Clinical trial NCT00783367: Combination Therapy Using Lenalidomide (Revlimid)- Low Dose Dexamethasone and Rituximab for Treatment of Rituximab-Resistant, Non-Aggressive B-Cell Lymphomas
Official title: Phase 2 Trial of Lenalidomide (Revlimid)-Dexamethasone + Rituximab in Recurrent Small B-Cell Non-Hodgkin Lymphomas (NHL) Resistant to Rituximab
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Follicular Lymphoma
Marginal Zone B-Cell Lymphoma
MALT Lymphoma
Lymphoma of Mucosa-Associated Lymphoid Tissue
Lymphoma, Small Lymphocytic
Waldenstrom Macroglobulinemia
Mantle-Cell Lymphoma
Keywords: Revlimid
Celgene brand of lenalidomide
lenalidomide
Rituxan
CD20 antibody, rituximab
rituximab
Follicular Lymphoma
Marginal Zone B-Cell Lymphoma
Lymphoma, Small Lymphocytic
Waldenstrom Macroglobulinemia
Mantle-Cell Lymphoma
Antigens, CD20
refractory
resistantRefractory/progressive lymphoma less than 6 months from first rituximab dose of previous rituximab-containing regimen
Previously treated
Treated with rituximab
Lead sponsor: Abramson Cancer Center at Penn Medicine
Sponsor class: OTHER
First posted: 2008-10-31
Enrollment: 50
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: Pre-clinical data and recently published clinical data suggest a synergistic effect between lenalidomide and dexamethasone. We hypothesize that a combination of lenalidomide-dexamethasone can overcome rituximab resistance. To determine the response rate to lenalidomide and dexamethasone plus rituximab therapy in subjects with recurrent small B-cell non-Hodgkin lymphoma who have had lymphoma progression within 6 months of being treated with rituximab alone or with a rituximab-containing regimen, we propose initial treatment with both drugs for two 28-day treatment cycles (Part I). After response assessment following two cycles of lenalidomide-dexamethasone, patients will enter Part II of the study. In Part II, patients will receive lenalidomide-dexamethasone and rituximab to evaluate the potential reversal of rituximab resistance as measured by response to rituximab and progression-free survival following rituximab.


Eligibility criteria: Inclusion Criteria:

* Previously treated, histologically confirmed follicular lymphoma (grade 1, 2, 3a), marginal zone lymphoma, small lymphocytic lymphoma with less than \<5000 lymphocytes/mm3 or lymphoplasmacytic lymphoma with \<3g/mL IgM, mantle cell lymphoma by WHO classification
* Flow cytometry or immunohistochemistry must document CD20 antigen expression. Past documentation of CD20 antigen expression is admissible.
* Subjects must have been treated with rituximab in combination with chemotherapy or as monotherapy and must have refractory or progressive disease \<6 months from the first rituximab dose of previous rituximab containing regimen
* At least 18 years of age
* ECOG performance status 0-2
* Measurable disease must be present on physical examination or imaging studies. Any tumor mass \>2cm is considered measurable.
* Lesions that are considered non-measurable, but assessable include the following: bone lesions, ascites, pleural/pericardial effusion, lymphangitis cutis/pulmonis, bone marrow
* Patients with a history of intravenous drug abuse or any behavior associated with increased risk of HIV infection should be tested for exposure to the HIV virus
* Understand and voluntarily sign an informed consent
* Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant of ASA may use warfarin or low molecular weight heparin)
* Laboratory test results within these ranges: absolute neutrophil count greater than or equal to 1500/mm3; platelet count greater than or equal to 75,000/mm3; serum creatinine less than or equal to 2.0mg/dL; total bilirubin less than or equal to 1.5mg/dL (unless due to Gilbert's syndrome); AST (SGOT) and ALT (SGPT) less than or equal to 2.5 x ULN or less than or equal to 5 x ULN if hepatic metastases are present
* Disease free of prior malignancies for greater than or equal to 5 years with the exception of currently treated basal cell or squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast
* All study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist
* 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 and again within 24 hours of prescribing lenalidomide (prescriptions must be filled within 7 days) 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.

