Mantle Cell LymphomaPhase 1/2NCT00633594
Rituximab, Lenalidomide, and Bortezomib in Mantle Cell Lymphoma
A Phase 1/2 study testing Rituximab, Bortezomib and Lenalidomide in people with Mantle Cell Lymphoma, run by SCRI Development Innovations, LLC at 7 sites in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Mantle Cell Lymphoma
- What is being tested?
- Rituximab, Bortezomib and Lenalidomide
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 39 participants
- Where
- 7 sitesUnited States
- Study dates
- Jun 2008to Nov 2016
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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.
Who cannot join
- 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.
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- 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.
- Evidence or history of bleeding diathesis or coagulopathy.
- Major surgery, open biopsy, or significant traumatic injury within 28 days of the first dose of study drug.
- Use of any other standard chemotherapy, radiation therapy, or experimental drug for the treatment of MCL within 28 days of starting treatment.
- 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).
- 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.
- Uncontrolled hypertension (systolic blood pressure [BP] > 180 or diastolic BP > 100mm Hg) or uncontrolled cardiac arrhythmias.
- Any prior use of lenalidomide.
Trial locations and contacts
7 sites in 1 country.
7 sites in 1 country
United States7 sites
Chattanooga Oncology Hematology Associates
Chattanooga, Tennessee, 37404
St. Louis Cancer Care
Chesterfield, Missouri, 63017
Oncology Hematology Care Inc.
Cincinnati, Ohio, 45242
Hematology-Oncology Associates of Northern NJ
Morristown, New Jersey, 07960
Tennessee Oncology, PLLC
Nashville, Tennessee, 37023
Providence Medical Group
Terre Haute, Indiana, 47802
RHHP/ Hope Cancer Center
Terre Haute, Indiana, 47802
About this study
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
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).
Read the 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.
- Conditions
- Mantle Cell Lymphoma
- Being tested
- Rituximab, Bortezomib, Lenalidomide
- Keywords
- Mantle Cell Lymphoma, Rituximab, Lenalidomide, Bortezomib, Phase 1/2
- Medical subject headings
- Lymphoma, Mantle-Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RituximabDrug
Also called Rituxan, MabThera
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.
BortezomibDrug
Also called Velcade
DL 1, DL 2, and DL 3: 1.3 mg/m2 IV Days 1, 4, 8, and 11
Same for DL-1.
LenalidomideDrug
Also called Revlimid
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
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Rituximab; Drug: Bortezomib; Drug: Lenalidomide |
What is being measured
The primary outcome is the main question the study is designed to answer.
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)
Measured: 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
Measured: 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
Response to treatment (Complete Response (CR) or Partial Response (PR)) determined using Non-Hodgkin's Lymphoma Revised Response Criteria for Malignant Lymphoma (Cheson et al. 2007.) CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms; PR: 50% or greater decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or extranodal masses, no increase in the size of other nodes, liver or spleen, no new sites of disease, patients who achieve CR but have persistent morphologic bone marrow involvement; Stable Disease (SD): failing to attain PR or CR, but not fulfilling criteria for progressive disease; Progressive Disease (PD)/Relapse: appearance of new lesions more than 1.5 cm in any axis, 50% or greater increase from nadir SPD of any previously involved sites, 50% or greater increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in short axis.
Measured: 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
Response to treatment (Complete Response (CR) or Partial Response (PR)) determined using Non-Hodgkin's Lymphoma Revised Response Criteria for Malignant Lymphoma (Cheson et al. 2007.) CR: complete disappearance of all detectable clinical evidence of disease and disease-related symptoms; PR: 50% or greater decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or extranodal masses, no increase in the size of other nodes, liver or spleen, no new sites of disease, patients who achieve CR but have persistent morphologic bone marrow involvement; Stable Disease (SD): failing to attain PR or CR, but not fulfilling criteria for progressive disease; Progressive Disease (PD)/Relapse: appearance of new lesions more than 1.5 cm in any axis, 50% or greater increase from nadir SPD of any previously involved sites, 50% or greater increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in short axis.
Measured: 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
Measured from the time of study entry to the documented beginning of response (CR or PR). This is measured in responders per Non-Hodgkin's Lymphoma Revised Response Criteria for Malignant Lymphoma (Cheson et al. 2007.) CR: complete disappearance of detectable clinical evidence of disease and disease-related symptoms; PR: 50% or greater decrease in sum of product of diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses, no increase in size of other nodes, liver or spleen, no new disease sites, patients with CR and persistent morphologic bone marrow involvement.
