FT536 Monotherapy and 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 FT536 given in combination with a monoclonal antibody following lymphodepletion in participants 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 FT536 as Monotherapy and in Combination With Monoclonal Antibodies in Subjects With Advanced Solid Tumors

Conditions
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Non Small Cell Lung Cancer, Colorectal Cancer, Breast Cancer, Ovarian Cancer, Pancreatic Cancer, Head and Neck Cancer, GastroEsophageal Cancer

Intervention / Treatment
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* Drug: FT536
* Drug: Cyclophosphamide
* Drug: Fludarabine
* Drug: IL-2
* Combination Product: Avelumab
* Combination Product: Pembrolizumab
* Combination Product: Nivolumab
* Combination Product: Atezolizumab
* Combination Product: Trastuzumab
* Combination Product: Cetuximab
* Combination Product: Amivantamab
* Drug: IL-2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants with locally advanced or metastatic disease who have progressed/relapsed, are refractory, intolerant to or refuse standard therapy approved for their specific tumor type: Cohort A/A2/AA/AA2: NSCLC, CRC, BC, ovarian cancer, or pancreatic cancer Cohorts B/B2/BB/BB2 and C/C2/CC/CC2: Subjects with NSCLC, HNSCC, gastroesophageal adenocarinoma, triple negative breast cancer, or urothelial carcinoma whose tumors express PD-L1 according to defined cutoff Cohort D/D2/DD/DD2: Subjects with advanced solid tumor whose tumor(s) express HER2 defined as: ≥2+ by IHC, Average HER2 copy number ≥4 signals per cell by in situ hybridization or ≥4 copies as determined by next generation sequencing Cohort E/E2/EE/EE2: Squamous NSCLC; head and neck cancer that relapsed or progressed following prior cetuximab treatment; CRC subjects who are KRAS/NRAS/BRAF wild-type are required to have progressed/relapsed on prior cetuximab or panitumumab Cohort F/F2/FF/FF2: NSCLC known to have at least one of the following: epidermal growth factor receptor (EGFR) driver mutation(s) and have progressed on or were intolerant to at least one prior line of EGFR Tyrosine Kinase Inhibitor (TKI) or were not candidates for or declined TKI; mesenchymal-epithelial transition (MET) exon 14 skipping mutation that has progressed on or intolerant of at least one prior line of MET TKI or were not candidates for or declined TKI; MET amplification defined as MET/CEP7 ratio ≥1.8 by Fluorescence in situ hybridization (FISH) Has measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 For subjects with >1 measurable lesion by RECIST v1.1 that can be safely accessed, willingness to undergo tumor biopsy Agrees to contraceptive use for women and men as defined in the protocol Exclusion Criteria: Is a pregnant or breast-feeding female Has Eastern Cooperative Oncology Group (ECOG) performance status ≥2 Has evidence of insufficient organ function Has clinically significant cardiovascular disease including left-ventricular ejection fraction < 45% Has received any 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 Has a known active malignancy in the central nervous system (CNS) that hasn't remained stable for at least 3 months following effective treatment for CNS disease Has a non-malignant CNS disease such as stroke, epilepsy, CNS vasculitis or neurodegenerative disease or receipt of medications for these conditions Has had any active malignancy other than those studied in this trial within 2 years of the first dose of study therapy Is currently receiving or likely to require immunosuppressive therapy Has an active bacterial, fungal, or viral infections including hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) Has received a live vaccine within 6 weeks prior to start of lympho-conditioning Has a known allergy to albumin (human) or dimethyl sulfoxide (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: Cohort A/A2/AA/AA2: FT536 Monotherapy<br>FT536 monotherapy in participants with locally advanced or metastatic non-small cell lung cancer (NSCLC), colorectal cancer (CRC), breast cancer (BC), ovarian cancer, or pancreatic cancer. | Drug: FT536<br>* FT536 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;Drug: IL-2<br>* For Cohort AA ONLY: To be combined with FT536 at the MTD or MAD<br>* Other names: Interleukin-2;|
| Experimental: Cohort B/B2/BB/BB2: FT536 + Avelumab<br>FT536 + avelumab combination therapy in participants with locally advanced or metastatic solid tumor indications with documented PD-L1 expression. | Drug: FT536<br>* FT536 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: Avelumab<br>* Monoclonal antibody<br>* Other names: Bavencio;Drug: IL-2<br>* For Cohorts BB-FF ONLY: To be combined with FT536 + mAb at the MTD or MAD<br>* Other names: Interleukin-2;|
| Experimental: Cohort C/C2/CC/CC2: FT536 + Pembrolizumab, Nivolumab, or Atezolizumab<br>FT536 + pembrolizumab, nivolumab, or atezolizumab in participants with locally advanced or metastatic solid tumor indications with documented PD-L1 expression. | Drug: FT536<br>* FT536 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: Pembrolizumab<br>* For Cohorts C/CC, the combination product (monoclonal antibody) will be ONE of the following: pembrolizumab, nivolumab, or atezolizumab.<br>* Other names: Keytruda;Combination Product: Nivolumab<br>* For Cohorts C/CC, the combination product (monoclonal antibody) will be ONE of the following: pembrolizumab, nivolumab, or atezolizumab.<br>* Other names: Opdivo;Combination Product: Atezolizumab<br>* For Cohorts C/CC, the combination product (monoclonal antibody) will be ONE of the following: pembrolizumab, nivolumab, or atezolizumab.<br>* Other names: Tecentriq;Drug: IL-2<br>* For Cohorts BB-FF ONLY: To be combined with FT536 + mAb at the MTD or MAD<br>* Other names: Interleukin-2;|
| Experimental: Cohort D/D2/DD/DD2: FT536 + Trastuzumab<br>FT536 + trastuzumab in participants with locally advanced or metastatic documented human epidermal growth factor receptor 2 (HER2+) expressing tumors | Drug: FT536<br>* FT536 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: Trastuzumab<br>* Monoclonal antibody<br>* Other names: Herceptin;Drug: IL-2<br>* For Cohorts BB-FF ONLY: To be combined with FT536 + mAb at the MTD or MAD<br>* Other names: Interleukin-2;|
| Experimental: Cohort E/E2/EE/EE2: FT536 + Cetuximab<br>FT536 + cetuximab in participants with locally advanced or metastatic squamous NSCLC, CRC, or head and neck cancer. | Drug: FT536<br>* FT536 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: Cetuximab<br>* Monoclonal antibody<br>* Other names: Erbitux;Drug: IL-2<br>* For Cohorts BB-FF ONLY: To be combined with FT536 + mAb at the MTD or MAD<br>* Other names: Interleukin-2;|
| Experimental: Cohort F/F2/FF/FF2: FT536 + Amivantamab<br>FT536 + amivantamab in participants with locally advanced or metastatic NSCLC. | Drug: FT536<br>* FT536 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: Amivantamab<br>* Monoclonal antibody<br>* Other names: Rybrevant;Drug: IL-2<br>* For Cohorts BB-FF ONLY: To be combined with FT536 + mAb at the MTD or MAD<br>* Other names: Interleukin-2;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the Recommended Phase 2 Dose (RP2D) | The RP2Ds of FT536 monotherapy and FT536 + monoclonal antibody (mAbs) will be determined. The RP2D will be determined based on the overall safety and efficacy profile. | Up to approximately 3 years | 
| Number of Participants with ≥ Adverse Event (AE) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v5.0 | The safety and tolerability of FT536 monotherapy and in combination with mAbs will be determined. | Following enrollment completion within dose escalation and expansion, approximately 3 years |