DCVax-L Vaccination With CD3/CD28 Costimulated Autologous T-Cells for Recurrent Ovarian or Primary Peritoneal Cancer

A Phase-I/II Randomized Trial of Maintenance Vaccination Combined With Metronomic Cyclophosphamide w/wo Adoptive Transfer of CD3/CD28-CoStimulated T-Cells for Recurrent Ovarian or Primary Peritoneal Cancer Previously Vaccinated DCVax-L

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

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