A Study of IMU-131(HER-Vaxx) and Chemotherapy Compared to Chemotherapy Only in Patients With HER2 Positive Advanced Gastric Cancer

Study Overview
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Brief Summary
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The Phase 1b study is an open-label, multicenter dose escalation study designed to assess the safety, tolerability, immunogenicity and recommended phase 2 dose (RP2D) of IMU-131. The RP2D will be evaluated in the dose expansion Phase 2 study. The Phase 2 study is a randomized, open label comparison of IMU-131 plus standard of care chemotherapy versus standard of care chemotherapy alone.

Detailed Description
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IMU-131 is a single peptide structure composed of 3 individual B-cell epitope peptide sequences selected from HER2/neu structure. Polyclonal antibodies against IMU-131 peptides bind three separate regions of the HER2 receptor and also to the dimerization loop of the HER2 receptor, preventing dimerization, which in turn inhibits intracellular signaling. This blockade of the HER2 signaling pathways is thought to be substantially greater than that with trastuzumab alone. Safety and immunogenicity of the 3 peptides have been shown in Phase 1a testing of an earlier formulation of IMU-131. The shelf stability of the Phase 1a vaccine was not optimal and hence the formulation was adjusted for IMU-131. The three B-cell epitope peptides (P4, P6 and P7) were combined in a specific order resulting in a single fusion peptide of 49 amino acids in length (P467). This new formulation of IMU-131 has extended stability and improved immunogenicity compared to the formulation used previously. The new vaccine IMU-131 produces a stronger and more rapid polyclonal antibody response and is efficient to manufacture compared with previous formulations. Based on these three known epitopes (P4, P6 and P7), the investigators developed a single peptide antigen (P467), which allows simplification of the manufacturing process. It is hypothesized that administration of IMU-131 in addition to chemotherapy will prolong survival and may delay tumor progression and/or reduce tumor burden in patients with HER2/neu overexpressing gastric or gastroesophageal junction (GEJ) adenocarcinoma (otherwise known as Advanced Cancer of the Stomach (ASC)). The Phase 1b study aims to determine the safety and tolerability of IMU-131 and identify the Recommended Phase 2 Dose (RP2D) of IMU-131 in combination with chemotherapy in HER2/neu overexpressing ACS to carry into the Phase 2 dose expansion study. The Phase 2 component will be submitted as an amendment and will be initiated following completion of Phase 1b. Phase 2 will be designed to further characterize the safety and to explore clinical activity of IMU-131 in combination with chemotherapy in HER2/neu overexpressing ACS.The Phase 2 study is a randomized, open label comparison of IMU-131 plus standard of care chemotherapy versus standard of care chemotherapy alone.

Official Title
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A Phase 1b/2 Open-Label Study With Randomization in Phase 2 of IMU-131 HER2/Neu Peptide Vaccine Plus Standard of Care Chemotherapy in Patients With HER2/Neu Overexpressing Metastatic or Advanced Adenocarcinoma of the Stomach or Gastroesophageal Junction

Conditions
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Gastrointestinal Neoplasms, Adenocarcinoma

