dcvax-l vaccination with cd3/cd28 costimulated autologous t-cells for recurrent ovarian or primary peritoneal cancer

Conditions: Ovarian Cancer; Primary Peritoneal Cancer

Summary: subjects with recurrent epithelial ovarian carcinoma or primary peritoneal cancer, who have previously undergone vaccination in clinical study upcc-11807 with dcvax-l, an autologous vaccine with dc loaded in vitro with autologous tumor lysate. phase i subjects enrolled in this study will receive leukapheresis; followed by cyclophosphamide/fludarabine-induced lymphodepletion; followed by adoptive transfer of ex vivo cd3/cd28-costimulated vaccine-primed peripheral blood autologous t cells; followed by a single dcvax-l vaccination, to establish feasibility and safety of this approach. primary objectives of phase i to determine the feasibility and safety of administering vaccine-primed, ex vivo cd3/cd28-costimulated autologous peripheral blood t cells in combination with dcvax-l vaccination, following lymphodepletion with high dose cyclophosphamide/fludarabine. phase ii twenty-two additional subjects will be randomized to receive either: * arm-iia: maintenance dcvax-l vaccination, in combination with oral metronomic cyclophosphamide, or * arm-iib: leukapheresis, followed by cyclophosphamide/fludarabine-induced lymphodepletion, followed by adoptive transfer of ex vivo cd3/cd28-costimulated vaccine-primed peripheral blood autologous t cells, followed by maintenance dcvax-l vaccination, plus oral metronomic cyclophosphamide. primary objective of phase ii to assess the distribution of progression-free survival at 6 months for patients treated with maintenance dcvax-l vaccination plus oral metronomic cyclophosphamide as well as patients treated with ex vivo cd3/cd28-costimulated vaccine-primed peripheral blood autologous t cells after lymphodepletion with high dose cyclophosphamide / fludarabine, followed by dcvax-l boost vaccination and metronomic oral cyclophosphamide.

description of treatment for phase i: * patients will be offered, if medically indicated, tumor resection or needle aspiration of malignant effusion in order to make additional doses of dcvax-l vaccine. * if subjects have not received dcvax-l vaccination within the last 3-4 weeks, and if dcvax-l is available, subjects have the option of receiving one dose of dcvax-l after enrolment, to boost the frequency of vaccine-primed t cells. * subjects will receive a single course of outpatient lymphodepleting chemotherapy with intravenous cyclophosphamide (300 mg/m2/d for 3 days) and intravenous fludarabine (30 mg/m2/d for 3 days) both administered on days 8 to 10. * ex vivo cd3/cd28-costimulated lymphocytes will be infused \~2 days after last day of fludarabine infusion. * patients will receive dcvax-l vaccine \~24-48 hrs after t cell infusion. * subjects will be contacted every 6 months for 5 years for survival. description of treatment for phase ii: in arm-iia: * patients will be offered, if medically indicated, tumor resection or needle aspiration of malignant effusion in order to make additional doses of dcvax-l vaccine. * subjects will receive intradermal vaccinations with dcvax-l every 8 weeks, for four cycles total. the first vaccine will be administered on day 0, which can be no sooner than 4 weeks from previous dcvax-l vaccination related to clinical study upcc-11807. * subjects will receive oral cyclophosphamide at metronomic schedule and dose (50 mg daily) every other week, starting \~3 weeks after dcvax-l in every vaccine cycle. * patients will be offered (with the right to refuse) ct-guided needle biopsy or needle aspiration of malignant effusion after the second vaccine. in arm-iib: * patients will be offered, if medically indicated, tumor resection or needle aspiration of malignant effusion in order to make additional doses of dcvax-l vaccine. * subjects will undergo \~10-15 liter leukapheresis to derive vaccine-primed peripheral blood lymphocytes (pbl) on day 0. the apheresis material will be transferred to the cell and vaccine facility at the university of pennsylvania (penn cvpf) for t cell manufacturing. * if subjects have not received dcvax-l vaccination within the last 3-4 weeks, and if dcvax-l is available, subjects have the option of receiving one dose of dcvax-l after enrolment, to boost the frequency of vaccine-primed t cells. * subjects will receive a single course of outpatient lymphodepleting chemotherapy with intravenous cyclophosphamide (300 mg/m2/d for 3 days) and intravenous fludarabine (30 mg/m2/d for 3 days). * ex vivo cd3/cd28-costimulated lymphocytes will be infused \~2 days after last day of fludarabine infusion. * patients will receive dcvax-l vaccine boosts every 8 weeks for a total of four vaccines. the first dcvax-l will be given \~24-48 hrs after t cell infusion. * following dcvax-l, subjects will receive oral cyclophosphamide at metronomic schedule and dose (50 mg daily) every other week x 3 cycles, starting \~3 weeks after dcvax-l in every vaccine cycle. * patients will be offered (with the right to refuse) ct-guided needle biopsy or needle aspiration of malignant effusion \~1-2 weeks after the second vaccine

Eligibility criteria:
inclusion criteria: * previous participation in upcc 11807 (a phase i clinical trial of autologous dendritic cell vaccine loaded with autologous tumor cell lysate for recurrent ovarian or primary peritoneal cancer) * ps \< 2 * subject must have tumor lysate sufficient to prepare at least 4 dcvax-l vaccines * 18 years of age or older * life expectancy \> 4 months * signed informed consent * normal organ and bone marrow function defined by: * anc ≥ 1,000/μl * platelets \>100,000/μl * ast(sgot)/alt(sgpt) \< 2.5 x institutional upper limit of normal * bilirubin \<2.0 mg/dl unless secondary to bile duct blockage by tumor * creatinine \<1.5 x the upper limit of normal exclusion criteria: * subjects with the following: * known brain metastases * renal insufficiency * liver failure * organ allograft * known autoimmune/collagen vascular disorders * pregnant or breast feeding * non-healing wounds, ulcers, or bone fractures * positive for serum anti-yo (cdr2) antibodies * uncontrolled hypertension * myocardial infarction or unstable angina within 6 months prior to registration * new york heart association (nyha) grade ii or greater congestive heart failure

Keywords: ovarian cancer peritoneal cancer