performance of 0, 1, or 2.
• Recovery from any previous treatment therapy.
• 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.
• 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.
• 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.

You may not qualify if:

• Patient has \>1.5 x ULN total bilirubin.
• Peripheral neuropathy ≥ CTCAE grade 2.
• Relapsed or refractory patients who have received more than one prior therapy.
• Pregnant or breastfeeding females. (Lactating females must agree not to breastfeed while taking lenalidomide.)
• 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.
• Thrombolic or embolic events (such as a cerebrovascular accident, including transient ischemic attacks) within the past 6 months.
• Pulmonary hemorrhage/bleeding event ≥ CTCAE grade 2 within 28 days of the first dose of study drug.
• Any other hemorrhage/bleeding event ≥ CTCAE grade 3 ≤ 28 days of the first dose of study drug
• Known brain metastasis. Patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasis.
• Central nervous system (CNS) involvement by lymphoma at time of enrollment.
• Other medical conditions or psychiatric illness that would potentially interfere with patient participation in this trial.
• 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.
• 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).
• 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.
• Active, clinically serious infection \> CTCAE grade 2. Patients may be eligible upon resolution of the infection.

Sponsors & Collaborators

• SCRI Development Innovations, LLC: lead
• Millennium Pharmaceuticals, Inc.: collaborator
• Celgene: collaborator

Study Sites (7)

Providence Medical Group

Terre Haute, Indiana, 47802, United States

Location

RHHP/ Hope Cancer Center

Terre Haute, Indiana, 47802, United States

Location

St. Louis Cancer Care

Chesterfield, Missouri, 63017, United States

Location

Hematology-Oncology Associates of Northern NJ

Morristown, New Jersey, 07960, United States

Location

Oncology Hematology Care Inc.

Cincinnati, Ohio, 45242, United States

Location

Chattanooga Oncology Hematology Associates

Chattanooga, Tennessee, 37404, United States

Location

Tennessee Oncology, PLLC

Nashville, Tennessee, 37023, United States

Location

Related Publications (14)

• 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.

  PMID: 9452276 BACKGROUND

• 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.

  PMID: 17242396 BACKGROUND

• 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.

  PMID: 10384139 BACKGROUND

• 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.

  PMID: 11418482 BACKGROUND

• 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.

  PMID: 15797261 BACKGROUND

• 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.

  PMID: 15598978 BACKGROUND

• 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.

  PMID: 11870171 BACKGROUND

• 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.

  PMID: 14563647 BACKGROUND

• 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.

  PMID: 15668467 BACKGROUND

• 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.

  PMID: 21507715 BACKGROUND

• 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.

  PMID: 16145068 BACKGROUND

• Weisenburger DD, Sanger WG, Armitage JO, Purtilo DT. Intermediate lymphocytic lymphoma: immunophenotypic and cytogenetic findings. Blood. 1987 Jun;69(6):1617-21.

  PMID: 3555648 BACKGROUND

• 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.

  PMID: 10637245 BACKGROUND

• 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.

  PMID: 12649301 BACKGROUND

MeSH Terms

Conditions

Lymphoma, Mantle-Cell

Interventions

Rituximab; Bortezomib; Lenalidomide

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Piperidones; Piperidines; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Ian Flinn, MD
• Organization: Sarah Cannon Research Institute

asksarah@scresearch.net

1-877-691-7274

Study Officials

• Ian W Flinn, M.D.

  SCRI Development Innovations, LLC

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 4, 2008
• First Posted: March 12, 2008
• Study Start: June 1, 2008
• Primary Completion: April 1, 2015
• Study Completion: November 1, 2016
• Last Updated: January 31, 2017
• Results First Posted: January 31, 2017

Record last verified: 2016-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (7)