A Randomized Phase 2 Trial of Atezolizumab (MPDL3280A), SGI-110 and CDX-1401 Vaccine in Recurrent Ovarian Cancer
Overview
- Phase
- Phase 1
- Intervention
- Atezolizumab
- Conditions
- Platinum-Resistant Fallopian Tube Carcinoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 12
- Locations
- 17
- Primary Endpoint
- Incidence of adverse events (AE) (Phase I)
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
This randomized phase I/IIb trial studies side effects and best dose of atezolizumab when given together with guadecitabine and CDX-1401 vaccine and to see how well they work in treating patients with ovarian, fallopian tube, or primary peritoneal cancer that has come back. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. CDX-1401 vaccine may enhance the expression of the genes encoding tumor antigens on the surface of tumor cells and enhance the activity of tumor-killing T cells against those tumor cells. Vaccines made from monoclonal antibodies combined with tumor cells may help the body build an effective immune response to kill tumor cells. Giving atezolizumab, guadecitabine, and CDX-1401 vaccine may work better than CDX-1401 alone in treating patients with ovarian, fallopian tube, or primary peritoneal cancer.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the safety of fixed doses of atezolizumab (MPDL3280A) in combination with guadecitabine (SGI-110). (Phase I) II. To evaluate toxicity of the combination as defined by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. (Phase I) III. To study if SGI-110 improves the benefit of atezolizumab and then if the further addition of the DEC-205/NY-ESO-1 fusion protein CDX-1401 (CDX-1401)/poly ICLC adds further clinical benefit by analyzing progression free survival (PFS), using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. (Phase IIb) SECONDARY OBJECTIVES: I. To observe and record anti-tumor activity. (Phase I) II. To determine overall survival (OS), objective response rate (complete and partial responses), clinical benefit rate (response + stable disease), CA-125 reduction (percentage of patients with CA-125 reduction by \>= 50%), and duration of response. (Phase IIb) III. To assess the impact of the combination of atezolizumab, SGI-110, and CDX-1401 on anti-tumor immune responses. (Phase IIb) IV. To assess the impact of SGI-110 on NY-ESO-1 expression in tumor tissue. (Phase IIb) V. To assess toxicities associated with the combination cohorts (2 and 3), as there is little human experience with these combinations. (Phase IIb) EXPLORATORY/TRANSLATIONAL OBJECTIVES: I. To determine the effectiveness of SGI-110 on enhancing vaccine efficacy by assessing NY ESO 1 specific cellular and humoral immunity. Ia. Peripheral blood NY ESO 1 specific CD8+ and CD4+ T cells. Ib. Peripheral blood NY ESO 1 specific antibodies. Ic. Peripheral blood unrelated CTA specific antibodies (antigen spreading). Id. Peripheral blood frequency of CD4+CD25+FOXP3+ regulatory T cells. Ie. Examine potential differential effect of NY-ESO-1 expression on PFS. II. To assess the impact on PDL1 expression in tumor tissue. III. Evaluation of therapeutic efficacy on immune cell phenotype. IV. Deoxyribonucleic acid (DNA) methylation and DNA methylome: in pre- and on-treatment peripheral blood, serum (circulating DNA), and tumor biopsies. V. Pre-and on-treatment density and location of tumor infiltrating CD3+ and CD8+ T cells. VI. Evaluate the pre- and post-treatment mutational and neo-antigen load and therapeutic efficacy. VII. Pre- and post-treatment T cell receptor (TCR) repertoire to study the effect of TCR V beta diversity due to combination of PDL1 blockade, epigenetic modification, and vaccination on therapeutic efficacy. VIII. Gut microbiota at baseline and one on-treatment sample at C4D1 (cycle 4, day 1) or at progression, whichever is earlier to evaluate the role of microbiota on the therapeutic efficacy of the proposed combination therapy. OUTLINE: This is a phase I, dose-escalation study of guadecitabine followed by a phase IIb study. Patients are randomized to 1 of 3 cohorts. COHORT I: Patients receive atezolizumab intravenously (IV) over 30-60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. COHORT II: Patients receive guadecitabine subcutaneously (SC) on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive atezolizumab IV over 30-60 minutes on days 8 and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. COHORT III: Patients receive guadecitabine and atezolizumab as in Cohort II. Patients also receive CDX-1401 vaccine IV on day 15 and poly ICLC SC on days 15-16. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then every 2 months for up to 1 year.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Women with epithelial ovarian, fallopian tube, or primary peritoneal carcinoma with platinum-resistant disease (defined as having relapsed within 6 months of last platinum-containing regimen because we would like to include both primary and secondary resistance); patients are allowed to have had more than 2 prior cytotoxic treatment regimens; all patients should have received standard of care agents, which confer clinical benefit
- •Presence of biopsiable disease and patient able to undergo pre-treatment and on-treatment biopsy
- •Tissue available from primary and/or recurrent disease to evaluate tumor expression of NY-ESO-1 or PDL1 by immunohistochemistry (IHC) and/or reverse transcriptase-polymerase chain reaction (RT-PCR), and for measurement of DNA methylation
- •No requirement for tumor expression of NY-ESO-1
- •Life expectancy \> 6 months as assessed by study physician
- •Because no dosing or adverse event data are currently available on the use of atezolizumab in combination with SGI-110 and CDX-1401 in patients \< 18 years of age, children are excluded from this study, but may be eligible for future pediatric trials