Exclusion Criteria:

* Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from following study procedure
* Pregnant or breast-feeding females
* Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
* Use of any other experimental drug or therapy within 28 days of baseline
* Known hypersensitivity to thalidomide
* The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs
* Any prior use of lenalidomide
* Known positivity for HIV or active infectious Hepatitis, type A, B, or C. Patients who test positive or who are known to be infected are not eligible due to an increased risk of infection with this regimen. HIV testing is not required for study entry, but is required if the patient is perceived to be at risk.
* Known central nervous system involvement by lymphoma

Primary outcomes:
measure: Response Rate to Lenalidomide-dexamethasone + Rituximab Therapy in Relapsed Small B-cell Lymphoma With Rituximab Resistance
timeFrame: 3 months
Secondary outcomes:
measure: Time Until Progression After Lenalidomide-dexamethasone + Rituximab Therapy in Relapsed Small B-cell Lymphomas With Rituximab Resistance
timeFrame: 9 years from enrollment of first subject
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: University of Pennsylvania; Abramson Cancer Center; Lymphoma Program
state: Pennsylvania
Study officials:
affiliation: University of Pennsylvania
name: Stephen J Schuster, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White CA, Cabanillas F, Jain V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998 Aug;16(8):2825-33. doi: 10.1200/JCO.1998.16.8.2825.
citation: Davis TA, Grillo-Lopez AJ, White CA, McLaughlin P, Czuczman MS, Link BK, Maloney DG, Weaver RL, Rosenberg J, Levy R. Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: safety and efficacy of re-treatment. J Clin Oncol. 2000 Sep;18(17):3135-43. doi: 10.1200/JCO.2000.18.17.3135.
citation: Golay J, Lazzari M, Facchinetti V, Bernasconi S, Borleri G, Barbui T, Rambaldi A, Introna M. CD20 levels determine the in vitro susceptibility to rituximab and complement of B-cell chronic lymphocytic leukemia: further regulation by CD55 and CD59. Blood. 2001 Dec 1;98(12):3383-9. doi: 10.1182/blood.v98.12.3383.
citation: Golay J, Zaffaroni L, Vaccari T, Lazzari M, Borleri GM, Bernasconi S, Tedesco F, Rambaldi A, Introna M. Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. Blood. 2000 Jun 15;95(12):3900-8.
citation: Harjunpaa A, Junnikkala S, Meri S. Rituximab (anti-CD20) therapy of B-cell lymphomas: direct complement killing is superior to cellular effector mechanisms. Scand J Immunol. 2000 Jun;51(6):634-41. doi: 10.1046/j.1365-3083.2000.00745.x.
citation: Smith MR. Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance. Oncogene. 2003 Oct 20;22(47):7359-68. doi: 10.1038/sj.onc.1206939.
citation: Hofmeister JK, Cooney D, Coggeshall KM. Clustered CD20 induced apoptosis: src-family kinase, the proximal regulator of tyrosine phosphorylation, calcium influx, and caspase 3-dependent apoptosis. Blood Cells Mol Dis. 2000 Apr;26(2):133-43. doi: 10.1006/bcmd.2000.0287.
citation: Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med. 2000 Apr;6(4):443-6. doi: 10.1038/74704.
citation: Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, Watier H. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood. 2002 Feb 1;99(3):754-8. doi: 10.1182/blood.v99.3.754.
citation: Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol. 2003 Nov 1;21(21):3940-7. doi: 10.1200/JCO.2003.05.013. Epub 2003 Sep 15.
citation: Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, Newman RA, Hanna N, Anderson DR. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994 Jan 15;83(2):435-45.
citation: van der Kolk LE, Grillo-Lopez AJ, Baars JW, Hack CE, van Oers MH. Complement activation plays a key role in the side-effects of rituximab treatment. Br J Haematol. 2001 Dec;115(4):807-11. doi: 10.1046/j.1365-2141.2001.03166.x.
