A Phase Ib Study of ISF35 in Combination With Chemotherapy (FCR) in Subjects With Relapsed, Refractory, and/or 17p- CLL

NCT00772486 | Completed Phase 1 DMC

• 1 other identifier: CLL-35-104
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

Brief Summary

The study is a Phase 1b open label, non-randomized, single institution clinical trial that is designed to evaluate the safety and tolerability of three repeat infusions of ISF35 followed by a standard regimen of three cycles of fludarabine, cyclophosphamide and rituximab (FCR) in subjects with refractory, resistant, and/or 17p- CLL.

Conditions

Chronic Lymphocytic Leukemia

Keywords

Chronic lymphocytic leukemia; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, B-Cell; Immune System Diseases; Rituximab; Fludarabine; Cyclophosphamide; ISF35; Ad-ISF35; Refractory; Resistant; 17p-; del 17p; 17p; Resistant CLL; Refractory CLL; 17p- CLL; CLL

Outcome Measures

Primary Outcomes (1)

• Assess toxicity, tolerability, and safety of repeat administration of three infusions of 3x10^8 ISF35 given intravenously in combination with a standard course of three treatments of fludarabine, rituximab and cyclophosphamide (FCR).

  Duration of the Trial

Secondary Outcomes (2)

• Explore the anti-leukemia activity of the repeat administration of ISF35 and FCR by evaluating reduction in leukemia count, reduction in lymphadenopathy and splenomegaly, improvement in bone marrow function, and response duration.

  Duration of the Trial

• Assess induction of B and T cell anti-leukemia immune responses, antibody production against autologous CLL B cells, changes in bystander leukemia cell phenotype, and expression of genes and proteins related to apoptosis

  Duration of the Trial

Study Arms (1)

Experimental: ISF35 and FCR

EXPERIMENTAL

ISF35 and FCR

Biological: ISF35

Interventions

ISF35 BIOLOGICAL

Subjects participating in this study will receive a course of three infusions of 3x10\^8 ISF35-transduced cells at periods of not less than 14 days apart followed by a standard regimen of three cycles of fludarabine, cyclophosphamide and rituximab (FCR) at monthly intervals.

Also known as: Ad-ISF35, AdISF35

Experimental: ISF35 and FCR

Eligibility Criteria

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

You may qualify if:

• Subjects must have a diagnosis of B cell CLL including:
• Lymphocytosis of monoclonal B-cells co-expressing ≥ one B-cell marker (CD19, CD20, or CD23) and CD5 in peripheral blood or lymph node AND
• Bone marrow with ≥ 30% mononuclear cells having the CLL/SLL phenotype
• Measurable disease, and at least one of the IWCLL 2008 Guidelines "Indications for Treatment" as follows:
• Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia.
• Massive (i.e., \>6 cm below the left costal margin) or progressive or asymptomatic splenomegaly.
• Massive nodes (i.e., \>10 cm in longest diameter) or progressive or symptomatic lymphadenopathy.
• Progressive lymphocytosis with an increase of \>50% over a 2-month period, or lymphocyte doubling time (LDT) of less than 6 months. LDT can be obtained by linear regression extrapolation of absolute lymphocyte counts (ALC) obtained at intervals of two weeks over an observation period of 2-3 months; patients with initial blood lymphocyte counts of less than 30,000 per microliter may require a longer observation period to determine the LDT. Also, factors contributing to lymphocytosis or lymphadenopathy other than CLL (e.g, infections) should be excluded.
• Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroids or other standard therapy.
• A minimum of any one of the following disease-related symptoms must be present:
• Unintentional weight loss ≥10% within the previous 6 months.
• Significant fatigue (i.e., ECOG PS 2 or worse; cannot work or unable to perform usual activities).
• Fevers of greater than 100.5 degrees F or 38.0 degrees C for 2 or more weeks without other evidence of infection.
• Night sweats for more than 1 month without evidence of infection. Hypogammaglobulinemia or monoclonal or oligoclonal paraproteinemia does not by itself constitute a basis to initiate treatment.
• Subjects must have CLL that is documented to be resistant or refractory to standard chemotherapy regimens containing alkylating agents and/or purine analogues. Chemotherapy refractory or resistant is defined as the following:

