Clinical trial NCT00779883: A Phase I Trial of Autologous CLL B Cells Transduced to Express Chimeric CD154 (ISF35)
Official title: A Phase I Trial of Autologous CLL B Cells Transduced to Express Chimeric CD154 (ISF35)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Chronic Lymphocytic Leukemia
Keywords: Chronic lymphocytic leukemia
CLL
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, B-Cell
Immune System Diseases
ISF35
Ad-ISF35
Immunotherapy
Immune therapy
Active immune therapy
Lead sponsor: Memgen, Inc.
Sponsor class: INDUSTRY
First posted: 2008-10-24
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The study is a Phase I, dose-escalating, non-randomized, single institution clinical trial assessing the safety and efficacy of autologous Ad-ISF35-transduced CLL B cells administered as a single intravenous infusion in patients with chronic lymphocytic leukemia (CLL).

Detailed description: Memgen's first TNF family derived product, ISF35, is a gene that encodes a recombinant protein molecule that binds and activates human CD40+ B lymphocytes that are found on a vast majority of malignant leukemias and lymphomas.

In this clinical trial, ISF35 will be introduced into the patients' CLL cells ex vivo using a replication-defective adenovirus Ad5 encoding the ISF35 cDNA transgene. After this ex vivo manipulation, the modified leukemia cells will be extensively washed and the amount of remaining free virus is measured before the cells are reinfused into the patient. Following ex vivo transduction, the CLL cells expressing ISF35 activate a therapeutic immune response directed against the target leukemia cells.

This ascending-dose trial will be divided into three dosing cohorts to determine the existence of a maximum tolerated dose.

Patients will be followed for 12 months after ISF35 administration or until initiation of another treatment.

Eligibility criteria: Inclusion Criteria:

1. Subjects must have a diagnosis of B cell CLL, measurable disease, and an

   NCI-WG indication for treatment with one of the following:
   * Massive (\>6 cm below left costal margin) or progressive splenomegaly;
   * Massive (\>10 cm longest diameter) lymph nodes, nodal clusters, or progressive lymphadenopathy;
   * Progressive anemia;
   * Progressive thrombocytopenia;
   * Weight loss \> 10% body weight over the preceding 6 month period;
   * Fatigue attributable to CLL;
   * Fever or night sweats without evidence of infection;
   * Progressive lymphocytosis.
2. Subjects must be age 18 years or older.
3. Women of childbearing potential (not postmenopausal for at least one year or not surgically incapable of bearing children) must agree not to become pregnant for the duration of the study. Both men and women participants must agree to use contraception for the duration of the study.
4. Subjects must have Zubrod performance status of ≤ 2 (Appendix B).
5. Subjects must have adequate hematologic, renal, hepatic, and coagulation function:

   * Adequate hematologic function:

     * Platelet count ≥ 50,000/μl; AND
     * Hemoglobin ≥ 10 g/dl (may be supported by erythropoietin or transfusion).
   * Adequate renal function:

     * Serum creatinine ≤ 1.5 times upper limit of normal; OR
     * Measured creatinine clearance ≥ 40 mL/min/1.73 m\^2.
   * Adequate hepatic function:

     * Total bilirubin ≤ 2.5 times upper limit of normal; AND
     * ALT ≤ 2.5 times upper limit of normal; AND
   * Adequate coagulation tests:

     * Prothrombin time international normalized ratio (INR) ≤ 2; AND
     * Partial thromboplastin time ≤ 1.66 times upper limit of normal
6. Subjects must be able to give written informed consent.

Exclusion Criteria:

1. Presence of more than 55% prolymphocytes.
2. 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.
3. Ongoing toxicity from prior anti-neoplastic therapy.
4. Prior gene therapy or allogeneic stem cell transplantation.
5. Untreated autoimmune hemolytic anemia or immune thrombocytopenia.
6. Active infection requiring parenteral antibiotics.
7. Known HIV/HBV/HCV seropositivity.
8. Uncompensated hypothyroidism (defined as TSH greater than 4x upper limit of normal not treated with replacement hormone).