citation: Alas S, Emmanouilides C, Bonavida B. Inhibition of interleukin 10 by rituximab results in down-regulation of bcl-2 and sensitization of B-cell non-Hodgkin's lymphoma to apoptosis. Clin Cancer Res. 2001 Mar;7(3):709-23.
citation: Bohen SP, Troyanskaya OG, Alter O, Warnke R, Botstein D, Brown PO, Levy R. Variation in gene expression patterns in follicular lymphoma and the response to rituximab. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1926-30. doi: 10.1073/pnas.0437875100. Epub 2003 Feb 5.
citation: Dave SS, Wright G, Tan B, Rosenwald A, Gascoyne RD, Chan WC, Fisher RI, Braziel RM, Rimsza LM, Grogan TM, Miller TP, LeBlanc M, Greiner TC, Weisenburger DD, Lynch JC, Vose J, Armitage JO, Smeland EB, Kvaloy S, Holte H, Delabie J, Connors JM, Lansdorp PM, Ouyang Q, Lister TA, Davies AJ, Norton AJ, Muller-Hermelink HK, Ott G, Campo E, Montserrat E, Wilson WH, Jaffe ES, Simon R, Yang L, Powell J, Zhao H, Goldschmidt N, Chiorazzi M, Staudt LM. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med. 2004 Nov 18;351(21):2159-69. doi: 10.1056/NEJMoa041869.
citation: Witzig TE, Flinn IW, Gordon LI, Emmanouilides C, Czuczman MS, Saleh MN, Cripe L, Wiseman G, Olejnik T, Multani PS, White CA. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's lymphoma. J Clin Oncol. 2002 Aug 1;20(15):3262-9. doi: 10.1200/JCO.2002.11.017.
citation: Ansell SM, Ristow KM, Habermann TM, Wiseman GA, Witzig TE. Subsequent chemotherapy regimens are well tolerated after radioimmunotherapy with yttrium-90 ibritumomab tiuxetan for non-Hodgkin's lymphoma. J Clin Oncol. 2002 Sep 15;20(18):3885-90. doi: 10.1200/JCO.2002.10.143.
citation: Davis TA, Maloney DG, Grillo-Lopez AJ, White CA, Williams ME, Weiner GJ, Dowden S, Levy R. Combination immunotherapy of relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma with rituximab and interferon-alpha-2a. Clin Cancer Res. 2000 Jul;6(7):2644-52.
citation: Friedberg JW, Kim H, McCauley M, Hessel EM, Sims P, Fisher DC, Nadler LM, Coffman RL, Freedman AS. Combination immunotherapy with a CpG oligonucleotide (1018 ISS) and rituximab in patients with non-Hodgkin lymphoma: increased interferon-alpha/beta-inducible gene expression, without significant toxicity. Blood. 2005 Jan 15;105(2):489-95. doi: 10.1182/blood-2004-06-2156. Epub 2004 Sep 9.
citation: Gluck WL, Hurst D, Yuen A, Levine AM, Dayton MA, Gockerman JP, Lucas J, Denis-Mize K, Tong B, Navis D, Difrancesco A, Milan S, Wilson SE, Wolin M. Phase I studies of interleukin (IL)-2 and rituximab in B-cell non-hodgkin's lymphoma: IL-2 mediated natural killer cell expansion correlations with clinical response. Clin Cancer Res. 2004 Apr 1;10(7):2253-64. doi: 10.1158/1078-0432.ccr-1087-3.
citation: Hernandez-Ilizaliturri FJ, Reddy N, Holkova B, Ottman E, Czuczman MS. Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse lymphoma model. Clin Cancer Res. 2005 Aug 15;11(16):5984-92. doi: 10.1158/1078-0432.CCR-05-0577.
citation: Wu L, Adams M, Carter T, Chen R, Muller G, Stirling D, Schafer P, Bartlett JB. lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clin Cancer Res. 2008 Jul 15;14(14):4650-7. doi: 10.1158/1078-0432.CCR-07-4405.
citation: Reddy N, Hernandez-Ilizaliturri FJ, Deeb G, Roth M, Vaughn M, Knight J, Wallace P, Czuczman MS. Immunomodulatory drugs stimulate natural killer-cell function, alter cytokine production by dendritic cells, and inhibit angiogenesis enhancing the anti-tumour activity of rituximab in vivo. Br J Haematol. 2008 Jan;140(1):36-45. doi: 10.1111/j.1365-2141.2007.06841.x. Epub 2007 Nov 9.
citation: Chanan-Khan A, Miller KC, Musial L, Lawrence D, Padmanabhan S, Takeshita K, Porter CW, Goodrich DW, Bernstein ZP, Wallace P, Spaner D, Mohr A, Byrne C, Hernandez-Ilizaliturri F, Chrystal C, Starostik P, Czuczman MS. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol. 2006 Dec 1;24(34):5343-9. doi: 10.1200/JCO.2005.05.0401. Epub 2006 Nov 6.