Phase II Protocol for CLL With Fludarabine and Cyclophosphamide With Rituximab (FCR) Plus Lenalidomide

Chronic Lymphocytic Leukemia (CLL) Clinical Trial

— FCR  

Official title:

Phase II Clinical Protocol for the Treatment of Patients With Previously Untreated CLL With Four or Six Cycles of Fludarabine and Cyclophosphamide With Rituximab (FCR) Plus Lenalidomide Followed by Lenalidomide Consolidation/ Maintenance

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01723839
• Other study ID #: Pro00002262 RV-CLL-PI-0530
• Status: Completed
• Phase: Phase 2
• Start date: February 22, 2012
• Est. completion date: June 8, 2021

Study information

• Verified date: October 2022
• Source: Hackensack Meridian Health
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

In previously-untreated subjects with CLL, fludarabine and rituximab with or without cyclophosphamide (FR or FCR) produces complete responses (CR) of 40-80%. The major complication of FCR has been grade 3/4 neutropenia which was reduced using a lower dose of fludarabine and cyclophosphamide (FCR-Lite) The objective of this study is to evaluate the minimal residual disease (MRD) complete response rate (using the 2008 IWCLL guidelines) after 4 cycles of FCR-Lite plus lenalidomide in subjects with previously untreated CLL. Lenalidomide is active in frontline treatment of CLL as well as in patients with refractory disease. MRD has been demonstrated to be a sensitive surrogate marker for progression-free survival. If patients are MRD negative complete responders (CR) they will stop at 4 cycles of FCR-Lite followed by the lenalidomide consolidation/maintenance arm of the study. If they have a MRD positive CR or partial response (PR) they will continue with 2 additional cycles of FCR-Lite plus lenalidomide followed by lenalidomide consolidation/maintenance. They will be re-tested for MRD after the 6th cycle of FCR-Lite and after 6 and 12 months of lenalidomide monotherapy If they have no response (NR) or progressive disease (PD) following 4 cycles of FCR-Lite plus lenalidomide they will be removed from the study.

Description:

STUDY OBJECTIVES: Primary: The primary objective is to evaluate the complete response rate following 4 cycles of FCR-Lite plus lenalidomide in previously untreated patients with CLL. Secondary: The first secondary objective is to evaluate the toxicity of patients with previously untreated CLL treated with FCR-Lite plus lenalidomide, followed by lenalidomide. The second is to evaluate the overall response rate and overall survival of patients with previously untreated CLL treated with FCR-Lite plus lenalidomide followed by lenalidomide. The third is to determine whether adding lenalidomide as a consolidation/maintenance therapy will eliminate bone marrow minimal residual disease in CR patients and whether patients who have a PR after 6 cycles of FCR-Lite plus lenalidomide will respond to 12 months of lenalidomide. The final secondary objective is to determine whether the expression of ZAP-70, CD38, and chromosomes correlate with response rate, duration of response, and survival for previously untreated patients with CLL. STUDY DESIGN: 2-stage phase 2 study-design. 19 subjects are treated in stage-1 with FCR-Lite plus 5mg lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity. If there are at least 5 CRs the study will accrue an additional 35 subjects (see statistical section). A secondary objective of this study will be to determine if MRD positive patients will become MRD negative with lenalidomide consolidation/maintenance and whether PR patients will convert to CRs Lenalidomide will begin 2 months after the last dose of FCR-Lite in all subjects with CR. It may begin as soon as 1 month after FCR-Lite plus lenalidomide in subjects with PR. Lenalidomide is given in 28 d cycles increasing the dose from 5 mg/d to 10 mg/d in cycle 2 and to 15mg in cycles 3-6 if well- tolerated (no grade-3 or -4 toxicity). Patients with creatinine clearance ≥30ml/min and <60ml/min will start at 2.5mg daily increasing to 5 and 10mg in subsequent cycles . Reduction to the prior dose is allowed for grade-3/-4 toxicity. MRD will be studied by flow cytometry from bone marrow and peripheral blood samples following 4 and 6 cycles of FCR-Lite and after 6 and 12 months of lenalidomide in CR patients.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 21
• Est. completion date: June 8, 2021
• Est. primary completion date: June 8, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients must have diagnosis of CLL (as defined by the NCI Criteria below:
• Patients must have peripheral blood absolute lymphocyte count of >5,000/mm3 obtained within 2 weeks prior to start of study.
• The lymphocytosis must consist of small, mature lymphocytes, with =55% (not greater than 55%) prolymphocytes.
• Patients must have phenotypically characterized CLL as defined as:

1. The predominant population of cells share B-cell antigens with CD5 in the absence of other pan-T-cell markers (CD3, CD2, etc.);

2. Surface immunoglobulin (slg) and CD20 with low-cell surface density expression.

3. If surface immunoglobulin can be demonstrated, the leukemic cells are restricted to expression of either kappa or lambda.

• Splenomegaly, hepatomegaly or lymphadenopathy are not required for the diagnosis of CLL
• Patients must require chemotherapy
• Patients must not have received prior treatment cytotoxic, immunotherapy or investigational therapy.
• Patients must not have history of corticosteroid treatment for CLL, Autoimmune thrombocytopenia, or autoimmune hemolytic anemia.
• Calculated creatinine clearance =30ml/min by Cockcroft-Gault formula
• Bilirubin must be =1.5mg/dl, unless secondary to tumor, obtained within 2 weeks prior to registration
• Platelets =75x109/L, unless due to CLL involvement of bone marrow
• Neutrophils =1.5x109/L, unless due to CLL involvement of bone marrow
• AST or ALT < 2x upper limit of normal, unless related to CLL
• Age =18 years
• ECOG performance status 0-2
• Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test
• Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy
• Able to take aspirin (81mg or 325mg) daily as prophylactic anticoagulation
• Subject must provide written informed consent
• All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®

Exclusion Criteria:

• Patients with autoimmune hemolytic anemia or autoimmune thrombocytopenia are not eligible
• No prior immunotherapy, investigational or cytotoxic chemotherapy
• Patients with a history of steroid treatment for CLL/SLL autoimmune hemolytic anemia, or autoimmune thrombocytopenia are not eligible
• Patients with active infections requiring oral or intravenous (IV) antibiotics until resolution of the infection and completion of therapeutic antibiotics
• Women of childbearing potential and sexually active males who both refuse to use an accepted and effective method of contraception or women who are breastfeeding
• Patients with a second malignancy other than basal cell carcinoma or squamous cell carcinoma of the skin or in situ carcinoma of the cervix are not eligible unless the tumor was treated with curative intent at least two years previously
• History of known HIV
• History or presence CNS disease
• Evidence of laboratory TLS by Cairo-Bishop definition of Tumor Lysis Syndrome
• History of corticosteroid treatment for CLL, Autoimmune thrombocytopenia, or autoimmune hemolytic anemia.

Related Conditions & MeSH terms

• Chronic Lymphocytic Leukemia (CLL)
• Leukemia, Lymphocytic, Chronic, B-Cell

Intervention

Drug:
• Fludarabine, Cyclophosphamide, Rituximab, Lenalidomide
19 subjects are treated in stage-1 with FCR plus 5mg lenalidomide increasing to 10mg and 15mg in subsequent cycles depending on toxicity.

Locations

Country	Name	City	State
United States	John Theurer Cancer Center at HackensackUMC	Hackensack	New Jersey

Sponsors (2)

Lead Sponsor	Collaborator
Hackensack Meridian Health	Celgene Corporation

Country where clinical trial is conducted

United States, 

References & Publications (68)

Anaissie E, Kontoyiannis DP, Kantarjian H, Elting L, Robertson LE, Keating M. Listeriosis in patients with chronic lymphocytic leukemia who were treated with fludarabine and prednisone. Ann Intern Med. 1992 Sep 15;117(6):466-9. — View Citation