- •Eastern Cooperative Oncology Group (ECOG) performance status =\< 2
- •Have been informed of other treatment options
- •Have measurable disease outside of biopsy site present per immune related (ir)RECIST criteria; (Rationale: Biopsy may also induce an inflammatory response and bias outcome measurements)
- •Patients may have received previous NY ESO 1 vaccine therapy; patients who received bevacizumab or other experimental therapies are eligible for enrollment provided they have discontinued therapy (at least 4 weeks) prior to randomization and recovered from toxicities to less than grade 2
Exclusion Criteria
- •Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation
- •Patients who have had chemotherapy or radiotherapy including complementary and alternative medicine treatments (CAMs) within 4 weeks prior to entering the study or those who have not recovered from adverse events (other than alopecia) due to agents administered more than 4 weeks earlier
- •Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents
- •Patients who have received prior treatment with anti-CTLA-4 may be enrolled, provided the following requirements are met:
- •Minimum of 12 weeks from the first dose of anti-CTLA-4 and \> 6 weeks from the last dose
- •No history of severe immune-related adverse effects from anti-CTLA-4 (NCI CTCAE grade 3 and 4)
- •Treatment with any other investigational agent within 4 weeks prior to cycle 1, day 1
- •Treatment with systemic immunostimulatory agents (including, but not limited to, interferon \[IFN\]-alpha or interleukin \[IL\]-2) within 6 weeks prior to cycle 1, day 1
- •Treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor \[anti-TNF\] agents) within 2 weeks prior to cycle 1, day 1
- •Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled
Arms & Interventions
Cohort I (atezolizumab)
Patients receive atezolizumab IV over 30-60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Atezolizumab
Cohort I (atezolizumab)
Patients receive atezolizumab IV over 30-60 minutes on days 1 and 15. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Cohort II (guadecitabine, atezolizumab)
Patients receive guadecitabine SC on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive atezolizumab IV over 30-60 minutes on days 8 and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Atezolizumab
Cohort II (guadecitabine, atezolizumab)
Patients receive guadecitabine SC on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive atezolizumab IV over 30-60 minutes on days 8 and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Guadecitabine
Cohort II (guadecitabine, atezolizumab)
Patients receive guadecitabine SC on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive atezolizumab IV over 30-60 minutes on days 8 and 22. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Cohort III (guadecitabine, atezolizumab, CDX-1401 vaccine)
Patients receive guadecitabine and atezolizumab as in Cohort II. Patients also receive CDX-1401 vaccine IV on day 15 and poly ICLC SC on days 15-16. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Atezolizumab
Cohort III (guadecitabine, atezolizumab, CDX-1401 vaccine)
Patients receive guadecitabine and atezolizumab as in Cohort II. Patients also receive CDX-1401 vaccine IV on day 15 and poly ICLC SC on days 15-16. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Intervention: DEC-205/NY-ESO-1 Fusion Protein CDX-1401
Cohort III (guadecitabine, atezolizumab, CDX-1401 vaccine)
Patients receive guadecitabine and atezolizumab as in Cohort II. Patients also receive CDX-1401 vaccine IV on day 15 and poly ICLC SC on days 15-16. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Guadecitabine
Cohort III (guadecitabine, atezolizumab, CDX-1401 vaccine)
Patients receive guadecitabine and atezolizumab as in Cohort II. Patients also receive CDX-1401 vaccine IV on day 15 and poly ICLC SC on days 15-16. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Cohort III (guadecitabine, atezolizumab, CDX-1401 vaccine)
Patients receive guadecitabine and atezolizumab as in Cohort II. Patients also receive CDX-1401 vaccine IV on day 15 and poly ICLC SC on days 15-16. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
Intervention: Poly ICLC
Outcomes
Primary Outcomes
Incidence of adverse events (AE) (Phase I)
Time Frame: Up to 30 days after last dose
Will be listed individually per patient according to Common Terminology Criteria for Adverse Events version 5.0, and the number of patients experiencing each AE will be summarized using descriptive statistics.
Progression free survival (PFS) (Phase IIb)
Time Frame: Up to 1 year
Assessed using standard imaging response (Response Evaluation Criteria in Solid Tumors \[RECIST\]) criteria. Will be carried forth using a Cox proportional hazards model with a factor for treatment with a stratification factor for disease subtype relative to the determining the form of the likelihood function. The global test statistic will combine from the one-sided tests using Fisher's method for combining p-values. Will also examine potential differential effect of NY-ESO-1 expression on PFS. The analysis of expression levels between the three groups will be carried out using analysis-of-variance methods on either the raw values or log transformed values.
Secondary Outcomes
- Anti-tumor activity (Phase I)(Up to 1 year)
- Overall survival (OS) (Phase IIb)(Up to 1 year)
- CA-125 reduction (Phase IIb)(Up to 1 year)
- Duration of response (Phase IIb)(Up to 1 year)
- Objective response rate (Phase IIb)(Up to 1 year)
- Clinical benefit rate (Phase IIb)(Up to 1 year)
- Anti-tumor immune responses (Phase IIb)(Up to 1 year)
- Epigenetic modification of immune gene signatures, NY-ESO-1, other CTAs, and PDL1 in the tumor microenvironment (Phase IIb)(Up to 1 year)
- Incidence of adverse events with the combination cohorts (2 and 3) (Phase IIb)(Up to 30 days after last dose)