Metastatic HER2 Positive Gastroesophageal Junction Cancer
Conditions
Keywords
CYNK-101, Natural Killer Cells, Cell Therapy, Metastatic HER2-positive Gastric Cancer, Gastric Cancer, Gastroesophageal Junction Adenocarcinoma
Brief summary
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.
Interventions
BIOLOGICALCYNK-101
CYNK-101 is a human placental hematopoietic stem/progenitor cell derived NK cell product, that is genetically modified to express a variant of CD16, Fc gamma receptor III (FcγRIII).
DRUGPembrolizumab
200 mg on Day 1 of each 3-week cycle as an IV infusion.
DRUGTrastuzumab
8 mg/kg loading dose and then 6 mg/kg maintenance dose administered IV on day 1 of each 3-week cycle.
6 million (M) international units (IU) of rhIL-2 administered subcutaneously (SC) on each CYNK-101 infusion day.
DRUGCyclophosphamide
Cyclophosphamide: 900 mg/m2 administered IV as part of a 3-day lymphodepletion regimen.
DRUGFludarabine
Fludarabine: 30 mg/m2 administered IV as part of a 3-day lymphodepletion regimen.
DRUGMesna
MESNA: shall be administered as part of a 3-day lymphodepletion regimen for the inhibition of hemorrhagic cystitis induced by cyclophosphamide. Route of administration, dosage, and frequency of Mesna should be based on institutional standards.
Sponsors
Celularity Incorporated
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This Phase I/IIa study will utilize a 3+3 open label design, and will evaluate two escalating dosing Cohort levels of CYNK-101 in combination with rhIL2 following and initial induction and lymphodepletion regimen. Once the Maximum Tolerated Dose (MTD) or Recommended Phase 2 Dose (RP2D) is determined in Phase I, the Phase IIa portion of the study will commence.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-Limiting Toxicity (DLT) | up to 28 days | Phase I |
| Maximum Tolerated Dose (MTD) | up to 28 days | Phase I |
| Overall Response Rate (ORR) as determined by the RECIST 1.1 Investigator using RECIST 1.1. | up to 12 months | Phase IIa |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Response conversion post CYNK-101 infusion | up to 12 months | Phase I/IIa |
| Incidence of Treatment Emergent adverse events (TEAE) | up to 12 months | Phase I/IIa |
| Progression Free Survival (PFS) | at 6 and 12 months | Phase I/IIa |
| Incidence of replication competent lentivirus (RCL) | up to 12 months | Phase I/IIa |
| Overall Survival (OS) | up to 12 months | Phase I/IIa |
| Incidence and Severity of adverse events (AEs) and clinically significant changes in laboratory values | up to 12 months | Phase I/IIa |
| Duration of Response (DoR) | up to 12 months | Phase I/IIa |
| Overall Response Rate (ORR) as determined by the RECIST 1.1 | up to 12 months | Phase I |
Countries
United States
Outcome results
None listed