You may not qualify if:

• Presence of \> 55% prolymphocytes or Richter's transformation
• Chemotherapy (e.g., purine analogues, alkylating agents, or corticosteroids), antibody therapy, immunotherapy, radiation therapy, or participation in any investigational drug treatment within 4 weeks of enrollment into protocol or at any time during the study
• Ongoing toxicity from prior anti-neoplastic therapy
• Untreated autoimmune hemolytic anemia or immune thrombocytopenia
• Active symptomatic fungal, bacterial and/or viral infection including active HIV or viral (A, B or C) hepatitis
• Positive serologies for HIV1,2 or HTLV I,II
• CMV disease with positive DNA PCR
• Syphilis with positive VDRL
• Acute Hepatitis A and C with positive serologies, and Hepatitis B, acutely or chronically infected based on CDC criteria
• Any illness or condition that in opinion of the investigator may affect safety of treatment or evaluation of any study's endpoints

Sponsors & Collaborators

• Memgen, LLC: lead
• The Leukemia and Lymphoma Society: collaborator
• University of California, San Diego: collaborator

Study Sites (1)

University of California, San Diego Moores Cancer Center

San Diego, California, 92093, United States

Location

Related Publications (25)

• 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. doi: 10.1200/JCO.2005.12.051. Epub 2005 Mar 14.

  PMID: 15767648 BACKGROUND

• Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner 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.

  PMID: 18216293 BACKGROUND

• Rai KR. Characteristics and Management of Chronic Lymphocytic Leukemia. Advances in Oncology. 1996;9 No.1:17-20.

  BACKGROUND

• Kalil N, Cheson BD. Chronic lymphocytic leukemia. Oncologist. 1999;4(5):352-69.

  PMID: 10551552 BACKGROUND

• Kay NE, Hamblin TJ, Jelinek DF, Dewald GW, Byrd JC, Farag S, Lucas M, Lin T. Chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2002:193-213. doi: 10.1182/asheducation-2002.1.193.

  PMID: 12446424 BACKGROUND

• Bosch F, Montserrat E. Refining prognostic factors in chronic lymphocytic leukemia. Rev Clin Exp Hematol. 2002 Dec;6(4):335-49; discussion 449-50. doi: 10.1046/j.1468-0734.2002.00302.x. No abstract available.

  PMID: 12823776 BACKGROUND

• Byrd JC, Waselenko JK, Keating M, Rai K, Grever MR. Novel therapies for chronic lymphocytic leukemia in the 21st century. Semin Oncol. 2000 Oct;27(5):587-97.

  PMID: 11049025 BACKGROUND

• Nabhan C, Gartenhaus RB, Tallman MS. Purine nucleoside analogues and combination therapies in B-cell chronic lymphocytic leukemia: dawn of a new era. Leuk Res. 2004 May;28(5):429-42. doi: 10.1016/j.leukres.2003.08.017.

  PMID: 15068894 BACKGROUND

• Nabhan C, Dyer MJ, Rosen ST. Current status of monoclonal antibody therapy for chronic lymphocytic leukemia. Oncology (Williston Park). 2003 Feb;17(2):253-62; discussion 264, 267, passim.

  PMID: 12632866 BACKGROUND

• Byrd JC, Stilgenbauer S, Flinn IW. Chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2004:163-83. doi: 10.1182/asheducation-2004.1.163.

  PMID: 15561682 BACKGROUND

• Rozman C, Montserrat E. Chronic lymphocytic leukemia. N Engl J Med. 1995 Oct 19;333(16):1052-7. doi: 10.1056/NEJM199510193331606. No abstract available.

  PMID: 7675049 BACKGROUND

• Ghia P, Caligaris-Cappio F. The origin of B-cell chronic lymphocytic leukemia. Semin Oncol. 2006 Apr;33(2):150-6. doi: 10.1053/j.seminoncol.2006.01.009.

  PMID: 16616061 BACKGROUND

• Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med. 2005 Feb 24;352(8):804-15. doi: 10.1056/NEJMra041720. No abstract available.