Intervention / Treatment
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* Biological: IMU-131
* Drug: Cisplatin and either Fluorouracil (5-FU) or Capecitabine or Oxaliplatin and capecitabine.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient has been informed of the investigational nature of this study and has given written informed consent in accordance with institutional, local, and national guidelines; Age ≥ 20 years old; Life expectancy of at least 12 weeks; Phase 1b: No prior chemotherapy or radiotherapy for advanced gastric or GEJ cancer within 6 months prior to Day 0; Phase 2: No prior chemotherapy or radiotherapy for advanced gastric or GEJ cancer within 3 months prior to Day 0; Metastatic gastric or GEJ adenocarcinoma, or locally advanced disease not amenable to surgical resection; HER2/neu overexpression (3+ by immunohistochemistry (IHC) or if IHC 2+ confirmed by fluorescent in situ hybridization [FISH] or chromogenic in situ hybridization [CISH]). Patients with IHC 2+ expression without confirmation of overexpression by fluorescent in situ hybridization [FISH] or chromogenic in situ hybridization [CISH]) may be included in Phase 1b with agreement of Imugene Limited; Phase 1b: ECOG performance status 0-1; Phase 2: ECOG performance status 0-2; At least one measurable lesion as defined by RECIST 1.1 criteria. Patients with non-measurable lesions may be included in Phase1b with agreement of Imugene Limited; Adequate left ventricular ejection function at baseline, defined as LVEF > 50% by echocardiogram or MUGA scan (Multi Gated Acquisition Scan); Adequate hematologic function: absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L, and hemoglobin ≥ 9 g/dL; Adequate liver function evidenced by bilirubin ≤ 1.5 x laboratory upper limit of normal [ULN], and ALT and AST ≤ 3 x laboratory ULN if no liver involvement or ALT and AST ≤ 5 times laboratory ULN with liver involvement; Adequate renal function (creatinine ≤ 1.5 x laboratory ULN); Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Male and female patients of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 28 days after the last dose of assigned treatment (see section 4.3 for details). A patient is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active. Exclusion Criteria: Previous treatment with trastuzumab or any other HER2/neu targeting antibody or agent; Continuous systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 4 weeks prior to first dose of study treatment. Inhaled or topical steroids and physiological replacement doses of up to 10 mg daily prednisone equivalents are permitted in the absence of active auto-immune disease; Prior organ transplant; Phase 1b: Patient not considered a candidate for 5-FU, capecitabine, or cisplatin chemotherapy; Phase 2: Patient not considered a candidate for 5-FU, capecitabine, cisplatin or oxaliplatin chemotherapy; History of documented congestive heart failure; angina pectoris requiring antianginal medication; evidence of transmural infarction on ECG; poorly controlled hypertension; clinically significant valvular heart disease; high risk uncontrolled arrhythmias; or New York Heart Association (NYHA) class II heart disease; If on warfarin (Coumadin®) or other vitamin K antagonists; Concurrent active malignancy except for adequately controlled limited basal cell carcinoma of the skin; Peripheral neuropathy or hearing loss of NCI CTCAE Grade > 2; History of uncontrolled seizures, central nervous disorders or psychiatric disability judged by the investigator to be clinically significant and precluding informed consent, participation in the study, or adversely affecting compliance to study drugs; Active infection requiring IV antibiotics; Positive 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; Pregnant or lactating females; Major surgery within 4 weeks prior to study entry. Minor surgery (excluding diagnostic biopsy) within 1 week prior to study entry; Has received a live-virus vaccination within 4 weeks of first study vaccination. Seasonal flu vaccines that do not contain live virus are permitted; Current or recent (within 4 weeks of first IMU-131 vaccination) treatment with another investigational drug or participation in another investigational study. Phase 2: Patients with a known diphtheria toxoid hypersensitivity.

