PANGEA-IMBBP: Personalized Antibodies for Gastro-Esophageal Adenocarcinoma - A 1st Pilot Metastatic Trial of Biologics Beyond Progression

Study Overview
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Brief Summary
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The purpose of this study is to determine if doctors can use the results of special tests of subjects tumor tissue, that will look for specific abnormalities in the tumor, to choose a specific drug that is targeted to work against that abnormality (called molecular profiling) and to see what effects (good and/or bad) that targeted drug has on subjects cancer when it is given with standard chemotherapy.

Official Title
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PANGEA: Personalized Antibodies for Gastro-Esophageal Adenocarcinoma

Conditions
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Adenocarcinoma

Intervention / Treatment
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* Drug: Trastuzumab
* Drug: ABT-806
* Drug: Bemarituzumab
* Drug: Ramucirumab
* Drug: Nivolumab
* Drug: Standard cytotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed metastatic gastric or esophagogastric junction (type I,II,III Siewert) adenocarcinoma Newly-diagnosed chemo-naïve or recurrent after curative-intent surgery >6 months after completion of adjuvant therapy (including chemotherapy and/or radiotherapy) No prior treatment with any targeted agent Patients who have started first line mFOLFOX6 therapy (+/-trastuzumab for HER2 amplified tumors) may be considered for trial participation if they have received no more than 4 doses of therapy at the time of consent and screening. Measurable metastatic disease by RECIST criteria, Must be amenable to ultrasound or CT-guided biopsy of one metastatic lesion Peritoneal disease as the sole site of occult metastasis or presenting as malignant ascites is acceptable if a cell block of tumor cells can be obtained showing >20% viable tumor cells. ECOG PS 0,1 Age > 18 years Patients must have normal organ and marrow function as defined below: granulocytes >1,2500/mcL platelets >100,000/mcL total bilirubin < 1.5 x ULN, <1.8 x ULN with liver metastases AST(SGOT)/ALT(SGPT) <2.5 X ULN without liver metastases; <5 X ULN with liver metastases creatinine within normal institutional limits (<1.5) OR creatinine clearance >50 mL/min/1.73m2, (for creatinine level above normal) INR: < 1.5 (patients on warfarin need to be converted to LMWH during study participation to be eligible) Consent to baseline metastatic and progressive disease biopsy (of metastatic/progressing lesion) for enabling biomarker assessment and treatment assignment (at each time point - baseline, PD1, PD2, PD3) as well as for correlative studies. • Consent to baseline and serial blood draws for plasma/serum/whole blood banking for correlative studies Ability to understand and the willingness to sign a written informed consent document and consent to the serial nature of the proposed PANGEA treatment with first, second and third line therapy as tolerated. Ability to comply with requirements of the protocol, as assessed by the investigator by the patient signing the consent form. If history of exposure to anthracyclines during perioperative treatment, the following cumulative doses of anthracyclines must be less than: Epirubicin < 720 mg/m2 Doxorubicin or liposomal doxorubicin < 360 mg/m2 Mitoxantrone > 120 mg/m2 and idarubicin > 90 mg/m2 If more than one anthracycline has been used, then the cumulative dose must not exceed the equivalent of 360 mg/m2 of doxorubicin. Cardiac Ejection Fraction >50% (for HER2+ patients) as assessed by echocardiogram, MUGA scan, or cardiac MRI Willingness to use effective and reliable methods of contraception (For appropriate methods of contraception considered acceptable see Appendix B). Both men and women and members of all races and ethnic groups are eligible for this trial. Exclusion Criteria: No CVA within 6 months, no recent MI within 6 months No currently active second malignancy No uncontrolled intercurrent illness or infection No peripheral edema > grade 2 at baseline. No peripheral neuropathy > grade 2 at baseline. No diarrhea > grade 2 at baseline.

