CYNK-101 in Combination with Trastuzumab and Pembrolizumab in Patients with Locally Advanced Unresectable or Metastatic HER2-Positive Gastric or Gastroesophageal Junction (G/GEJ) Adenocarcinoma

A Phase I/IIa Open Label, Non-Randomized, Multicenter Study of CYNK-101 in Combination with Trastuzumab and Pembrolizumab in Patients with Locally Advanced Unresectable or Metastatic HER2-Positive Gastric or Gastroesophageal Junction (G/GEJ) Aenocarcinoma

This study will find the maximum tolerated dose (MTD) of CYNK-101 which contains Natural Killer (NK) cells derived from human placental CD34+ cells and culture-expanded. CYNK-101 will be administered as first-line treatment, following induction therapy consisting of Pembrolizumab, Trastuzumab and a Fluoropyrimidine / Platinum based Chemotherapy regimen. Patients are required to undergo a biopsy for confirmation of HER2 positivity defined as either IHC 3+ or IHC 2+ with a positive fluorescent in-situ hybridization (FISH) or FISH + alone. The safety of this treatment will be evaluated, and researchers will want to learn if NK cells will help in treating patients with Locally Advanced Unresectable or Metastatic HER2-Positive Gastric or Gastroesophageal Junction (G/GEJ) Adenocarcinoma.

Inclusion Criteria:

1. Be at least 18 years of age on the day of signing informed consent.

2. Have cytologically or histologically confirmed diagnosis for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-Positive Gastric or Gastroesophageal junction (G/GEJ) adenocarcinoma.

   • Patients who have received adjuvant therapy more than 12 months prior to Visit 2 will be allowed to participate in the study. Any patient who has completed an INDUCTION regimen prior to study entry and achieved best tumor response as either (1) Stable Disease per RECIST after 6 cycles or (2) Progressive Disease per RECIST and meets all other inclusion/exclusion criteria per protocol, will be eligible for enrollment in this clinical trial to continue with LYMPHODEPLETION and NK CELL INDUCTION and MAINTENANCE.

3. Patients will be required to undergo a biopsy for confirmation of HER2 expression prior to study entry.

   • HER2 overexpression is defined by immunohistochemistry (IHC) or in situ hybridization (ISH) for amplification of HER2 gene.
   • Patients must have either IHC 3+ or IHC 2+ with a positive fluorescent in-situ hybridization (FISH) or FISH + alone, as assessed locally on primary or metastatic tumor.
   • Due to differences in tumor histopathology, use of FDA-approved tests, specific for Gastric Cancers, will be required when assessing HER2 Expression [HERCEPTIN package insert; 202120].

4. Have measurable disease as assessed by the investigator according to RECIST 1.1 [Eisenhauer EA et al, 200913].

5. Have a performance status of 0-1 on the Eastern Cooperative Oncology Group (ECOG) performance scale.

6. Have a life expectancy of ≥ 6 months.

7. Patients must agree to use a highly effective method of contraception from the start of the study until 1 year after the last dose of lymphodepletion or 4 months from last dose of pembrolizumab, or 6 months from last dose of trastuzumab; whichever comes later.

8. Have adequate cardiac function, defined as left ventricular ejection fraction > 45% as determined by MUGA scan or ECHO and QT interval calculated according to the Fridericia method (≤ 470 ms for men and ≤480 ms for women).

9. Demonstrate adequate organ function by laboratory values as follows:

   • Hematological:

     • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L,
     • Platelet count ≥ 100 x 109/L
     • Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L

   • Renal:

     o Calculated creatinine clearance (Cockcroft-Gault Formula) ≥ 50 mL/min

   • Hepatic:

     o Total bilirubin ≤1.5 x ULN

     • Exception: Patients with Gilbert's disease total bilirubin ≤ 3.0 x ULN

       o Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN

     • Exception: AST and ALT ≤ 5 x ULN for patients with liver metastases.

   • Coagulation:

     • Prothrombin Time (PT) ≤ 1.5 x ULN unless patient is receiving anticoagulant therapy if PT or PTT is within therapeutic range of intended use of anticoagulants
     • activated Partial Thromboplastin Time (aPTT) ≤ 1.5 x ULN unless patient is receiving anticoagulant therapy if PT or PTT is within therapeutic range of intended use of anticoagulants

Exclusion Criteria:

1. Patients who have received prior systemic therapy for locally advanced unresectable or metastatic disease.

2. Has had major surgery, open biopsy, or significant traumatic injury within 28 days prior to Visit 2, or anticipation of the need for major surgery during the course of study treatment.

3. Has had radiotherapy within 14 days prior to Visit 2.

4. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.

   • Exceptions: Squamous or Basal cell carcinoma of the skin, superficial bladder cancer, and prostate cancer not requiring treatment.

5. Patients with symptomatic, untreated, or actively progressing CNS metastases. Patients with a history of CNS metastases are eligible if they have not received radiotherapy within 7 days or whole-brain radiation for the past 14 days. Patients should not be receiving ongoing treatment with either corticosteroids or anticonvulsants. Patients with new CNS metastases detected during the Screening period, may participate in the study if they receive radiotherapy or surgery resulting in stable metastatic disease.

6. Has an active autoimmune disease that has required systemic treatment in the past 2 years.

7. Patients with hypothyroidism who are on stable replacement therapy will be allowed.

8. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy greater than 10 mg per day of prednisone or equivalent.

   • Patients who require replacement for adrenal insufficiency will be allowed.

9. Has a history of (non-infectious) pneumonitis that requires steroids or current pneumonitis.

10. Has a known history of active tuberculosis.

11. Has an active infection requiring systemic therapy.

12. Accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs within 14 days prior to Visit 2. If the participant is receiving diuretic drugs for other reasons, it is acceptable.

13. Has peripheral neuropathy > Grade 1.

14. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial.

15. Has active or clinically significant cardiac disease including:

    • History of myocarditis
    • History or presence of serious uncontrolled cardiac arrhythmias.
    • Clinically significant resting bradycardia.
    • Left ventricular ejection fraction (LVEF) as determined by echocardiogram (ECHO) < 45% or multiple gated acquisition scan (MUGA) < 45%.
    • Any of the following within 6 months prior to the start of the study treatments:

    myocardial infarction (MI), severe/unstable angina, congestive heart failure (CHF), cerebrovascular accident (CVA), transient ischemic attack (TIA).

16. Patients with history of human immunodeficiency virus (HIV) infection must be seronegative.

17. Known active infection with hepatitis B, hepatitis C, SARS-CoV-2, or other viral infections requiring systemic therapy.

18. Patients having a potential hypersensitivity (≥ Grade 3) to pembrolizumab, trastuzumab, study chemotherapy agents, rhIL-2 and/or to any excipients, murine proteins, or platinum-containing products. NOTE: any adverse events which has occurred because of prior therapy MUST have resolved to ≤ Grade 1 according to CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 5 prior to study entry.

19. Has had an allogeneic tissue/solid organ transplant.

20. Immunized with live vaccine ≤ 28 days before Visit 2.

21. Participation in study of investigational agent or device ≤ 28 day prior to Visit 2.

22. Patient is pregnant or breastfeeding.