Ages Eligible for Study
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Minimum Age: 20 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: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b<br>10, 30, 50μg IMU-131 plus Cisplatin and either Fluorouracil (5-FU) or Capecitabine | Biological: IMU-131<br>* IMU-131 vaccine is a P467-CRM197 peptide antigen in PBS buffer and Montanide ISA 51 Sterile adjuvant<br>* Other names: HER-Vaxx;Drug: Cisplatin and either Fluorouracil (5-FU) or Capecitabine or Oxaliplatin and capecitabine.<br>* Chemotherapy will consist of: cisplatin by intravenous administration at 80 mg/m2 on the first day of each cycle and either 5-FU, 4000 mg/m2 CIV (administered as 1000 mg/m2/day as continuous infusion for 96 hours on days 1 to 4 of each cycle) or capecitabine for 14 days at 2000 mg/m2/day, orally (administered as 1000 mg/m2 twice daily morning and evening for a total of 2000 mg/m2/day on days 1 to 14 of each cycle), or (in Phase 2 only) oxaliplatin, by intravenous administration at 130 mg/m2 on Day 1 of each cycle and capecitabine for 14 days at 2000 mg/m2/day, orally (administered as 1000 mg/m2 twice daily morning and evening for a total of 2000 mg/m2/day on days 1 to 14 of each cycle).<br>* Other names: Standard of Care Chemotherapy;|
| Experimental: Phase 2 - IMU 131 plus chemotherapy<br>50 μg IMU-131 plus Cisplatin and either Fluorouracil (5-FU) or Capecitabine or Oxaliplatin and Capecitabine. | Biological: IMU-131<br>* IMU-131 vaccine is a P467-CRM197 peptide antigen in PBS buffer and Montanide ISA 51 Sterile adjuvant<br>* Other names: HER-Vaxx;Drug: Cisplatin and either Fluorouracil (5-FU) or Capecitabine or Oxaliplatin and capecitabine.<br>* Chemotherapy will consist of: cisplatin by intravenous administration at 80 mg/m2 on the first day of each cycle and either 5-FU, 4000 mg/m2 CIV (administered as 1000 mg/m2/day as continuous infusion for 96 hours on days 1 to 4 of each cycle) or capecitabine for 14 days at 2000 mg/m2/day, orally (administered as 1000 mg/m2 twice daily morning and evening for a total of 2000 mg/m2/day on days 1 to 14 of each cycle), or (in Phase 2 only) oxaliplatin, by intravenous administration at 130 mg/m2 on Day 1 of each cycle and capecitabine for 14 days at 2000 mg/m2/day, orally (administered as 1000 mg/m2 twice daily morning and evening for a total of 2000 mg/m2/day on days 1 to 14 of each cycle).<br>* Other names: Standard of Care Chemotherapy;|
| Experimental: Phase 2 - Chemotherapy only<br>Cisplatin and either Fluorouracil (5-FU) or Capecitabine or Oxaliplatin and Capecitabine. | Drug: Cisplatin and either Fluorouracil (5-FU) or Capecitabine or Oxaliplatin and capecitabine.<br>* Chemotherapy will consist of: cisplatin by intravenous administration at 80 mg/m2 on the first day of each cycle and either 5-FU, 4000 mg/m2 CIV (administered as 1000 mg/m2/day as continuous infusion for 96 hours on days 1 to 4 of each cycle) or capecitabine for 14 days at 2000 mg/m2/day, orally (administered as 1000 mg/m2 twice daily morning and evening for a total of 2000 mg/m2/day on days 1 to 14 of each cycle), or (in Phase 2 only) oxaliplatin, by intravenous administration at 130 mg/m2 on Day 1 of each cycle and capecitabine for 14 days at 2000 mg/m2/day, orally (administered as 1000 mg/m2 twice daily morning and evening for a total of 2000 mg/m2/day on days 1 to 14 of each cycle).<br>* Other names: Standard of Care Chemotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of IMU-131 (Phase 1b) | The safety and tolerability of IMU-131 will be evaluated by adverse events (AEs) and laboratory measurements. | Day 0 to Day 56 | 
| Recommended Phase 2 dose of IMU-131 (Phase 1b) | The recommended phase 2 dose will be evaluated by safety/tolerability and immunogenicity data for IMU-131 (P467- specific antibodies (IgG) and Her-2- specific antibodies (IgG) titers). | Day 0 to Day 56 | 
| Clinical efficacy of IMU-131 (Phase 2) | To evaluate the clinical efficacy of IMU-131 based on overall survival (OS). | Day 0 to Death (Approximately 17.5 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (Phase 2) | To evaluate other efficacy measures of IMU-131: progression-free survival (PFS). | Day 0 to Progression (approx. 7.5 months) | 
| Time to progression (Phase 2) | To evaluate other efficacy measures of IMU-131: time to progression (TTP). | Day 0 to Progression (approx. 7.5 months) | 
| Disease Control Rate (Phase 2) | To evaluate other efficacy measures of IMU-131: disease control rate (DCR). | Day 0 to Progression (approx. 7.5 months) | 
| Objective Response Rate (Phase 2) | To evaluate other efficacy measures of IMU-131: objective response rate (ORR). | Day 0 to Progression (approx. 7.5 months) | 
| Duration of Objective Response (Phase 2) | To evaluate other efficacy measures of IMU-131: duration of objective response (DOR). | Day 0 to Progression (approx. 7.5 months) | 
| Change in Tumor Size (Phase 2) | To evaluate other efficacy measures of IMU-131: change in tumor size (CTS). | Day 0 to Progression (approx. 7.5 months) | 
| Humoral and cellular immunogenicity of IMU-131(Phase 2) | Values and changes from randomization in humoral and cellular immunogenicity data including P467-specific antibodies (IgG), Her-2-specific antibodies (IgG), vaccine-specific cytokine levels and regulatory and effector T and B cells. | Day 0 to Progression (approx. 7.5 months) | 
| Incidence of TEAE's (Phase 2) | Safety will be assessed by comparing the incidence of TEAE's & SAE's in each group. | Day 0 to Progression (approx. 7.5 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Secondary