Andritsos LA, Johnson AJ, Lozanski G, Blum W, Kefauver C, Awan F, Smith LL, Lapalombella R, May SE, Raymond CA, Wang DS, Knight RD, Ruppert AS, Lehman A, Jarjoura D, Chen CS, Byrd JC. Higher doses of lenalidomide are associated with unacceptable toxicity including life-threatening tumor flare in patients with chronic lymphocytic leukemia. J Clin Oncol. 2008 May 20;26(15):2519-25. doi: 10.1200/JCO.2007.13.9709. Epub 2008 Apr 21. — View Citation

Begleiter A, Pugh L, Israels LG, Johnston JB. Enhanced cytotoxicity and inhibition of DNA damage repair in irradiated murine L5178Y lymphoblasts and human chronic lymphocytic leukemia cells treated with 2'-deoxycoformycin and deoxyadenosine in vitro. Cancer Res. 1988 Jul 15;48(14):3981-6. — View Citation

Bird ML, Ueshima Y, Rowley JD, Haren JM, Vardiman JW. Chromosome abnormalities in B cell chronic lymphocytic leukemia and their clinical correlations. Leukemia. 1989 Mar;3(3):182-91. — View Citation

Boettcher S, Fischer K, Stilgenbauer S, Busch R, Fingerle-Rowson G, Fink AM et al. Quantitative MRD assessments predict progression-free survival in CLL patients treated with fludarabine and cyclophosphamide with or without rituximab - a prospective analysis in 471 patients from the randomized GCLLSG CLL8 trial. Blood 2008; 112: 11, abstract 326)

Bosch F, Ferrer A, López-Guillermo A, Giné E, Bellosillo B, Villamor N, Colomer D, Cobo F, Perales M, Esteve J, Altés A, Besalduch J, Ribera JM, Montserrat E; GELCAB (Grup per l'Estudi dels Limfomes a Catalunya i Balears). Fludarabine, cyclophosphamide and mitoxantrone in the treatment of resistant or relapsed chronic lymphocytic leukaemia. Br J Haematol. 2002 Dec;119(4):976-84. — View Citation

Brown JR, Abramson J, Hochberg E, Mikler E, Dalton V, Werner L, Reynolds H, Thompson C, McDonough SM, Kuang Y, Ritz J, Neuberg D, Freedman AS. A phase I study of lenalidomide in combination with fludarabine and rituximab in previously untreated CLL/SLL. Leukemia. 2010 Nov;24(11):1972-5. doi: 10.1038/leu.2010.199. Epub 2010 Sep 16. — View Citation

Byrd JC, Murphy T, Howard RS, Lucas MS, Goodrich A, Park K, Pearson M, Waselenko JK, Ling G, Grever MR, Grillo-Lopez AJ, Rosenberg J, Kunkel L, Flinn IW. Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol. 2001 Apr 15;19(8):2153-64. — View Citation

Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, Vardiman JW, Rai K, Schiffer CA, Larson RA. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood. 2003 Jan 1;101(1):6-14. Epub 2002 Jul 5. — View 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. Epub 2006 Nov 6. — View Citation

Chen C, Paul H, Xu W, et al: A phase II study of lenalidomide in previously untreated, symptomatic chronic lymphocytic leukemia (CLL). Blood 112:23, 2008 (abstr 44).

Crespo M, Bosch F, Villamor N, Bellosillo B, Colomer D, Rozman M, Marcé S, López-Guillermo A, Campo E, Montserrat E. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003 May 1;348(18):1764-75. — View Citation

Damle RN, Wasil T, Fais F, Ghiotto F, Valetto A, Allen SL, Buchbinder A, Budman D, Dittmar K, Kolitz J, Lichtman SM, Schulman P, Vinciguerra VP, Rai KR, Ferrarini M, Chiorazzi N. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999 Sep 15;94(6):1840-7. — View Citation

Dufy DE, Santner TJ, Confidence intervals for binomial parameter based on multistage tests. Biometrics 43:81-93, 1987.

