Perioperative mFOLFOX Plus Pembrolizumab in Gastroesophageal Junction (GEJ) and Stomach Adenocarcinoma

A Phase II Study of Perioperative mFOLFOX (Fluorouracil, Leucovorin, and Oxaliplatin) Chemotherapy Plus Pembrolizumab(MK-3475) Combination in Patients With Potentially Resectable Adenocarcinoma of the Gastroesophageal Junction (GEJ) and Stomach (MISP #52216)

To evaluate the antitumor activity and safety/tolerability of the combination (mFOLFOX + Pembrolizumab) in patients with potentially resectable adenocarcinoma of the Gastroesophageal Junction (GEJ) and stomach.

This study will evaluate the efficacy and safety of perioperative mFOLFOX plus Pembrolizumab combination regimen in participants with potentially resectable adenocarcinoma of the GEJ and stomach.

• The study is a non-randomized, open-label, single-arm phase II study.
• The enrolled participants will receive neoadjuvant combination of mFOLFOX every 2 weeks for 4 doses (on Days 1, 15, 29, 43) and Pembrolizumab every 3 weeks for 3 doses (on Days 1, 22, 43).
• Serious adverse events (SAEs) will be assessed on an ongoing basis using CTCAE v4.0, and the Thall, Simon, and Estey's design to monitor the efficacy and toxicity continuously together.
• Repeat PET-CT will be obtained approximately 2-3 weeks after completion of neoadjuvant combination therapy.
• If no evidence of metastatic disease on PET-CT, participants will undergo potentially curative surgical resection 4-6 weeks after completion of neoadjuvant combination therapy. This will be followed by adjuvant combination therapy (to be started 6-8 weeks after surgery) consisting of mFOLFOX every 2 weeks for additional 4 doses (total 4 months of therapy) plus Pembrolizumab every 3 weeks for additional 12 doses (total 1 year of therapy). If there is evidence of metastatic disease on PET-CT, participant will come off the study (i.e., will not undergo surgical resection and adjuvant therapy).
• Participants will continue to receive treatment until either one of the following occurs: completion of adjuvant therapy, development of radiographically confirmed progression, participant withdraws consent, intercurrent illness that prevents further administration of treatment, or sponsor-investigator decides to withdraw the participant.
• Efficacy outcomes during the adjuvant chemotherapy phase will be determined by radiologic measurements by CT using RECIST v1.1. Assessment of response will be performed every 3 months for the first year and as per the standard institutional guidelines thereafter.

Inclusion Criteria:

1. Male/female participants who are 18 - 75 years of age on the day of signing informed consent with histologically or cytologically confirmed diagnosis of adenocarcinoma of the gastroesophegeal junction (GEJ) or stomach will be enrolled in this study.

2. Have newly diagnosed localized or locally advanced, potentially resectable disease without any prior systemic chemotherapy.

3. Have no evidence of distant metastases.

4. Be eligible and reasonably fit to undergo potentially curative resection

   Male participants:

5. A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the participant.

   Female participants:

6. Female participants of childbearing potential must have a negative serum pregnancy within 72 hours prior to enrollment.

7. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

   1. Not a woman of childbearing potential (WOCBP) OR
   2. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at 120 days after the last dose of study treatment. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the participant.

8. The participant (or legally authorized representative, if applicable) must be willing and able to provide written informed consent for the trial.

9. Have evaluable disease . Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

10. Have pre-resection tissue available.

11. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion.

12. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

13. Have adequate organ function.

14. Be willing to provide blood and tissue samples for research purposes.

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

1. A WOCBP who has a positive serum pregnancy test within 72 hours prior to enrollment on study.

2. Has received prior therapy with an anti-PD-1 (Programmed death-1), anti-PD-L1 (programmed death ligand-1), or anti PD L2 (programmed death ligand-2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor.

3. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to study enrollment.

4. Has received prior chemotherapy (including investigational agents) for any malignant disorder, thoracic radiation therapy or prior surgical resection of an esophagogastric tumor.

   a. Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.

5. Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.

6. Has biopsy-proven invasion of tracheobronchial tree or tracheo-esophageal fistula.

7. Has distant metastatic disease on imaging or staging laparoscopy at the time of study entry.

8. Has a known history of active TB (tuberculosis)

9. Hypersensitivity to pembrolizumab or any of its excipients.

10. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered from adverse events due to agents administered more than 4 weeks earlier.

11. Clinically significant peripheral neuropathy at the time of study entry.

12. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines are live attenuated vaccines and are not allowed.

13. Is currently participating in 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.

    a. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.

14. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.

15. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.

16. Has active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically serious autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Participants with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Participants that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Participants with hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be excluded from the study.

17. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.

18. Has an active infection requiring systemic therapy.

19. Has a known history of Human Immunodeficiency Virus (HIV).

20. Has a known history of Hepatitis B or known active Hepatitis C virus infection. Note: testing for Hepatitis B and Hepatitis C is required only if mandated by local health authority.

21. Inoperable on the basis of co-existent medical problems.

22. Non-malignant systemic disease (cardiovascular, renal, hepatic, etc.) that would preclude any of the study drugs.

23. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.

24. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

25. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.