  PMID: 15728813 BACKGROUND

• Perz J, Topaly J, Fruehauf S, Hensel M, Ho AD. Level of CD 20-expression and efficacy of rituximab treatment in patients with resistant or relapsing B-cell prolymphocytic leukemia and B-cell chronic lymphocytic leukemia. Leuk Lymphoma. 2002 Jan;43(1):149-51. doi: 10.1080/10428190210178.

  PMID: 11908720 BACKGROUND

• Cheson BD, Bennett JM, Rai KR, Grever MR, Kay NE, Schiffer CA, Oken MM, Keating MJ, Boldt DH, Kempin SJ, et al. Guidelines for clinical protocols for chronic lymphocytic leukemia: recommendations of the National Cancer Institute-sponsored working group. Am J Hematol. 1988 Nov;29(3):152-63. doi: 10.1002/ajh.2830290307.

  PMID: 3189311 BACKGROUND

• Lin TS, Lucas MS, Byrd JC. Rituximab in B-cell chronic lymphocytic leukemia. Semin Oncol. 2003 Aug;30(4):483-92. doi: 10.1016/s0093-7754(03)00239-2.

  PMID: 12939717 BACKGROUND

• 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. doi: 10.1200/JCO.2001.19.8.2165.

  PMID: 11304768 BACKGROUND

• Byrd JC, Rai K, Peterson BL, Appelbaum FR, Morrison VA, Kolitz JE, Shepherd L, Hines JD, Schiffer CA, Larson RA. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood. 2005 Jan 1;105(1):49-53. doi: 10.1182/blood-2004-03-0796. Epub 2004 May 11.

  PMID: 15138165 BACKGROUND

• Wierda W, O'Brien S, Wen S, Faderl S, Garcia-Manero G, Thomas D, Do KA, Cortes J, Koller C, Beran M, Ferrajoli A, Giles F, Lerner S, Albitar M, Kantarjian H, Keating M. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol. 2005 Jun 20;23(18):4070-8. doi: 10.1200/JCO.2005.12.516. Epub 2005 Mar 14.

  PMID: 15767647 BACKGROUND

• Kipps TJ. Chronic lymphocytic leukemia and related diseases. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U, eds. Williams Hematology (ed 6). New York: McGraw-Hill, Inc.; 2001:1163-1194.

  BACKGROUND

• Wierda WG, Cantwell MJ, Woods SJ, Rassenti LZ, Prussak CE, Kipps TJ. CD40-ligand (CD154) gene therapy for chronic lymphocytic leukemia. Blood. 2000 Nov 1;96(9):2917-24.

  PMID: 11049967 BACKGROUND

• Dicker F, Kater AP, Fukuda T, Kipps TJ. Fas-ligand (CD178) and TRAIL synergistically induce apoptosis of CD40-activated chronic lymphocytic leukemia B cells. Blood. 2005 Apr 15;105(8):3193-8. doi: 10.1182/blood-2003-10-3684. Epub 2004 Aug 31.

  PMID: 15339846 BACKGROUND

• Chu P, Deforce D, Pedersen IM, Kim Y, Kitada S, Reed JC, Kipps TJ. Latent sensitivity to Fas-mediated apoptosis after CD40 ligation may explain activity of CD154 gene therapy in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3854-9. doi: 10.1073/pnas.022604399. Epub 2002 Mar 12.

  PMID: 11891278 BACKGROUND

• Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L, Dohner K, Bentz M, Lichter P. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 28;343(26):1910-6. doi: 10.1056/NEJM200012283432602.

  PMID: 11136261 BACKGROUND

• Cantwell MJ, Sharma S, Friedmann T, Kipps TJ. Adenovirus vector infection of chronic lymphocytic leukemia B cells. Blood. 1996 Dec 15;88(12):4676-83.

  PMID: 8977261 BACKGROUND

Related Links

• LLS, Memgen Collaborate on CLL Clinical Trial

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia; Leukemia, B-Cell; Immune System Diseases; Chromosome 17 deletion

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Januario Castro, MD

  Assistant Clinical Professor in the Blood and Marrow Transplantation Division

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: October 14, 2008
• First Posted: October 15, 2008
• Study Start: September 1, 2008
• Primary Completion: April 1, 2011
• Study Completion: April 1, 2013
• Last Updated: September 22, 2021

Record last verified: 2010-11

Locations

US (1)