Fais F, Ghiotto F, Hashimoto S, Sellars B, Valetto A, Allen SL, Schulman P, Vinciguerra VP, Rai K, Rassenti LZ, Kipps TJ, Dighiero G, Schroeder HW Jr, Ferrarini M, Chiorazzi N. Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J Clin Invest. 1998 Oct 15;102(8):1515-25. — View Citation

Ferrajoli A, Lee BN, Schlette EJ, O'Brien SM, Gao H, Wen S, Wierda WG, Estrov Z, Faderl S, Cohen EN, Li C, Reuben JM, Keating MJ. Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood. 2008 Jun 1;111(11):5291-7. doi: 10.1182/blood-2007-12-130120. Epub 2008 Mar 11. — View Citation

Flinn IW, Byrd JC, Morrison C, Jamison J, Diehl LF, Murphy T, Piantadosi S, Seifter E, Ambinder RF, Vogelsang G, Grever MR. Fludarabine and cyclophosphamide with filgrastim support in patients with previously untreated indolent lymphoid malignancies. Blood. 2000 Jul 1;96(1):71-5. — View Citation

Foon KA, Boyiadzis M, Land SR, Marks S, Raptis A, Pietragallo L, Meisner D, Laman A, Sulecki M, Butchko A, Schaefer P, Lenzer D, Tarhini A. Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009 Feb 1;27(4):498-503. doi: 10.1200/JCO.2008.17.2619. Epub 2008 Dec 15. — View Citation

Gahrton G, Juliusson G. Clinical implication of chromosomal aberrations in chronic B-lymphocytic leukaemia cells. Nouv Rev Fr Hematol (1978). 1988;30(5-6):389-92. — View Citation

Grever MR, Kopecky KJ, Coltman CA, Files JC, Greenberg BR, Hutton JJ, Talley R, Von Hoff DD, Balcerzak SP. Fludarabine monophosphate: a potentially useful agent in chronic lymphocytic leukemia. Nouv Rev Fr Hematol (1978). 1988;30(5-6):457-9. — View Citation

Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE, Greco FA; Minnie Pearl Cancer Research Network. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003 May 1;21(9):1746-51. — View Citation

Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Döhner H, Hillmen P, Keating MJ, Montserrat E, Rai KR, Kipps TJ; International Workshop on Chronic Lymphocytic Leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008 Jun 15;111(12):5446-56. doi: 10.1182/blood-2007-06-093906. Epub 2008 Jan 23. Erratum in: Blood. 2008 Dec 15;112(13):5259. — View Citation

Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, Hensel M, Hopfinger G, Hess G, von Grünhagen U, Bergmann M, Catalano J, Zinzani PL, Caligaris-Cappio F, Seymour JF, Berrebi A, Jäger U, Cazin B, Trneny M, Westermann A, Wendtner CM, Eichhorst BF, Staib P, Bühler A, Winkler D, Zenz T, Böttcher S, Ritgen M, Mendila M, Kneba M, Döhner H, Stilgenbauer S; International Group of Investigators; German Chronic Lymphocytic Leukaemia Study Group. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010 Oct 2;376(9747):1164-74. doi: 10.1016/S0140-6736(10)61381-5. — View Citation

Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999 Sep 15;94(6):1848-54. — View Citation

Han T, Bhargava A, Henderson ES, et al. Prognostic significance of beta-2-microglobulin (-2m) in chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL). Proc Amer Soc Clin Oncol 1989; 8:270 (abstr 270).

