Nivolumab, Ipilimumab and OTSGC-A24 Therapeutic Peptide Vaccine in Gastric Cancer - a Combination Immunotherapy Phase Ib Study.

Phase 1

• Conditions: Gastric Cancer
• Interventions: Drug: OTSGC-A24; Drug: Nivolumab; Drug: Ipilimumab

• Registration Number: NCT03784040
• Lead Sponsor: National University Hospital, Singapore

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).

Study Timeline

• Study First Submitted: 2018-12-20
• Study First Submitted QC: 2018-12-20
• Study First Posted: 2018-12-21
• Study Start: 2019-02-21
• Status Verified: 2019-04
• Last Update Submitted: 2019-04-05
• Last Update Posted: 2019-04-08
• Primary Completion: 2023-03-01
• Study Completion: 2024-03-01

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 40

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
(Arm A) OTSGC-A24 + nivolumab	OTSGC-A24	Study subjects will receive nivolumab 240 mg intravenously (IV) and OTSGC-A24 consisted of 1 μmol (\~1 mg) of OTSGC-A24-Fo, OTSGC-A24-De, OTSGC-A24-Ki, OTSGC-A24-VE1 and OTSGC-A24-Ur 1.0 μmol (as API) administered subcutaneously on Day 1 and D14 each 28 day cycle (q28d) for up to 24 months.
(Arm B) OTSGC-A24 + nivolumab + ipilimumab	OTSGC-A24	Study subjects will receive nivolumab 240 mg intravenously (IV) and OTSGC-A24 consisted of 1 μmol (\~1 mg) of OTSGC-A24-Fo, OTSGC-A24-De, OTSGC-A24-Ki, OTSGC-A24-VE1 and OTSGC-A24-Ur 1.0 μmol (as API) administered subcutaneously on Day 1 and D14. Ipilimumab 1mg/kg (IV) will be administered q6w (i.e. C1D1, C2D15, C3D1 ...) of each 28 day cycle for up to 24 months.
(Arm A) OTSGC-A24 + nivolumab	Nivolumab	Study subjects will receive nivolumab 240 mg intravenously (IV) and OTSGC-A24 consisted of 1 μmol (\~1 mg) of OTSGC-A24-Fo, OTSGC-A24-De, OTSGC-A24-Ki, OTSGC-A24-VE1 and OTSGC-A24-Ur 1.0 μmol (as API) administered subcutaneously on Day 1 and D14 each 28 day cycle (q28d) for up to 24 months.
(Arm B) OTSGC-A24 + nivolumab + ipilimumab	Ipilimumab	Study subjects will receive nivolumab 240 mg intravenously (IV) and OTSGC-A24 consisted of 1 μmol (\~1 mg) of OTSGC-A24-Fo, OTSGC-A24-De, OTSGC-A24-Ki, OTSGC-A24-VE1 and OTSGC-A24-Ur 1.0 μmol (as API) administered subcutaneously on Day 1 and D14. Ipilimumab 1mg/kg (IV) will be administered q6w (i.e. C1D1, C2D15, C3D1 ...) of each 28 day cycle for up to 24 months.
(Arm B) OTSGC-A24 + nivolumab + ipilimumab	Nivolumab	Study subjects will receive nivolumab 240 mg intravenously (IV) and OTSGC-A24 consisted of 1 μmol (\~1 mg) of OTSGC-A24-Fo, OTSGC-A24-De, OTSGC-A24-Ki, OTSGC-A24-VE1 and OTSGC-A24-Ur 1.0 μmol (as API) administered subcutaneously on Day 1 and D14. Ipilimumab 1mg/kg (IV) will be administered q6w (i.e. C1D1, C2D15, C3D1 ...) of each 28 day cycle for up to 24 months.

Primary Outcome Measures

Name	Time	Method
Adverse Event and Adverse Drug Reaction	3 years
Response Rate	3 years

Secondary Outcome Measures

Name	Time	Method
Rate of induction of specific CTL response	3 years
Progression-free Survival	3 years
Overall Survival	3 years

Trial Locations

Locations (1)

National University Hospital; 🇸🇬 Singapore, Singapore