Primary outcomes:
measure: Assess the toxicity, tolerability, and safety of 1x10^8, 3x10^8, and 1x10^9 autologous Ad-ISF35-transduced CLL B cells given as a single intravenous infusion in patients with CLL.
timeFrame: Duration of the trial
Secondary outcomes:
measure: Assess the anti-leukemia activity of a single intravenous dose by evaluating reduction in leukemia count, reduction in adenopathy and splenomegaly, and improvement in bone function.
timeFrame: Duration of the trial
measure: Assess the quality of life with ISF35 treatment.
timeFrame: Two months
measure: Assess pharmacodynamic endpoints including induction of T cell anti-leukemia immune responses, antibody production against autologous CLL B cells, and changes in bystander leukemia cell phenotype.
timeFrame: Two months
Other outcomes:
Locations:
city: Houston
country: United States
facility: University of Texas M.D. Anderson Cancer Center
state: Texas
Study officials:
affiliation: M.D. Anderson Cancer Center
name: William G. Wierda, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Aguilar-Santelises M, Rottenberg ME, Lewin N, Mellstedt H, Jondal M. Bcl-2, Bax and p53 expression in B-CLL in relation to in vitro survival and clinical progression. Int J Cancer. 1996 Apr 22;69(2):114-9. doi: 10.1002/(SICI)1097-0215(19960422)69:23.0.CO;2-3.
citation: Armitage RJ, Fanslow WC, Strockbine L, Sato TA, Clifford KN, Macduff BM, Anderson DM, Gimpel SD, Davis-Smith T, Maliszewski CR, et al. Molecular and biological characterization of a murine ligand for CD40. Nature. 1992 May 7;357(6373):80-2. doi: 10.1038/357080a0.
citation: Bacik J, Mazumdar M, Murphy BA, Fairclough DL, Eremenco S, Mariani T, Motzer RJ, Cella D. The functional assessment of cancer therapy-BRM (FACT-BRM): a new tool for the assessment of quality of life in patients treated with biologic response modifiers. Qual Life Res. 2004 Feb;13(1):137-54. doi: 10.1023/B:QURE.0000015297.91158.01.
citation: Banchereau J, Bazan F, Blanchard D, Briere F, Galizzi JP, van Kooten C, Liu YJ, Rousset F, Saeland S. The CD40 antigen and its ligand. Annu Rev Immunol. 1994;12:881-922. doi: 10.1146/annurev.iy.12.040194.004313.
citation: Bosch F, Ferrer A, Lopez-Guillermo A, Gine E, Bellosillo B, Villamor N, Colomer D, Cobo F, Perales M, Esteve J, Altes 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. doi: 10.1046/j.1365-2141.2002.03959.x.
citation: Caligaris-Cappio F. B-chronic lymphocytic leukemia: a malignancy of anti-self B cells. Blood. 1996 Apr 1;87(7):2615-20. No abstract available.
citation: 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.
citation: Cantwell M, Hua T, Pappas J, Kipps TJ. Acquired CD40-ligand deficiency in chronic lymphocytic leukemia. Nat Med. 1997 Sep;3(9):984-9. doi: 10.1038/nm0997-984.
citation: Castle BE, Kishimoto K, Stearns C, Brown ML, Kehry MR. Regulation of expression of the ligand for CD40 on T helper lymphocytes. J Immunol. 1993 Aug 15;151(4):1777-88.
citation: Castro JE, Cantwell MJ, Prusak CE, Bole J, Wierda WG, Kipps TJ. long-term followup of chronic lymphocytic leukemia patients treated with CD40-ligand (CD154) gene therapy. Blood 2003; 102(11):491a (Abstract #1790).
citation: Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, Rai KR. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood. 1996 Jun 15;87(12):4990-7. No abstract available.
citation: 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.
citation: Clark EA, Ledbetter JA. How B and T cells talk to each other. Nature. 1994 Feb 3;367(6462):425-8. doi: 10.1038/367425a0.
citation: Clavio M, Miglino M, Spriano M, Pietrasanta D, Vallebella E, Celesti L, Canepa L, Pierri I, Cavaliere M, Ballerini F, Beltrami G, Rossi E, Vimercati R, Bruni R, Congiu M, Nati S, Damasio E, Santini G, Gobbi M. First line Fludarabine treatment of symptomatic chronic lymphoproliferative diseases: clinical results and molecular analysis of minimal residual disease. Eur J Haematol. 1998 Sep;61(3):197-203. doi: 10.1111/j.1600-0609.1998.tb01084.x.
citation: 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.