Hansen MM, Andersen E, Christensen BE, Christiansen I, Geisler C, Kristensen D, Jensen KB, Junker P. CHOP versus prednisolone + chlorambucil in chronic lymphocytic leukemia (CLL): preliminary results of a randomized multicenter study. Nouv Rev Fr Hematol (1978). 1988;30(5-6):433-6. — View 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. — View Citation

Huhn D, von Schilling C, Wilhelm M, Ho AD, Hallek M, Kuse R, Knauf W, Riedel U, Hinke A, Srock S, Serke S, Peschel C, Emmerich B; German Chronic Lymphocytic Leukemia Study Group. Rituximab therapy of patients with B-cell chronic lymphocytic leukemia. Blood. 2001 Sep 1;98(5):1326-31. — View Citation

Jaksic B, Vitale B, Hauptmann E, Planinc-Peraica A, Ostojic S, Kusec R. The roles of age and sex in the prognosis of chronic leukaemias. A study of 373 cases. Br J Cancer. 1991 Aug;64(2):345-8. — View Citation

Johnston JB, Verburg L, Shore T, Williams M, Israels LG, Begleiter A. Combination therapy with nucleoside analogs and alkylating agents. Leukemia. 1994 Apr;8 Suppl 1:S140-3. — View Citation

Kay NE, Geyer SM, Call TG, Shanafelt TD, Zent CS, Jelinek DF, Tschumper R, Bone ND, Dewald GW, Lin TS, Heerema NA, Smith L, Grever MR, Byrd JC. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood. 2007 Jan 15;109(2):405-11. Epub 2006 Sep 28. — View Citation

Keating MJ, Kantarjian H, O'Brien S, Koller C, Talpaz M, Schachner J, Childs CC, Freireich EJ, McCredie KB. Fludarabine: a new agent with marked cytoreductive activity in untreated chronic lymphocytic leukemia. J Clin Oncol. 1991 Jan;9(1):44-9. — View Citation

Keating MJ, O'Brien S, Albitar M, Lerner S, Plunkett W, Giles F, Andreeff M, Cortes J, Faderl S, Thomas D, Koller C, Wierda W, Detry MA, Lynn A, Kantarjian H. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4079-88. Epub 2005 Mar 14. — View Citation

Kröber A, Seiler T, Benner A, Bullinger L, Brückle E, Lichter P, Döhner H, Stilgenbauer S. V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood. 2002 Aug 15;100(4):1410-6. — View Citation

Ladetto M, Bergui L, Ricca I, Campana S, Pileri A, Tarella C. Rituximab anti-CD20 monoclonal antibody induces marked but transient reductions of peripheral blood lymphocytes in chronic lymphocytic leukaemia patients. Med Oncol. 2000 Aug;17(3):203-10. — View Citation

LeBlanc R, Hideshima T, Catley LP, Shringarpure R, Burger R, Mitsiades N, Mitsiades C, Cheema P, Chauhan D, Richardson PG, Anderson KC, Munshi NC. Immunomodulatory drug costimulates T cells via the B7-CD28 pathway. Blood. 2004 Mar 1;103(5):1787-90. Epub 2003 Sep 25. — View Citation

Liepman M, Votaw ML. The treatment of chronic lymphocytic leukemia with COP chemotherapy. Cancer. 1978 May;41(5):1664-9. — View Citation

Lin K, Sherrington PD, Dennis M, Matrai Z, Cawley JC, Pettitt AR. Relationship between p53 dysfunction, CD38 expression, and IgV(H) mutation in chronic lymphocytic leukemia. Blood. 2002 Aug 15;100(4):1404-9. Erratum in: Blood 2002 Oct 1;100(7):2291. — View Citation

Linet MS, Cartwright RA. Chronic lymphocytic leukemia: epidemiology and etiologic findings. Nouv Rev Fr Hematol (1978). 1988;30(5-6):353-7. — View Citation

List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, Powell B, Greenberg P, Thomas D, Stone R, Reeder C, Wride K, Patin J, Schmidt M, Zeldis J, Knight R; Myelodysplastic Syndrome-003 Study Investigators. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006 Oct 5;355(14):1456-65. — View Citation

List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, Rimsza L, Heaton R, Knight R, Zeldis JB. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005 Feb 10;352(6):549-57. — View Citation

Mangiameli DP, Blansfield JA, Kachala S, Lorang D, Schafer PH, Muller GW, Stirling DI, Libutti SK. Combination therapy targeting the tumor microenvironment is effective in a model of human ocular melanoma. J Transl Med. 2007 Jul 18;5:38. — View Citation

