A Study of IMU-131 (HER-Vaxx) in Combination With Chemotherapy or Pembrolizumab in Patients With Metastatic HER2/Neu Over-Expressing Gastric Cancer (nextHERIZON)

Study Overview
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Brief Summary
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This is a Phase 2, signal generating, open-label, 2-Arm, non-randomized study, in patients with metastatic HER2/neu over-expressing gastric cancer or gastroesophageal adenocarcinomas.

Detailed Description
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It is hypothesized that the introduction of HER-Vaxx after 1L treatment in patients that have progressed under trastuzumab may overcome potential resistance against trastuzumab in combination with chemotherapy and can be continued after chemotherapy is terminated. Based on pre-clinical data HER-Vaxx may also synergize with pembrolizumab and therefore serve as a potentially better tolerated and chemotherapy-free treatment opportunity in metastatic patients that progressed under their previous therapy. The study is designed to generate safety data and efficacy signals to support further development of HER-Vaxx in ≥2L mGC/GEJ cancer after progression with trastuzumab. The study includes two treatment arms that will be analyzed independently using a 2-Stage design: Arm 1: HER-Vaxx in combination with chemotherapy (ramucirumab plus paclitaxel) Arm 2: HER-Vaxx in combination with pembrolizumab. All patients must have received trastuzumab and progressed after 1L to be eligible for enrolment. Patients who have received an immune checkpoint inhibitor (ICI) previously will exclusively be enrolled in Arm 1 (HER-Vaxx + chemotherapy). Patients who are naïve to ICI treatment will exclusively be enrolled into Arm 2 (HER-Vaxx + pembrolizumab).

Official Title
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nextHERIZON: An Open-Label, Signal Generating, Phase 2 Study of HER-Vaxx in Combination With Chemotherapy or Pembrolizumab in Patients With Metastatic HER2/Neu Over-Expressing Gastric or Gastroesophageal Junction (GEJ) Adenocarcinomas Who Have Previously Received Trastuzumab and Progressed on This Treatment

Conditions
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Gastric Cancer, Cancer of Stomach, Gastric Adenocarcinoma, Stomach Cancer, Stomach Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma

Intervention / Treatment
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* Biological: IMU-131
* Drug: Ramucirumab plus Paclitaxel
* Biological: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years with confirmed diagnosis of advanced or metastatic HER2/neu overexpressing gastric or GEJ adenocarcinoma; Progressed on or after trastuzumab therapy; Eastern Cooperative Oncology Group (ECOG) performance status 0-1; Life expectancy of a minimum of 3 months; At least one measurable lesion as defined by RECIST 1.1 criteria and assessed by the local investigator; HER2/neu overexpression assessed using post-progression fresh or archival tissue, or post-progression pathology report; Adequate left ventricular ejection function at baseline, defined as left ventricular ejection fraction (LVEF) > 50% by echocardiogram or Multi Gated Acquisition (MUGA) scan; Adequate hematologic, liver and renal function; A female patient of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 120 days after the last dose of assigned treatment. Exclusion Criteria: Previous malignant disease (other than primary malignancy) within the last 5 years, except basal or squamous cell carcinoma of the skin or cervical carcinoma in situ; Concurrent active malignancy except for adequately controlled limited basal cell carcinoma of the skin; Systemic chemotherapy or major surgery within 28 days before starting study treatment and recovered from all adverse events ≤ Grade 1 or baseline with possible exceptions for neuropathy and endocrine-related AEs; Received prior radiotherapy within 2 weeks of start of study treatment and recovered from all radiation-related toxicities and not require corticosteroids; or history of radiation pneumonitis. Previous treatment with trastuzumab-deruxtecan or any other anti-HER2 therapy (except trastuzumab); Clinically significant cardiovascular disease, or other diseases that in the Investigator's opinion may influence the patient's tolerance to study treatment; Pleural effusion or ascites requiring more than weekly drainage; Prior organ transplantation, including allogenic stem-cell transplantation; Chronic immunosuppressive therapy within 7 days prior the first dose of study drug; Active, known, or suspected autoimmune disease; History of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease; Positivity for human immunodeficiency virus (HIV) (HIV 1/2 antibodies) or active hepatitis B (HBsAg reactive) or active hepatitis C (HCV ribonucleic acid [RNA] qualitative) infection; Current participation or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment; Any vaccination within 30 days prior to starting study treatment; Pregnant or lactating females; Arm 2 only: Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent; Arm 2 only: Has received prior therapy with an ICI or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) and was discontinued from treatment due to a grade 3 or higher adverse event.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: HER-Vaxx in combination with chemotherapy (ramucirumab plus paclitaxel)<br>Patients who have received an immune checkpoint inhibitor (ICI) previously will exclusively be enrolled in Arm 1 treated with HER-Vaxx (IM) in combination with chemotherapy (ramucirumab plus paclitaxel) | Biological: IMU-131<br>* IMU-131 will be administered intramuscularly into the deltoid region of the arm on Day 1, 15, 29 and 57 and then every 63 days until disease progression or treatment discontinuation.<br>* Other names: HER-Vaxx;Drug: Ramucirumab plus Paclitaxel<br>* Chemotherapy to be administered every 3 weeks (Q3W) starting on Day 1.<br>* Other names: Standard of Care Chemotherapy;|
| Experimental: Arm 2: HER-Vaxx in combination with pembrolizumab<br>Arm 2 will investigate the combination of HER-Vaxx plus pembrolizumab in patients who are naïve to ICI treatment including patients who have had chemotherapy only treatment after progression on trastuzumab. As the combination treatment has not been investigated, Arm 2 is planned to initiate with a safety run-in phase. | Biological: IMU-131<br>* IMU-131 will be administered intramuscularly into the deltoid region of the arm on Day 1, 15, 29 and 57 and then every 63 days until disease progression or treatment discontinuation.<br>* Other names: HER-Vaxx;Biological: Pembrolizumab<br>* Pembrolizumab will be administered every 3 weeks (Q3W) starting on Day 1 until disease progression or treatment discontinuation.<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and Severity of Treatment-Emergent Adverse Events [safety and tolerability] of HER-Vaxx in combination with chemotherapy or pembrolizumab | Treatment-Emergent Adverse Events [safety and tolerability] will be graded according to CTCAE v5.0 | From date of enrollment through study completion, an average of 6 months | 
| Objective Response Rate of HER-Vaxx in combination with chemotherapy or pembrolizumab | Objective Response Rate (ORR) measured from enrollment as the proportion of patients achieving a confirmed best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1 | From date of enrollment until the date of first documented progression or date of death from any cause, an average of 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall Survival (OS) is defined as the time from first dose of study drug to death due from any cause. | From date of enrollment until the date of death from any cause, an average of 1 year | 
| Progression Free Survival | Progression Free Survival (PFS) defined as the time from first dose of study drug to first documentation of progressive disease (PD) based on RECIST 1.1, or to death from any cause | From date of enrollment until the date of first documented progression or date of death from any cause, an average of 6 months | 
| Duration of Response | Duration of Response (DoR) measured from earliest CR or PR until first documentation of PD based on RECIST 1.1 or death due to any cause. | From date of earliest CR or PR until the date of first documented progression or date of death from any cause, an average of 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2, Immunotherapy