Clinical trial NCT03784040: Nivolumab, Ipilimumab and OTSGC-A24 Therapeutic Peptide Vaccine in Gastric Cancer - a Combination Immunotherapy Phase Ib Study.
Official title: da VINci Study (OTSGC-A24 Therapeutic Peptide Vaccine + Ipilimumab + Nivolumab) Nivolumab, Ipilimumab and OTSGC-A24 Therapeutic Peptide Vaccine in Gastric Cancer - a Combination Immunotherapy Phase Ib Study.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Gastric Cancer
Keywords: Nivolumab
Ipilimumab
OTSGC-A24
Lead sponsor: National University Hospital, Singapore
Sponsor class: OTHER
Collaborators: name: OncoTherapy Science, Inc.
name: Bristol-Myers Squibb
First posted: 2018-12-21
Enrollment: 40
Sex: ALL
Minimum age (years): 21
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary hypothesis is that cancer vaccine can convert non-immunogenic gastric cancer into immunogenic phenotype susceptible to PD1 inhibition. This would lead to an improved radiological response rate and favorable immune contexture for immune checkpoint blockade

Detailed description: Primary Objectives

1. Safety cohorts: To evaluate the safety of OTSGC-A24 and nivolumab (+ ipilimumab) in patients with refractory gastric cancer.
2. Arm A: To determine the objective response rate of OTSGC-A24 and nivolumab in advanced gastric cancer.
3. Arm B: To determine the objective response rate of OTSGC-A24 and nivolumab + ipilimumab in advanced gastric cancer.

Secondary Objectives

1. To compare the difference in objective response rates between Arm A and Arm B
2. To compare the tumoral immune contexture and PDL-1 expression before treatment, after OTSGC-A24, and after nivolumab (+ ipilimumab) in combination with OTSGC-A24.
3. To determine the serum cytotoxic T-cell response using enzyme-linked immunospot assay (ELISPOT) in PBMC.
4. To determine the progression-free survival (PFS) and overall survival (OS) of Arm A and Arm B.
5. To evaluate the effect of OTSGC-A24 and nivolumab + ipilimumab on clinical and immune PD markers.
6. Evaluate the effects of treatment on peripheral T-cell phenotypic profiles with epitope-specificities by coupling mass cytometric analyses with highly-multiplexed peptide-MHC tetramer staining technology.
7. Identify potential biomarkers for treatment response and mechanisms of secondary resistance by studying gene expression profiles and phenotypic/functional markers of tumour and infiltrating immune cells.

End Points - Efficacy

The endpoints for efficacy are:

* Induction of specific CTL response after vaccination
* Response rate
* Progression-free survival
* Overall survival End Points - Safety

The endpoints for safety are:

• overall adverse events observed, treatment-related adverse events, and category (eg percentage of patients with any-grade treatment-related adverse events and grade 3-4 treatment-related adverse events).

Eligibility criteria: Inclusion Criteria:

1. Histologically or cytologically confirmed inoperable or metastatic gastric cancer that has failed or demonstrated intolerance to standard therapy - which includes platinum or fluoropyrimidine or taxane based chemotherapy.
2. Patients must have measurable disease.
3. Age ≥ 21 years
4. ECOG performance status (PS) of 0 to 1
5. Life expectancy at least 3 months
6. Patients must have normal organ and marrow function as defined below:

   * Absolute neutrophil count (ANC) ≥ 1,500/mcL
   * Platelets ≥ 100,000/mcL
   * Total bilirubin within normal institutional limits
   * AST(SGOT)/ALT(SGPT) ≤ 2.5 X institutional upper limit of normal
   * Creatinine \<1.5x normal institutional limits
7. Patients must be HLA-A\*24:02
8. Patients must have recovered (\< grade 1) from all reversible treatment toxicity from prior chemotherapy, radiotherapy or surgery.
9. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Patients receiving any other investigational products
2. Patients who have previously received prior nivolumab or PD-/L1 blockade therapy
3. Active autoimmune disease requiring disease-modifying therapy.
4. Concurrent systemic steroid therapy higher than physiologic dose (equivalent of prednisolone 10mg daily)
5. Any form of active primary or secondary immunodeficiency.
6. History of significant gastrointestinal bleeding that required intervention within the prior 1 month is ineligible; inherited bleeding diathesis or coagulopathy.
7. Serious non healing wound and peptic ulcer disease
8. Previous history of intestinal perforation
9. Symptomatic central nervous system (CNS) metastasis
10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, uncontrolled hypertension (systolic \>160 mmHg and/or diastolic \>100 mmHg), symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction/cerebrovascular event (≤ 6 months prior to study entry), cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, long term systemic immunosuppressant or corticosteroid, and active viral hepatitis.
11. Women who are breast-feeding or pregnant are excluded from this study.

Primary outcomes:
measure: Adverse Event and Adverse Drug Reaction
timeFrame: 3 years
measure: Response Rate
timeFrame: 3 years
Secondary outcomes:
measure: Rate of induction of specific CTL response
timeFrame: 3 years
measure: Progression-free Survival
timeFrame: 3 years
measure: Overall Survival
timeFrame: 3 years
Other outcomes:
Locations:
city: Singapore
country: Singapore
facility: National University Hospital
Study officials:
affiliation: National University Hospital, Singapore
name: Wei Peng Yong
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wagner AD, Grothe W, Haerting J, Kleber G, Grothey A, Fleig WE. Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data. J Clin Oncol. 2006 Jun 20;24(18):2903-9. doi: 10.1200/JCO.2005.05.0245.
citation: Ishikawa N, Takano A, Yasui W, Inai K, Nishimura H, Ito H, Miyagi Y, Nakayama H, Fujita M, Hosokawa M, Tsuchiya E, Kohno N, Nakamura Y, Daigo Y. Cancer-testis antigen lymphocyte antigen 6 complex locus K is a serologic biomarker and a therapeutic target for lung and esophageal carcinomas. Cancer Res. 2007 Dec 15;67(24):11601-11. doi: 10.1158/0008-5472.CAN-07-3243.
citation: Janunger KG, Hafstrom L, Nygren P, Glimelius B; SBU-group. Swedish Council of Technology Assessment in Health Care. A systematic overview of chemotherapy effects in gastric cancer. Acta Oncol. 2001;40(2-3):309-26. doi: 10.1080/02841860151116385.