Marriott JB, Clarke IA, Dredge K, Muller G, Stirling D, Dalgleish AG. Thalidomide and its analogues have distinct and opposing effects on TNF-alpha and TNFR2 during co-stimulation of both CD4(+) and CD8(+) T cells. Clin Exp Immunol. 2002 Oct;130(1):75-84. — View Citation

Montserrat E, Alcalá A, Parody R, Domingo A, García-Conde J, Bueno J, Ferrán C, Sanz MA, Giralt M, Rubio D, et al. Treatment of chronic lymphocytic leukemia in advanced stages. A randomized trial comparing chlorambucil plus prednisone versus cyclophosphamide, vincristine, and prednisone. Cancer. 1985 Nov 15;56(10):2369-75. — View Citation

Montserrat E, Rozman C. Bone marrow biopsy in chronic lymphocytic leukemia: a review of its prognostic importance. Blood Cells. 1987;12(2):315-26. Review. — View Citation

Montserrat E, Rozman C. Chronic lymphocytic leukaemia: prognostic factors and natural history. Baillieres Clin Haematol. 1993 Dec;6(4):849-66. Review. — View Citation

Montserrat E, Viñolas N, Reverter JC, Rozman C. Natural history of chronic lymphocytic leukemia: on the progression and progression and prognosis of early clinical stages. Nouv Rev Fr Hematol (1978). 1988;30(5-6):359-61. — View Citation

Moreton P, Kennedy B, Lucas G, Leach M, Rassam SM, Haynes A, Tighe J, Oscier D, Fegan C, Rawstron A, Hillmen P. Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol. 2005 May 1;23(13):2971-9. Epub 2005 Feb 28. — View Citation

O'Brien S, Kantarjian H, Beran M, Smith T, Koller C, Estey E, Robertson LE, Lerner S, Keating M. Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment. Blood. 1993 Sep 15;82(6):1695-700. — View Citation

O'Brien SM, Kantarjian H, Thomas DA, Giles FJ, Freireich EJ, Cortes J, Lerner S, Keating MJ. Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol. 2001 Apr 15;19(8):2165-70. — View Citation

O'Brien SM, Kantarjian HM, Cortes J, Beran M, Koller CA, Giles FJ, Lerner S, Keating M. Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. J Clin Oncol. 2001 Mar 1;19(5):1414-20. — View Citation

Oken MM, Kaplan ME. Combination chemotherapy with cyclophosphamide, vincristine, and prednisone in the treatment of refractory chronic lymphocytic leukemia. Cancer Treat Rep. 1979 Mar;63(3):441-7. — View Citation

Oscier DG, Thompsett A, Zhu D, Stevenson FK. Differential rates of somatic hypermutation in V(H) genes among subsets of chronic lymphocytic leukemia defined by chromosomal abnormalities. Blood. 1997 Jun 1;89(11):4153-60. — View Citation

Pangalis GA, Boussiotis VA, Kittas C. B-chronic lymphocytic leukemia. Disease progression in 150 untreated stage A and B patients as predicted by bone marrow pattern. Nouv Rev Fr Hematol (1978). 1988;30(5-6):373-5. — View Citation

Pellagatti A, Jädersten M, Forsblom AM, Cattan H, Christensson B, Emanuelsson EK, Merup M, Nilsson L, Samuelsson J, Sander B, Wainscoat JS, Boultwood J, Hellström-Lindberg E. Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q- syndrome patients. Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11406-11. Epub 2007 Jun 18. — View Citation

Provan D, Bartlett-Pandite L, Zwicky C, Neuberg D, Maddocks A, Corradini P, Soiffer R, Ritz J, Nadler LM, Gribben JG. Eradication of polymerase chain reaction-detectable chronic lymphocytic leukemia cells is associated with improved outcome after bone marrow transplantation. Blood. 1996 Sep 15;88(6):2228-35. — View Citation

Rai KR, Patel DV. Chronic Lymphocytic Leukemia, in Hoffman R, Benz E, Shattil 5, Furie B, Cohen H, Silberstein L (eds): Hematology: Basic Principles and Practice, New York, Churchill Livingstone, 1995, p. 1308.

Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, Hines J, Threatte GA, Larson RA, Cheson BD, Schiffer CA. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 14;343(24):1750-7. — View Citation

Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975 Aug;46(2):219-34. — View Citation

Rai KR, Sawitsky A. A review of the prognostic role of cytogenetic, phenotypic, morphologic, and immune function characteristics in chronic lymphocytic leukemia. Blood Cells. 1987;12(2):327-38. Review. — View Citation

Rajkumar SV, Hayman SR, Lacy MQ, Dispenzieri A, Geyer SM, Kabat B, Zeldenrust SR, Kumar S, Greipp PR, Fonseca R, Lust JA, Russell SJ, Kyle RA, Witzig TE, Gertz MA. Combination therapy with lenalidomide plus dexamethasone (Rev/Dex) for newly diagnosed myeloma. Blood. 2005 Dec 15;106(13):4050-3. Epub 2005 Aug 23. — View Citation

Raphael B, Andersen JW, Silber R, Oken M, Moore D, Bennett J, Bonner H, Hahn R, Knospe WH, Mazza J, et al. Comparison of chlorambucil and prednisone versus cyclophosphamide, vincristine, and prednisone as initial treatment for chronic lymphocytic leukemia: long-term follow-up of an Eastern Cooperative Oncology Group randomized clinical trial. J Clin Oncol. 1991 May;9(5):770-6. — View Citation

Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, Schlossman RL, Rajkumar SV, Desikan KR, Hideshima T, Munshi NC, Kelly-Colson K, Doss D, McKenney ML, Gorelik S, Warren D, Freeman A, Rich R, Wu A, Olesnyckyj M, Wride K, Dalton WS, Zeldis J, Knight R, Weller E, Anderson KC. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006 Nov 15;108(10):3458-64. Epub 2006 Jul 13. — View Citation

Richardson PG, Schlossman RL, Weller E, Hideshima T, Mitsiades C, Davies F, LeBlanc R, Catley LP, Doss D, Kelly K, McKenney M, Mechlowicz J, Freeman A, Deocampo R, Rich R, Ryoo JJ, Chauhan D, Balinski K, Zeldis J, Anderson KC. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood. 2002 Nov 1;100(9):3063-7. — View Citation

Rozman C, Montserrat E. Bone marrow biopsy in chronic lymphocytic leukemia. Nouv Rev Fr Hematol (1978). 1988;30(5-6):369-71. Review. — View Citation

Shustik C, Mick R, Silver R, Sawitsky A, Rai K, Shapiro L. Treatment of early chronic lymphocytic leukemia: intermittent chlorambucil versus observation. Hematol Oncol. 1988 Jan-Mar;6(1):7-12. — View Citation

Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials. 1989 Mar;10(1):1-10. — View Citation

Tai YT, Li XF, Catley L, Coffey R, Breitkreutz I, Bae J, Song W, Podar K, Hideshima T, Chauhan D, Schlossman R, Richardson P, Treon SP, Grewal IS, Munshi NC, Anderson KC. Immunomodulatory drug lenalidomide (CC-5013, IMiD3) augments anti-CD40 SGN-40-induced cytotoxicity in human multiple myeloma: clinical implications. Cancer Res. 2005 Dec 15;65(24):11712-20. — View Citation

* Note: There are 68 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Complete Response	Analysis of the Primary Endpoint: The complete responses will be estimated by the number of patients with CR divided by the total number of evaluable patients.	28 day cycle, up to 4 cycles
Secondary	Overall Response Rate	Analysis of the other Secondary Endpoints: The overall response rate will be estimated by the number of patients with complete and partial responses divided by the total number of evaluable patients.	28 day cycle, up to 6 cycles