A Study to Evaluate the Safety and Effectiveness of ILIxadencel Administered Into Tumors in Combination With Checkpoint Inhibitor (CPI) in Patients With ADvanced Cancer

Study Overview
=================
Brief Summary
-----------------
Patients in the Phase 1b part of the study will be treated with ilixadencel at an increasing dose and frequency, in combination with standard doses and schedules of checkpoint inhibitor (CPI) pembrolizumab. The Phase 1b study will determine the optimal dose and schedule of ilixadencel. Patients in the Phase 2 part of the study will be randomly assigned to receive either ilixadencel (at the dose determined in Phase 1b) combined with the CPI, or only the CPI. Note: Recruitment to Phase 1b of the study has been completed.

Detailed Description
-----------------
Despite improvements achieved with the use of CPIs, 50-80% of cancer patients do not respond to this therapy. There is growing evidence that combining CPIs with other forms of immunotherapy has the potential to improve the desired effects of both CPIs and immunotherapies. This study looks at the safety and effectiveness of the immunotherapy ilixadencel when used in combination with a CPI. A Dose-escalation Committee (DEC) will monitor the study for any significant safety issues during Phase 1b. Note: Recruitment to Phase 1b of the study has been completed. The study did not move forward to Phase 2.

Official Title
-----------------
A Randomized, Open-label, Multi-center, Phase 1b/2 Trial Evaluating the Safety and Efficacy of Intratumorally-administered Ilixadencel in Combination With Checkpoint Inhibitor (CPI) in Advanced Cancer Subjects Who Are Candidates for CPI Therapy

Conditions
-----------------
Gastric Adenocarcinoma, Carcinoma, Squamous Cell of Head and Neck, Gastroesophageal Junction Adenocarcinoma, Non-small Cell Lung Cancer