citation: Durie FH, Foy TM, Masters SR, Laman JD, Noelle RJ. The role of CD40 in the regulation of humoral and cell-mediated immunity. Immunol Today. 1994 Sep;15(9):406-11. doi: 10.1016/0167-5699(94)90269-0.
citation: Finn WG, Thangavelu M, Yelavarthi KK, Goolsby CL, Tallman MS, Traynor A, Peterson LC. Karyotype correlates with peripheral blood morphology and immunophenotype in chronic lymphocytic leukemia. Am J Clin Pathol. 1996 Apr;105(4):458-67. doi: 10.1093/ajcp/105.4.458.
citation: Forstpointner R, Dreyling M, Repp R, Hermann S, Hanel A, Metzner B, Pott C, Hartmann F, Rothmann F, Rohrberg R, Bock HP, Wandt H, Unterhalt M, Hiddemann W; German Low-Grade Lymphoma Study Group. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004 Nov 15;104(10):3064-71. doi: 10.1182/blood-2004-04-1323. Epub 2004 Jul 29.
citation: Fox JP, Brandt CD, Wassermann FE, Hall CE, Spigland I, Kogon A, Elveback LR. The virus watch program: a continuing surveillance of viral infections in metropolitan New York families. VI. Observations of adenovirus infections: virus excretion patterns, antibody response, efficiency of surveillance, patterns of infections, and relation to illness. Am J Epidemiol. 1969 Jan;89(1):25-50. doi: 10.1093/oxfordjournals.aje.a120913. No abstract available.
citation: Han T, Ezdinli EZ, Shimaoka K, Desai DV. Chlorambucil vs. combined chlorambucil-corticosteroid therapy in chronic lymphocytic leukemia. Cancer. 1973 Mar;31(3):502-8. doi: 10.1002/1097-0142(197303)31:33.0.co;2-7. No abstract available.
citation: Hallek M, Schmitt B, Wilhelm M, Busch R, Krober A, Fostitsch HP, Sezer O, Herold M, Knauf W, Wendtner CM, Kuse R, Freund M, Franke A, Schriever F, Nerl C, Dohner H, Thiel E, Hiddemann W, Brittinger G, Emmerich B; German Chronic Lymphocytic Leukaemia Study Group. Fludarabine plus cyclophosphamide is an efficient treatment for advanced chronic lymphocytic leukaemia (CLL): results of a phase II study of the German CLL Study Group. Br J Haematol. 2001 Aug;114(2):342-8. doi: 10.1046/j.1365-2141.2001.02959.x.
citation: Hendry L, Bowen A, Matutes E, Swansbury J, Catovsky D. Fludarabine, cyclophosphamide and mitoxantrone in relapsed or refractory chronic lymphocytic leukemia and low grade non-Hodgkin's lymphoma. Leuk Lymphoma. 2004 May;45(5):945-50. doi: 10.1080/10428190310001639489.
citation: Hermann P, Blanchard D, de Saint-Vis B, Fossiez F, Gaillard C, Vanbervliet B, Briere F, Banchereau J, Galizzi JP. Expression of a 32-kDa ligand for the CD40 antigen on activated human T lymphocytes. Eur J Immunol. 1993 Apr;23(4):961-4. doi: 10.1002/eji.1830230430.
citation: Holzner B, Kemmler G, Kopp M, Nguyen-Van-Tam D, Sperner-Unterweger B, Greil R. Quality of life of patients with chronic lymphocytic leukemia: results of a longitudinal investigation over 1 yr. Eur J Haematol. 2004 Jun;72(6):381-9. doi: 10.1111/j.1600-0609.2004.00233.x.
citation: Kato K, Santana-Sahagun E, Rassenti LZ, Weisman MH, Tamura N, Kobayashi S, Hashimoto H, Kipps TJ. The soluble CD40 ligand sCD154 in systemic lupus erythematosus. J Clin Invest. 1999 Oct;104(7):947-55. doi: 10.1172/JCI7014.
citation: Keating MJ, Kantarjian H, Talpaz M, Redman J, McCredie KB. Fludarabine therapy in chronic lymphocytic leukemia (CLL). Nouv Rev Fr Hematol (1978). 1988;30(5-6):461-6.
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. doi: 10.1200/JCO.1991.9.1.44.
citation: Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J, Albitar M, Brettman L, Santabarbara P, Wacker B, Rai KR. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood. 2002 May 15;99(10):3554-61. doi: 10.1182/blood.v99.10.3554.
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. doi: 10.1200/JCO.2005.12.051. Epub 2005 Mar 14.
citation: Koduru PR, Lichtman SM, Smilari TF, Sun T, Goh JC, Karp L, Hall W, Hashimoto S, Chiorazzi N, Broome JD. Serial phenotypic, cytogenetic and molecular genetic studies in Richter's syndrome: demonstration of lymphoma development from the chronic lymphocytic leukaemia cells. Br J Haematol. 1993 Nov;85(3):613-6. doi: 10.1111/j.1365-2141.1993.tb03357.x.
citation: Leporrier M, Chevret S, Cazin B, Boudjerra N, Feugier P, Desablens B, Rapp MJ, Jaubert J, Autrand C, Divine M, Dreyfus B, Maloum K, Travade P, Dighiero G, Binet JL, Chastang C; French Cooperative Group on Chronic Lymphocytic Leukemia. Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood. 2001 Oct 15;98(8):2319-25. doi: 10.1182/blood.v98.8.2319.
