FT538 in Combination With Monoclonal Antibodies in Advanced Solid Tumors

Study Overview
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Brief Summary
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This is a Phase 1 dose-finding study of FT538 in combination with monoclonal antibodies.

Detailed Description
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This is a Phase 1 dose-finding study of FT538 given in combination with a monoclonal antibody following lymphodepletion in subjects with advanced solid tumors. The study will consist of a dose-escalation stage and an expansion stage where participants will be enrolled into indication-specific cohorts.

Official Title
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A Phase I, Open-Label, Multicenter Study of FT538 in Combination With Monoclonal Antibodies in Subjects With Advanced Solid Tumors

Conditions
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Solid Tumor, Adult

Intervention / Treatment
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* Drug: FT538
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Combination Product: Monoclonal antibody - Dose Escalation
* Combination Product: Monoclonal antibody - Dose Expansion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with locally advanced or metastatic disease who have progressed after at least one line of therapy and diagnosis of one of the following by treatment cohort: Cohort A: The following solid tumor malignancies where anti-PD-1/PD-L1 antibodies are approved: cutaneous melanoma, non-small cell/small cell lung cancer, renal cell carcinoma, head and neck squamous cell cancer, microsatellite instability-high/ mismatch repair deficient cancer, gastric cancer, esophageal cancer, cervical cancer, merkel cell carcinoma, endometrial carcinoma, tumor mutation burden-high ≥ 10 mutations/megabase], cutaneous squamous cell carcinoma, triple-negative breast cancer. Cohort B: HER2+ breast cancer that has relapsed or progressed on trastuzumab and progressed on either pertuzumab or HER2-targeting antibody drug conjugate; HER2+ gastric cancer that has relapsed or progressed on trastuzumab-containing therapy; OR any other HER2+ solid tumor having progressed on at least one line of standard-of-care therapy. For any tumor type in this cohort, HER2 status must be documented by a U.S. Food and Administration (FDA) approved test to be ≥2+ IHC or Average HER2 copy number ≥4 signals per cell by in situ hybridization. Cohort C: CRC having progressed following prior cetuximab treatment or has KRAS/NRAS mutation; HNSCC having progressed following prior cetuximab. Capable of giving signed informed consent Aged   18 years old Willingness to comply with study procedures and duration Measurable disease per RECIST v1.1 For subjects with >1 measurable lesion by RECIST v1.1 that can be safely accessed, willingness to undergo tumor biopsy Contraceptive use for women and men as defined in the protocol Exclusion Criteria: Pregnant or breast-feeding women ECOG performance status greater than or equal to 2 Evidence of insufficient organ function Clinically significant cardiovascular disease including left-ventricular ejection fraction < 45% Receipt of therapy within 2 weeks prior to Day 1 or five half-lives, whichever is shorter or any investigational therapy within 28 days prior to Day 1 Known active central nervous system (CNS) involvement by malignancy that hasn'thas not remained stable for at least 3 months following effective treatment for CNS disease Non-malignant CNS disease such as stroke, epilepsy, CNS vasculitis or neurodegenerative disease or receipt of medications for these conditions Currently receiving or likely to require immunosuppressive therapy Active bacterial, fungal, or viral infections including hep B, Hep C or HIV Live vaccine within 6 weeks prior to start of lympho-conditioning Known allergy to albumin (human) or DMSO

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>Cohort A: FT538 plus avelumab in subjects with advanced solid tumors malignancies where anti-PD-1/PD-L1 antibodies are approved Cohort B: FT538 plus trastuzumab in subjects with advanced documented HER2+ tumors Cohort C: FT538 plus cetuximab in subjects with advanced colorectal cancer (CRC) or head and neck squamous cell carcinoma (HNSCC) | Drug: FT538<br>* FT538 is an allogeneic natural killer (NK)-cell immunotherapy<br>* Other names: NK Cell Therapy;Drug: Cyclophosphamide<br>* Lympho-conditioning agent<br>* Other names: Cy;Drug: Fludarabine<br>* Lympho-conditioning agent<br>* Other names: Flu;Combination Product: Monoclonal antibody - Dose Escalation<br>* either avelumab, trastuzumab or cetuximab<br>* Other names: mAb;|
| Experimental: Dose Expansion<br>Cohort A, Arm 1: FT538 plus avelumab in subjects with advanced solid tumors malignancies where anti-PD-1/PD-L1 antibodies are approved (except urothelial carcinoma (UC)) Cohort A, Arm 2: FT538 plus an anti-PD-1 antibody (nivolumab or pembrolizumab) in subjects with solid tumor malignancies where anti-PD-1/PD-L1 antibodies are approved (except UC) Cohort B, Arm 1: FT538 plus trastuzumab in subjects with HER2+ tumors Cohort C, Arm 1: FT538 plus cetuximab in subjects with advanced CRC or HNSCC Subjects with UC may be enrolled in the randomized expansion cohorts as follows: Cohort A, Arm R1: FT538 plus avelumab Cohort A, Arm R2: FT538 plus atezolizumab | Drug: FT538<br>* FT538 is an allogeneic natural killer (NK)-cell immunotherapy<br>* Other names: NK Cell Therapy;Drug: Cyclophosphamide<br>* Lympho-conditioning agent<br>* Other names: Cy;Drug: Fludarabine<br>* Lympho-conditioning agent<br>* Other names: Flu;Combination Product: Monoclonal antibody - Dose Expansion<br>* either avelumab, atezolizumab, nivolumab, pembrolizumab, trastuzumab or cetuximab<br>* Other names: mAb;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Define the Recommended Phase 2 Dose (RP2D) | To define the RP2D of FT538 in combination with the following mAbs in subjects with advanced solid tumors: avelumab, trastuzumab, cetuximab, atezolizumab, nivolumab, and pembrolizumab | Up to  1.5 years | 
| Incidence and Severity of Adverse Events (AEs)0 | To evaluate the safety and tolerability of FT538 in combination with the following mAbs in subjects with advanced solid tumors: avelumab, trastuzumab, cetuximab, atezolizumab, nivolumab, and pembrolizumab | Up to  5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anti-PD-1 / PD-L1 antibodies approved, HER2+, Metastatic CRC, Head and Neck Squamous Cell Carcinoma, NK Cells, Urothelial Cancer, Renal Cell Carcinoma, merkel cell carcinoma, non-small cell lung cancer, NSCLC, triple negative breast cancer, immune checkpoint inhibitor, melanoma, renal cell carcinoma, lung cancer,, triple-negative breast cancer,, head and neck squamous cell carcinoma,, urothelial carcinoma (UC),, Merkel cell carcinoma, squamous, hepatocellular carcinoma, gastric cancer, esophageal cancer, endometrial cancer,