Intervention / Treatment
-----------------
* Biological: ilixadencel
* Drug: Pembrolizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Must provide written informed consent. Must have histologically confirmed and specific (Human Papilloma Virus) HPV-positive or HPV-negative squamous cell carcinoma of the head and neck (SCCHN), non-small-cell lung cancer (NSCLC) or gastric or gastroesophageal junction (GEJ) adenocarcinoma. Patients with other tumor types who are candidates for pembrolizumab therapy (according to the FDA-approved prescribing information at the time of inclusion) can also be enrolled in Phase 1b. Tumor histology and most recent pathology report must be in subject's medical record. Tumor samples and/or biopsies will not be collected as part of this study. Eligible for pembrolizumab treatment per country-specific label and per physician's decision. ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1. Adequate organ function. Women of childbearing potential must follow contraceptive requirements; must have a negative pregnancy blood test at screening, and a negative blood or urine pregnancy test within 24 hours before each dose of ilixadencel; and must not be breastfeeding. Male subjects must agree to use condoms from screening until 90 days after the last dose of ilixadencel, or must have a female partner using a highly effective method of contraception as described above. Exclusion Criteria: Prior history of invasive malignancy, unless complete remission has been achieved for at least 3 years and no additional therapy is required except for hormonal therapy or bisphosphonates. Active or previously untreated brain and/or leptomeningeal metastasis. Active autoimmune disease, pneumonitis or interstitial lung disease. Certain heart conditions including, but not limited to: Congestive heart failure; uncontrolled hypertension; unstable angina pectoris; pericarditis; myocarditis; mycardial infarction 6 months prior to study. Systemic immunosuppression except for replacement therapy. Life expectancy of less than 3 months. Any prior treatment with ilixadencel or prior treatment with anticancer agents (except pembrolizumab or other CPI for subjects in Phase 1b) within 4 weeks of starting study medication. Major surgery or significant traumatic injury within 4 weeks before study start. Known infection with human immunodeficiency virus (HIV). Active tuberculosis; active infection requiring anti-infective therapy (hepatitis with a negative viral load on maintenance will not be excluded). Other protocol-defined inclusion/exclusion criteria could apply.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Single arm phase 1b. Randomized phase 2.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b: Cohort 1, ilixadencel + pembrolizumab<br>3 x 10⁶ DCs (Dendritic Cells) of ilixadencel, 2x over 4 weeks (w). Pembrolizumab I.V. q3w | Biological: ilixadencel<br>* Intra-tumoral injection<br>Drug: Pembrolizumab<br>* Administered intravenously over 30 minutes, every 3 weeks, at a dose of 200 mg<br>|
| Experimental: Phase 1b: Cohort 2, ilixadencel + pembrolizumab<br>10 x 10⁶ DCs of ilixadencel, 2x over 4 weeks. Pembrolizumab I.V. q3w | Biological: ilixadencel<br>* Intra-tumoral injection<br>Drug: Pembrolizumab<br>* Administered intravenously over 30 minutes, every 3 weeks, at a dose of 200 mg<br>|
| Experimental: Phase 1b: Cohort 3, ilixadencel + pembrolizumab<br>10 x 10⁶ DCs of ilixadencel, 3x over 10 weeks. Pembrolizumab I.V. q3w | Biological: ilixadencel<br>* Intra-tumoral injection<br>Drug: Pembrolizumab<br>* Administered intravenously over 30 minutes, every 3 weeks, at a dose of 200 mg<br>|
| Experimental: Phase 1b: Cohort 4, ilixadencel + pembrolizumab<br>Ilixadencel 3 times over 10 weeks: 1st dose 20 x 10⁶ DCs ilixadencel; 2nd dose 10 x 10⁶ DCs; 3rd dose 10 x 10⁶ DCs. Pembrolizumab I.V. q3w | Biological: ilixadencel<br>* Intra-tumoral injection<br>Drug: Pembrolizumab<br>* Administered intravenously over 30 minutes, every 3 weeks, at a dose of 200 mg<br>|
| Experimental: Phase 2 exp. cohorts HNSCC/NSCLC/Gastric/GEJ<br>Subjects with HNSCC, NSCLC, gastric or gastroesophageal junction (GEJ) adenocarcinoma. ilixadencel administered intra-tumorally up to 3 times over 10 weeks; dose determined after Phase 1b. Pembrolizumab I.V. q3w according to currently approved doses and indications. | Biological: ilixadencel<br>* Intra-tumoral injection<br>Drug: Pembrolizumab<br>* Administered intravenously over 30 minutes, every 3 weeks, at a dose of 200 mg<br>|
| Active Comparator: Phase 2 comparator cohorts HNSCC/NSCLC/Gastric/GEJ<br>Subjects with HNSCC, NSCLC, gastric/GEJ adenocarcinoma receiving active treatment with pembrolizumab I.V. q3w according to currently approved doses and indications. | Drug: Pembrolizumab<br>* Administered intravenously over 30 minutes, every 3 weeks, at a dose of 200 mg<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of adverse events (AEs) (Phase 1b) | Number of adverse events | Up to Week 27 | 
| Severity of adverse events (AEs) (Phase 1b) | Grading per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | Up to Week 27 | 
| Number of Dose Limiting Toxicities (DLTs) (Phase 1b) | Dose Limiting Toxicities measured using CTCAE v5.0 and protocol DLT definition. | Up to Week 27 | 
| Number of subjects with clinically significant laboratory test abnormalities (Phase 1b) | Grading per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | Up to Week 27 | 
| Number of subjects with vital sign abnormalities (Phase 1b) | Vital signs grading per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | Up to Week 27 | 
| Antitumor Objective Response Rate (ORR) (Phase 2) | Antitumor activity of ilixadencel plus CPI (checkpoint inhibitor) in each tumor type, centrally assessed using RECIST (Response Evaluation Criteria in Solid Tumors) v1.1 | Up to Week 27 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antitumor Objective Response Rate (ORR) RECIST 1.1 (Phase 1b and Phase 2) | Antitumor activity of ilixadencel plus CPI (checkpoint inhibitor) in each tumor type, investigator and centrally assessed using RECIST (Response Evaluation Criteria in Solid Tumors) v1.1 | Up to Week 27 | 
| Antitumor Objective Response Rate (ORR) iRECIST (Phase 1b and Phase 2) | Antitumor activity of ilixadencel plus CPI (checkpoint inhibitor) in each tumor type, investigator assessed using iRECIST (Immune Response Evaluation Criteria in Solid Tumors) | Up to Week 27 | 
| Clinical Benefit Rate (Phase 1b and Phase 2) | Rate of complete and partial response and stable disease by investigator and centrally assessed RECIST (Response Evaluation Criteria in Solid Tumors) v1.1 | Up to Week 27 | 
| Duration of response (Phase 1b and Phase 2) | Measured in weeks. Assessed using RECIST v1.1 and iRECIST | Up to 24 months after Cycle 1 Day 1 | 
| Time to Progression (TTP) (Phase 1b and Phase 2) | Measured in weeks. Assessed using RECIST v1.1 and iRECIST | Up to 24 months after Cycle 1 Day 1 | 
| Progression-free Survival (PFS) (Phase 1b and Phase 2) | Measured in weeks. Centrally assessed using RECIST v1.1 | Up to 24 months after Cycle 1 Day 1 | 
| Overall Survival (OS) (Phase 1b and Phase 2) | Measured in months | Up to 5 years | 
| Frequency of adverse events (AEs) (Phase 2) | Number of adverse events | Up to Week 27 | 
| Severity of adverse events (AEs) (Phase 2) | Grading per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | Up to Week 27 | 
| Number of Dose Limiting Toxicities (DLTs) (Phase 2) | Dose Limiting Toxicities measured using CTCAE v5.0 and protocol DLT definition. | Up to week 27 | 
| Number of subjects with clinically significant laboratory test abnormalities (Phase 2) | Grading per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | Up to Week 27 | 
| Number of subjects with vital sign abnormalities (Phase 2) | Vital signs grading per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | Up to Week 27 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
immunotherapy, ilixadencel, checkpoint inhibitor, allogeneic, somatic cell therapy, dendritic cell, intratumoral, in situ