citation: Montserrat E, Lopez-Lorenzo JL, Manso F, Martin A, Prieto E, Arias-Sampedro J, Fernandez MN, Oyarzabal FJ, Odriozola J, Alcala A, Garcia-Conde J, Guardia R, Bosch F. Fludarabine in resistant or relapsing B-cell chronic lymphocytic leukemia: the Spanish Group experience. Leuk Lymphoma. 1996 May;21(5-6):467-72. doi: 10.3109/10428199609093445.
citation: Montgomery C, Pocock M, Titley K, Lloyd K. Individual quality of life in patients with leukaemia and lymphoma. Psychooncology. 2002 May-Jun;11(3):239-43. doi: 10.1002/pon.557.
citation: Noelle RJ, Roy M, Shepherd DM, Stamenkovic I, Ledbetter JA, Aruffo A. A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6550-4. doi: 10.1073/pnas.89.14.6550.
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.
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. doi: 10.1200/JCO.2001.19.5.1414.
citation: Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics, 1996. CA Cancer J Clin. 1996 Jan-Feb;46(1):5-27. doi: 10.3322/canjclin.46.1.5.
citation: 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. doi: 10.1056/NEJM200012143432402.
citation: Ranheim EA, Kipps TJ. Activated T cells induce expression of B7/BB1 on normal or leukemic B cells through a CD40-dependent signal. J Exp Med. 1993 Apr 1;177(4):925-35. doi: 10.1084/jem.177.4.925.
citation: Ranheim EA, Cantwell MJ, Kipps TJ. Expression of CD27 and its ligand, CD70, on chronic lymphocytic leukemia B cells. Blood. 1995 Jun 15;85(12):3556-65.
citation: Ranheim EA, Kipps TJ. Tumor necrosis factor-alpha facilitates induction of CD80 (B7-1) and CD54 on human B cells by activated T cells: complex regulation by IL-4, IL-10, and CD40L. Cell Immunol. 1995 Apr 1;161(2):226-35. doi: 10.1006/cimm.1995.1031.
citation: ROWE WP, HUEBNER RJ, GILMORE LK, PARROTT RH, WARD TG. Isolation of a cytopathogenic agent from human adenoids undergoing spontaneous degeneration in tissue culture. Proc Soc Exp Biol Med. 1953 Dec;84(3):570-3. doi: 10.3181/00379727-84-20714. No abstract available.
citation: Roy M, Waldschmidt T, Aruffo A, Ledbetter JA, Noelle RJ. The regulation of the expression of gp39, the CD40 ligand, on normal and cloned CD4+ T cells. J Immunol. 1993 Sep 1;151(5):2497-510.
citation: Saville W, Kipps TJ, Cantwell MJ, et al. A phase II trial of immune therapy for chronic lymphocytic leukemia. Blood. 2003; 102(11 ):437a (Abstract #1592).
citation: Sawitsky A, Rai KR, Glidewell O, Silver RT. Comparison of daily versus intermittent chlorambucil and prednisone therapy in the treatment of patients with chronic lymphocytic leukemia. Blood. 1977 Dec;50(6):1049-59.
citation: Shanafelt TD, Call TG. Current approach to diagnosis and management of chronic lymphocytic leukemia. Mayo Clin Proc. 2004 Mar;79(3):388-98. doi: 10.4065/79.3.388.
citation: Tamura N, Kobayashi S, Kato K, Bando H, Haruta K, Oyanagi M, Kuriyama M, Kipps TJ, Hashimoto H. Soluble CD154 in rheumatoid arthritis: elevated plasma levels in cases with vasculitis. J Rheumatol. 2001 Dec;28(12):2583-90.
citation: Thall PF, Simon R. A Bayesian approach to establishing sample size and monitoring criteria for phase II clinical trials. Control Clin Trials. 1994 Dec;15(6):463-81. doi: 10.1016/0197-2456(94)90004-3.
citation: 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.
citation: 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.
citation: Yang Y, Wilson JM. CD40 ligand-dependent T cell activation: requirement of B7-CD28 signaling through CD40. Science. 1996 Sep 27;273(5283):1862-4. doi: 10.1126/science.273.5283.1862.
citation: Yeh P, Perricaudet M. Advances in adenoviral vectors: from genetic engineering to their biology. FASEB J. 1997 Jul;11(8):615-23. doi: 10.1096/fasebj.11.8.9240963.
citation: Wierda WG, Castro JE, Aguillon R, Sampath D, Jalayer A, McMannis J, Prussak CE, Keating M, Kipps TJ. A phase I study of immune gene therapy for patients with CLL using a membrane-stable, humanized CD154. Leukemia. 2010 Nov;24(11):1893-900. doi: 10.1038/leu.2010.191. Epub 2010 Sep 30.