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

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.

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

Study Overview

• Status: Recruiting
• Conditions: Gastric Cancer
• Intervention / Treatment: Drug: OTSGC-A24; Drug: Nivolumab; Drug: Ipilimumab

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 Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Wei Peng Yong; Phone Number: (65) 6779 5555; Email: Wei_Peng_Yong@nuhs.edu.sg

Study Locations

• Singapore
  • Singapore, Singapore, 119074
    • Recruiting
    • National University Hospital
    • Contact: Wei Peng Yong; Phone Number: (65) 6779 5555; Email: Wei_Peng_Yong@nuhs.edu.sg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years to 95 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: (Arm A) OTSGC-A24 + 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.	Drug: OTSGC-A24; OTSGC-A24 is administered as a subcutaneous (under the skin) injection. Nivolumab and ipilimumab are administered by intravenous (IV) infusion, meaning the drug is given through a catheter in a vein. A pump will be used to ensure the correct amount of medicine is given through the catheter. The nivolumab and ipilimumab infusions each take about 30 minutes. There will be a break of about 30 minutes in between the nivolumab and ipilimumab infusions (if given on the same day). OTSGC-A24 and nivolumab are administered every 2 weeks, while ipilimumab is administered every 6 weeks.; Drug: Nivolumab; OTSGC-A24 is administered as a subcutaneous (under the skin) injection. Nivolumab and ipilimumab are administered by intravenous (IV) infusion, meaning the drug is given through a catheter in a vein. A pump will be used to ensure the correct amount of medicine is given through the catheter. The nivolumab and ipilimumab infusions each take about 30 minutes. There will be a break of about 30 minutes in between the nivolumab and ipilimumab infusions (if given on the same day). OTSGC-A24 and nivolumab are administered every 2 weeks, while ipilimumab is administered every 6 weeks.
Experimental: (Arm B) OTSGC-A24 + nivolumab + 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.	Drug: OTSGC-A24; OTSGC-A24 is administered as a subcutaneous (under the skin) injection. Nivolumab and ipilimumab are administered by intravenous (IV) infusion, meaning the drug is given through a catheter in a vein. A pump will be used to ensure the correct amount of medicine is given through the catheter. The nivolumab and ipilimumab infusions each take about 30 minutes. There will be a break of about 30 minutes in between the nivolumab and ipilimumab infusions (if given on the same day). OTSGC-A24 and nivolumab are administered every 2 weeks, while ipilimumab is administered every 6 weeks.; Drug: Nivolumab; OTSGC-A24 is administered as a subcutaneous (under the skin) injection. Nivolumab and ipilimumab are administered by intravenous (IV) infusion, meaning the drug is given through a catheter in a vein. A pump will be used to ensure the correct amount of medicine is given through the catheter. The nivolumab and ipilimumab infusions each take about 30 minutes. There will be a break of about 30 minutes in between the nivolumab and ipilimumab infusions (if given on the same day). OTSGC-A24 and nivolumab are administered every 2 weeks, while ipilimumab is administered every 6 weeks.; Drug: Ipilimumab; OTSGC-A24 is administered as a subcutaneous (under the skin) injection. Nivolumab and ipilimumab are administered by intravenous (IV) infusion, meaning the drug is given through a catheter in a vein. A pump will be used to ensure the correct amount of medicine is given through the catheter. The nivolumab and ipilimumab infusions each take about 30 minutes. There will be a break of about 30 minutes in between the nivolumab and ipilimumab infusions (if given on the same day). OTSGC-A24 and nivolumab are administered every 2 weeks, while ipilimumab is administered every 6 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Response Rate	3 years
Adverse Event and Adverse Drug Reaction	3 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall Survival	3 years
Rate of induction of specific CTL response	3 years
Progression-free Survival	3 years

Collaborators and Investigators

• Sponsor: National University Hospital, Singapore
• Collaborators: Bristol-Myers Squibb; OncoTherapy Science, Inc.

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 21, 2019
• Primary Completion (Anticipated): March 1, 2023
• Study Completion (Anticipated): March 1, 2024

Study Registration Dates

• First Submitted: December 20, 2018
• First Submitted That Met QC Criteria: December 20, 2018
• First Posted (Actual): December 21, 2018

Study Record Updates

• Last Update Posted (Actual): April 8, 2019
• Last Update Submitted That Met QC Criteria: April 5, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: Nivolumab; Ipilimumab; OTSGC-A24
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Stomach Diseases; Stomach Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab; Ipilimumab
• Other Study ID Numbers: GA01/03/18; 2018/00422 (Other Identifier: NHG Domain Specifics Research Board)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No