Response Adapted Neoadjuvant Therapy in Gastroesophageal Cancers (RANT-GC Trial)

Study Overview
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Brief Summary
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This is a phase 1b prospective, single arm, open-label trial determining the efficacy and feasibility of using a ctDNA assay (test) result to help guide neoadjuvant chemotherapy in subjects with Stage IB, II or Stage III adenocarcinoma of the stomach or gastroesophageal junction (GEA).

Official Title
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Response Adapted Neoadjuvant Therapy in Gastroesophageal Cancers (RANT-GC Trial) - a Phase Ib Feasibility Trial

Conditions
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Gastroesophageal Adenocarcinoma

Intervention / Treatment
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* Device: ctDNA Blood Test
* Combination Product: FLOT
* Combination Product: FOLFOX
* Combination Product: FOLFIRI
* Combination Product: FOLFIRINOX
* Combination Product: PACLITAXEL with or without CARBOPLATIN
* Combination Product: DOCETAXEL and IRINOTECAN (alone or combined)
* Drug: NIVOLUMAB (alone or when added to a regimen above)
* Drug: PEMBROLIZUMAB (alone or when added to a regimen above)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed adenocarcinoma of the stomach or gastroesophageal junction (GEA). Other GE histologies which are treated per NCCN guidelines for neoadjuvant treatment are eligible. Must have Stage IB, II or Stage III GEA eligible for (neo)adjuvant doublet or triplet chemotherapy for up to 6 months. Must have baseline ctDNA positive assay (tested by Signatera MRD assay) prior to initiation of neoadjuvant chemotherapy. Patients who are otherwise eligible may start per protocol treatment if ctDNA result is not available at the time of initiation of systemic therapy. However, once the results is available, they can only remain on study if the ctDNA is positive. Age ≥ 18 years Because the safety or efficacy of neoadjuvant chemotherapy for LGEA has not been tested or established for patients <18 years of age, children are excluded from this study but will be eligible for future pediatric trials, if applicable. Performance status: ECOG performance status ≤2 Life expectancy of greater than 6 months Adequate organ and marrow function as defined below: leukocytes ≥ 3,000/mcL absolute neutrophil count ≥ 1,500/mcL platelets ≥ 80,000/mcl total bilirubin within normal institutional limits AST(SGOT)/ALT(SPGT) ≤ 5 X institutional upper limit of normal creatinine <2 X ULN Docetaxel can cause fetal harm and irinotecan is known to be teratogenic. Since these compounds are part of the treatment regimens, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. 1. A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: Has not undergone a hysterectomy or bilateral oophorectomy; or Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months). Ability to understand and the willingness to sign a written informed consent. 1. Both men and women and members of all races and ethnic groups are eligible for this trial. Non-English speaking, deaf, hard of hearing and illiterate individuals are eligible for this trial. Exclusion Criteria: Patients may not be receiving any other investigational agents. Patients with known metastases from GEA. History of allergic reactions attributed to agents used in study. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. History of another primary cancer which requires active treatment or is expected to require treatment within 12 months after enrollment. Inability to comply with study and follow-up procedures as judged by the Investigator. Patients who are pregnant or nursing due to the potential for congenital abnormalities and the potential of this regimen to harm nursing infants.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant chemotherapy with ctDNA testing<br>The patients will be treated with one of the standard neoadjuvant protocols (FLOT or FOLFOX.) If no decline in ctDNA detected after 4 cycles, treatment will be switched to a different chemotherapy backbone (e.g. irinotecan based regimen, or taxane based if not used upfront). ctDNA will be re-evaluated after 3 cycles (if a 21 day regimen) or 4 cycles (if a 14 day regimen) of the 2nd line regimen. If ctDNA is lower than the previous measurement, then the same regimen continues for 3-4 more cycles (depending on 14 day or 21 day cycle), followed by gastrectomy. Adjuvant treatment is given based on the investigator's discretion. | Device: ctDNA Blood Test<br>* Blood will be collected for ctDNA testing<br>Combination Product: FLOT<br>* Oxaliplatin 85 mg/m2 IV on Day 1 Docetaxel 50 mg/m2 IV on Day 1 Leucovorin 200 mg/m2 IV on Day 1 Fluorouracil 2600 mg/m2 continuous infusion over 24 hours daily on Day 1 Every 14 Days<br>Combination Product: FOLFOX<br>* Oxaliplatin 85 mg/m2 IV on Day 1 Leucovorin 400 mg/m2 IV on Day 1 Fluorouracil 400 mg/m2 IV Push on Day 1 Fluorouracil 1200 mg/m2 continuous infusion over 24 hours daily on Days 1 and 2 Every 14 Days<br>Combination Product: FOLFIRI<br>* Irinotecan 180 mg/m2 IV on Day 1 Leucovorin 400 mg/m2 IV on Day 1 Fluorouracil 400 mg/m2 IV Push on Day 1 Fluorouracil 1200 mg/m2 continuous infusion over 24 hours daily on Days 1 and 2 Every 14 Days<br>Combination Product: FOLFIRINOX<br>* Oxaliplatin 85 mg/m2 IV on Day 1 Irinotecan 150 mg/m2 IV on Day 1 Leucovorin 200 mg/m2 IV on Day 1 Fluorouracil 1200 mg/m2 continuous infusion over 24 hours daily on Days 1 and 2 Every 14 days<br>Combination Product: PACLITAXEL with or without CARBOPLATIN<br>* Paclitaxel 200 mg/m2 IV on Day 1 Carboplatin AUC 5 IV on day 1 Every 21 Days OR - Paclitaxel 80mg/m2 IV on Days 1,8,15 Every 28 Days<br>Combination Product: DOCETAXEL and IRINOTECAN (alone or combined)<br>* Docetaxel 35 mg/m2 IV on Days 1 and 8 Irinotecan 50 mg/m2 IV on Days 1 and 8 Every 21 Days Docetaxel 75 mg/m2 IV on Day 1 Every 21 Days Docetaxel 150 mg/m2 IV on Day 1 Every 14 Days<br>Drug: NIVOLUMAB (alone or when added to a regimen above)<br>* 240 mg IV on Day 1 every 14 days, or 360 mg IV on Day 1 every 21 days, or 480 mg IV on Day 1 every 28 days<br>Drug: PEMBROLIZUMAB (alone or when added to a regimen above)<br>* 200 mg IV on Day 1 every 21 days, or 400 mg IV on Day 1 every 42 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of completing per protocol treatment. | Percent of patients who will undergo attempt at curative intent resection. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients completing gastrectomy. | Percent of patients completing gastrectomy | Up to 3 years | 
| Rate of negative ctDNA after completion of neoadjuvant treatment and within 8 weeks after surgery | Percent of patients with ctDNA clearance after neoadjuvant chemotherapy and after surgery (within 6-8 weeks) | 8 weeks | 
| Rate of R0 resection | R0 resection is defined as complete tumor removal with negative surgical margins. | Up to 3 years | 
| Rate of post-operative complication rate within 30 days after surgery |  | Up to 3 years | 
| Percentage of Grade 3-5 Adverse Events | Toxicity and adverse events are based on the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5.0. | Up to 3 years | 
| Relapse-free survival time | The lead time in ctDNA detection before clinical recurrence | Up to 3 years | 
| Rate of ctDNA positive patients at diagnosis | Percent of patients positive for ctDNA at diagnosis | Up to 3 years |