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: ITT-PTS: Personalized Treatment Strategy (Immuno-oncology)<br>For patients with monclonal antibiodies available, initial therapy was tailored based on biomarker profile as follows: Immuno-oncology included PD-L1 IHC combined positivity score >10, high microsatellite instability, tumor mutation burden >15 mutations per megabase, and/or Epstein-Barr virus positive. These patients received standard cytotherapy plus Nivolumab. | Drug: Nivolumab<br>* Nivolumab<br>* Other names: Opdivo;Drug: Standard cytotherapy<br>* FOLFOX (First Line) +FOLFIRI (Second Line) +FOLTAX (Third Line)<br>|
| Experimental: ITT-PTS: Personalized Treatment Strategy (HER2 amplified)<br>HER2 amplified. These patients received standard cytotherapy plus Trastuzumab. | Drug: Trastuzumab<br>* Trastuzumab<br>* Other names: Herceptin®;Drug: Standard cytotherapy<br>* FOLFOX (First Line) +FOLFIRI (Second Line) +FOLTAX (Third Line)<br>|
| Experimental: ITT-PTS: Personalized Treatment Strategy (EFGR amplified)<br>EGFR amplified. These patients received ABT-806. | Drug: ABT-806<br>* ABT-806<br>Drug: Standard cytotherapy<br>* FOLFOX (First Line) +FOLFIRI (Second Line) +FOLTAX (Third Line)<br>|
| Experimental: ITT-PTS: Personalized Treatment Strategy (FGFR2 amplified)<br>FGFR2 amplified. These patients received standard cytotherapy plus Bemarituzumab. | Drug: Bemarituzumab<br>* Bemarituzumab<br>Drug: Standard cytotherapy<br>* FOLFOX (First Line) +FOLFIRI (Second Line) +FOLTAX (Third Line)<br>|
| Experimental: ITT-PTS: Personalized Treatment Strategy (MAPK/PIK3CA aberrant)<br>MAPK/PIK3CA aberrant. These patients received standard cytotherapy plus Ramucirumab. | Drug: Ramucirumab<br>* Ramucirumab<br>* Other names: Cyramza;Drug: Standard cytotherapy<br>* FOLFOX (First Line) +FOLFIRI (Second Line) +FOLTAX (Third Line)<br>|
| Experimental: ITT-PTS: Personalized Treatment Strategy (EGFR expressing)<br>EGFR expressing. These patients received standard cytotherapy plus ABT 806. | Drug: ABT-806<br>* ABT-806<br>Drug: Standard cytotherapy<br>* FOLFOX (First Line) +FOLFIRI (Second Line) +FOLTAX (Third Line)<br>|
| Experimental: ITT-PTS: Personalized Treatment Strategy (All negative)<br>All negative. These patients received standard cytotherapy plus Ramucirumab. | Drug: Ramucirumab<br>* Ramucirumab<br>* Other names: Cyramza;Drug: Standard cytotherapy<br>* FOLFOX (First Line) +FOLFIRI (Second Line) +FOLTAX (Third Line)<br>|
| Other: Non-ITT: Standard Therapy<br>Patients without monoclonal antibodies available received standard cytotherapy. | Drug: Standard cytotherapy<br>* FOLFOX (First Line) +FOLFIRI (Second Line) +FOLTAX (Third Line)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Time from enrollment to death from any cause. | Up to 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Biopsies Leading to an Adverse Event | Number of biopsies leading to an adverse event of the total undergoing baseline biopsies of a primary and metastatic disease site (liver, lung, lymph node, peritoneum/carcinomatosis). | 1 Month | 
| Completion of Biopsy and Successful, Molecularly-based Treatment Assignment | Completion of biopsies with successful assignment per the treatment algorithm. Biomarker profile assays included next generation sequencing (NGS). EGFR expression was performed by selected-reaction-monitoring mass spectrometry (SRM-MS). | Up to 1 month | 
| Adverse Event From Serial Biopsy for Second-line Treatment | Number of participants with adverse events from serial biopsies of progressing metastatic disease sites (liver, lung, lymph node, peritoneum/carcinomatosis) | Up to 60 Months | 
| Completion of Serial Biopsy for Second Line Therapy and Successful, Molecularly-based Treatment Assignment | Completion of biopsy with successful treatment assignment per the treatment algorithm. Biomarker profile assays included next generation sequencing (NGS). EGFR expression was performed by selected-reaction-monitoring mass spectrometry (SRM-MS). | Up to 60 months | 
| Adverse Event From Serial Biopsy for Third-line Treatment | Number of participants with adverse events from serial biopsies of progressing metastatic disease sites (liver, lung, lymph node, peritoneum/carcinomatosis) | Up to 60 months | 
| Completion of Serial Biopsy for Third Line Therapy and Successful, Molecularly-based Treatment Assignment | Completion of biopsy with successful treatment assignment per the treatment algorithm. Biomarker profile assays included next generation sequencing (NGS). EGFR expression was performed by selected-reaction-monitoring mass spectrometry (SRM-MS). | Up to 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gastric, Esophagogastric