Time to Best Response will be examined using time-to-event analysis methods. Kaplan-Meier figures will be generated and the log-rank test will be used to examine differences existing between various levels of stratification.
Measured: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years
Time to Best Response of Previously Treated and Previously Untreated Participants
Measured from the time of study entry to the documented beginning of response (CR or PR). This is measured in responders per Non-Hodgkin's Lymphoma Revised Response Criteria for Malignant Lymphoma (Cheson et al. 2007.) CR: complete disappearance of detectable clinical evidence of disease and disease-related symptoms; PR: 50% or greater decrease in sum of product of diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses, no increase in size of other nodes, liver or spleen, no new disease sites, patients with CR and persistent morphologic bone marrow involvement.
Measured: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years
Duration of Response (DoR) of Phase I and Phase II Participants
Measured from the documented beginning of response (CR or PR) to the time of relapse. This is measured in responders per Non-Hodgkin's Lymphoma Revised Response Criteria for Malignant Lymphoma (Cheson et al. 2007.) CR: complete disappearance of detectable clinical evidence of disease and disease-related symptoms; PR: 50% or greater decrease in sum of product of diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses, no increase in size of other nodes, liver or spleen, no new disease sites, patients with CR and persistent morphologic bone marrow involvement.
Duration of Response will be examined using time-to-event analysis methods. Kaplan-Meier figures will be generated and the log-rank test will be used to examine differences existing between various levels of stratification.
Measured: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years or until documented disease progression
Duration of Response (DoR) of Previously Treated and Previously Untreated Participants
Measured from the documented beginning of response (CR or PR) to the time of relapse. This is measured in responders per Non-Hodgkin's Lymphoma Revised Response Criteria for Malignant Lymphoma (Cheson et al. 2007.) CR: complete disappearance of detectable clinical evidence of disease and disease-related symptoms; PR: 50% or greater decrease in sum of product of diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses, no increase in size of other nodes, liver or spleen, no new disease sites, patients with CR and persistent morphologic bone marrow involvement.
Measured: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years or until documented disease progression
Progression Free Survival (PFS) of Phase I and Phase II Participants
Defined as the time from entry onto study until lymphoma progression or death from any cause.
Progression Free Survival will be examined using time-to-event analysis methods. Kaplan-Meier figures will be generated and the log-rank test will be used to examine differences existing between various levels of stratification.
Measured: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years, then every 6 months after documented disease progression
Progression Free Survival (PFS) of Previously Treated and Previously Untreated Participants
Defined as the time from entry onto study until lymphoma progression or death from any cause.
Progression Free Survival will be examined using time-to-event analysis methods. Kaplan-Meier figures will be generated and the log-rank test will be used to examine differences existing between various levels of stratification.
Measured: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years, then every 6 months after documented disease progression
Overall Survival of Phase I and Phase II Participants
Defined as the date of study entry to the date of death.
Overall Survival will be examined using time-to-event analysis methods. Kaplan-Meier figures will be generated and the log-rank test will be used to examine differences existing between various levels of stratification
Measured: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years, then every 6 months after documented disease progression
Overall Survival of Previously Treated and Previously Untreated Participants
Defined as the date of study entry to the date of death.
Overall Survival will be examined using time-to-event analysis methods. Kaplan-Meier figures will be generated and the log-rank test will be used to examine differences existing between various levels of stratification
Measured: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years, then every 6 months after documented disease progression
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Mar 2008 (estimated)
- Study startJun 2008
- Primary completionApr 2015
- Study completionNov 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (14)Papers the sponsor has linked to this study.
- Other trials for Mantle Cell LymphomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 39 participants (actual)
Sponsor and investigators
- Lead sponsor
- SCRI Development Innovations, LLC
- Sponsor type
- University, hospital or other
- Collaborators
- Millennium Pharmaceuticals, Inc., Celgene
- Responsible party
- Sponsor
- Investigators
- Ian W Flinn, M.D., Study chair, SCRI Development Innovations, LLC
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00633594
- Sponsor's protocol ID
- SCRI LYM 58
- Status last verified
- Dec 2016
- First submitted
- 4 Mar 2008
- Last updated
- 31 Jan 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
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.
PubMed 9452276Cheson 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.
PubMed 17242396Corral 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.
PubMed 10384139Davies 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.
PubMed 11418482Dredge 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.
PubMed 15797261Ghielmini 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.
PubMed 15598978Howard 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.
PubMed 11870171Kaufman 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.
PubMed 14563647Lenz 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.
PubMed 15668467Moreau 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.
PubMed 21507715Romaguera 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.
PubMed 16145068Weisenburger DD, Sanger WG, Armitage JO, Purtilo DT. Intermediate lymphocytic lymphoma: immunophenotypic and cytogenetic findings. Blood. 1987 Jun;69(6):1617-21.
PubMed 3555648Foran 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.
PubMed 10637245Schafer 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.
PubMed 12649301
Study at a glance
From the registry record, last updated by the sponsor on 31 Jan 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00633594
- Acronym / sponsor ID
- SCRI LYM 58
- Conditions
- Mantle Cell Lymphoma
- Keywords
- Mantle Cell Lymphoma, Rituximab, Lenalidomide, Bortezomib, Phase 1/2
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 39 participants (actual)
- Lead sponsor
- SCRI Development Innovations, LLCUniversity, hospital or other
- Collaborators
- Millennium Pharmaceuticals, Inc., Celgene
- Study start
- Jun 2008
- Primary completion
- Apr 2015 (actual)
- Study completion
- Nov 2016 (actual)
- First posted
- 12 Mar 2008 (estimated)
- Results
- Posted 31 Jan 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| rituximab/bortezomib/lenalidomide | Experimental | Drug: Rituximab, Drug: Bortezomib, Drug: LenalidomidePatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- 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).
Key exclusion criteria (30 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RituximabAlso: Rituxan, MabTheraDL 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. | Drug | rituximab/bortezomib/lenalidomide |
| BortezomibAlso: VelcadeDL 1, DL 2, and DL 3: 1.3 mg/m2 IV Days 1, 4, 8, and 11 Same for DL-1. | Drug | rituximab/bortezomib/lenalidomide |
| LenalidomideAlso: RevlimidDL 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 | Drug | rituximab/bortezomib/lenalidomide |
Primary outcome
Maximum Tolerated Dose of Lenalidomide Combined With Bortezomib and Rituximab in Phase I Participants
Time frame: Collected from day of first dose to the end of the first treatment cycle, up to 21 days
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)
Incidence of Non-Serious Adverse Events as a Measure of Safety and Tolerability, Phase II
Time frame: 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
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
10 secondary outcomes
Overall Response Rate (ORR) of Phase I and Phase II Participants
Time frame: 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
Time frame: 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
Time frame: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years
Time to Best Response of Previously Treated and Previously Untreated Participants
Time frame: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years
Duration of Response (DoR) of Phase I and Phase II Participants
Time frame: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years or until documented disease progression
Duration of Response (DoR) of Previously Treated and Previously Untreated Participants
Time frame: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years or until documented disease progression
Progression Free Survival (PFS) of Phase I and Phase II Participants
Time frame: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years, then every 6 months after documented disease progression
Progression Free Survival (PFS) of Previously Treated and Previously Untreated Participants
Time frame: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years, then every 6 months after documented disease progression
Overall Survival of Phase I and Phase II Participants
Time frame: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years, then every 6 months after documented disease progression
Overall Survival of Previously Treated and Previously Untreated Participants
Time frame: Every 3 months (+/- 2 weeks) after discontinuation of study treatment for 2 years, then every 6 months after documented disease progression
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Jan 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 9452276Bosch 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.
- Background: PubMed 17242396Cheson 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.
- Background: PubMed 10384139Corral 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.
- Background: PubMed 11418482Davies 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.
- Background: PubMed 15797261Dredge 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.
- Background: PubMed 15598978Ghielmini 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.
- Background: PubMed 11870171Howard 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.
- Background: PubMed 14563647Kaufman 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.
- Background: PubMed 15668467Lenz 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.
- Background: PubMed 21507715Moreau 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.
- Background: PubMed 16145068Romaguera 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.
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- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ian W Flinn, M.D. study chair
SCRI Development Innovations, LLC
7 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Rituximab, Bortezomib and Lenalidomide in people with Mantle Cell Lymphoma, run by SCRI Development Innovations, LLC at 7 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 31 Jan 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 7 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 31 Jan 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum Tolerated Dose of Lenalidomide Combined With Bortezomib and Rituximab in Phase I Participants (time frame: Collected from day of first dose to the end of the first treatment cycle, up to 21 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00633594, which also lists 14 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Jan 2017; AzTrials last refreshed its copy on 7 Nov 2026.