A Phase 1b Study of WU-NK-101 in Combination With Cetuximab

Study Overview
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Brief Summary
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This study is a Phase 1b open-label study designed to characterize the safety, tolerability, and preliminary anti-tumor activity of WU-NK-101 in combination with cetuximab in patients with advanced and/or metastatic CRC (Cohort 1), and in patients with advanced and/or metastatic SCCHN (Cohort 2). The overall study will be comprised of two phases, a Dose Escalation Phase, and a Cohort Expansion Phase.

Detailed Description
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In the Dose Escalation Phase, up to 12 patients with either advanced and/or metastatic CRC or advanced and/or metastatic SCCHN will be treated with WU-NK-101, alone and in combination with cetuximab, in successive cohorts of 3 to 6 patients using a standard 3 + 3 design. Intra-patient dose escalation is not permitted. Patients may receive up to one 8-week cycle of treatment. Each 8-week cycle is divided into two 28-day segments, (Segments A and B). During Segment A, only WU-NK-101 (monotherapy) will be administered. Segment A will consist of two doses of WU-NK-101 infused on Day 1 and Day 15. Patients that do not experience a dose limiting toxicity (DLT) will proceed to Segment B. During Segment B, WU-NK-101 will be administered in combination with cetuximab (combination therapy). WU-NK-101 cells will be administered on Days 30 and 44. Cetuximab will be administered on Days 29 and 43 at 500 mg/m2 (FDA-approved dose). Once the MTD/MAD is defined in the Dose Escalation Phase, up to 9 additional patients will be enrolled in 2 parallel, disease specific, expansion cohorts (Cohort 1 [patients with CRC] and Cohort 2 [patients with SCCHN]) to further characterize the safety, tolerability, and preliminary anti-tumor activity of WU-NK-101 cells in combination with cetuximab. Patients will receive cetuximab dosed at 500 mg/m2 on Days 1 and 15, and WU-NK-101 on Days 2 and 16, in each 4-week cycle. At the end of Cycle 2, patients who achieve a partial response (PR) or stable disease (SD) may receive up to 4 additional cycles of treatment of WU-NK-101 cells in combination with cetuximab with disease assessments on Day 28 (+/- 3 days) of each even numbered cycle, for a maximum of 6 cycles.

Official Title
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A Phase 1b Study of WU-NK-101 in Combination With Cetuximab for Advanced and/or Metastatic Colorectal Cancer (CRC) and Advanced and/or Metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN)

Conditions
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Colorectal Cancer Metastatic, Squamous Cell Carcinoma of Head and Neck

Intervention / Treatment
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* Biological: WU-NK-101 - Dose Escalation
* Drug: Cetuximab - Dose Escalation
* Biological: WU-NK-101 - Cohort Expansion
* Biological: Cetuximab - Cohort Expansion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a histologically confirmed diagnosis of advanced and/or metastatic CRC that has failed or progressed beyond first line or higher line standard of care therapy including bevacizumab combination, cetuximab combination, 5-FU based regimens, or checkpoint inhibitors alone or in combination. Patients must have received all targeted therapies for which they are eligible. Patients may be included in this study regardless of mutation status (e.g., RAS-mutant, wild-type, or unknown status, BRAF V600E, etc.) and EGFR expression. Or, Patients must have a histologically confirmed diagnosis of SCCHN that has failed or progressed beyond first or higher line standard of care therapy including cetuximab alone or in combination, checkpoint inhibitors alone and in combination, or regimens containing radiotherapy. Patients may be included in this study regardless of EGFR expression. Measurable disease, in accordance with RECIST 1.1. Eastern Cooperative Oncology Group Performance (ECOG) Status ≤ 2 at screening. Adequate organ function as defined in the protocol. Ejection fraction ≥ 45%. Life expectancy >12 weeks. Exclusion Criteria: Experienced toxicities related to prior cetuximab treatment which required permanent discontinuation of cetuximab per the current label. Active autoimmune disorder requiring immunosuppression (physiologic steroids defined as ≤ 15 mg prednisone or equivalent are acceptable). Symptomatic central nervous system (CNS) metastases. Patients with a history of CNS metastasis must have been treated, must be asymptomatic, and must not have any of the following at the time of enrollment: No concurrent treatment for the CNS disease (e.g., surgery, radiation, corticosteroids > 10 mg prednisone/day or equivalent). No progression of CNS metastases on magnetic resonance imaging (MRI) or computed tomography (CT) for at least 14 days after last day of prior therapy for the CNS metastases, no concurrent leptomeningeal disease or cord compression. Known hypersensitivity to one or more of the study agents. Known hypersensitivity to IL-2 or any component of IL-2 formulation. Patients with organ allografts. Uncontrolled or untreated bacterial, fungal, or viral infections, including but not limited to human immunodeficiency virus, hepatitis B or C infection, or uncontrolled infection of any etiology. Uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiogram (ECG) suggestive of acute ischemia, active conduction system abnormalities, or abnormal cardiac stress test. New progressive pulmonary infiltrates on screening chest x-ray or chest CT scan that have not been evaluated with bronchoscopy. Infiltrates attributed to infection must be stable/ improving after 1 week of appropriate therapy (4 weeks for presumed or proven fungal infections). Received any investigational drugs within the 14 days or 5 half- lives (whichever is longer) prior to the first dose of fludarabine. Radiotherapy or chemotherapy within 2 weeks prior to the first dose of fludarabine. Severe renal impairment, defined as creatinine clearance <40 mL/min. Pregnant and/or breastfeeding women. Any condition that, in the opinion of the investigator, would prevent the participant from consenting to or participating in the study.

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: Parallel Assignment
Interventional Model Description: In dose expansion patients will be enrolled in 2 parallel, disease specific cohorts to further characterize the safety, tolerability and preliminary anti- tumor activity of WU-NK-101 in combination with cetuximab
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: WU-NK-101 Monotherapy/Cetuximab combo Run-in<br>WU-NK-101 is a non-engineered Natural Killer (NK) cell derived from peripheral blood mononuclear cells (PBMC) that is cytokine-reprogrammed, expanded, and cryopreserved to create an allogeneic enhanced memory-like anti-tumor NK cell therapy product. Each 8 week cycle in dose escalation is divided into two 28- days segments. Patients will receive WU-NK-101 (Days 1 and 15) in the first segment and a combination of cetuximab (500mg/m2 on Days 29 and 43) plus WU-NK-101 (Days 30 and 44) in the second segment. | Biological: WU-NK-101 - Dose Escalation<br>* WU-NK-101 administered on Days 1, 15, 30 and 44<br>Drug: Cetuximab - Dose Escalation<br>* Cetuximab 500mg/m2 administered on Days 29 and 43<br>|
| Experimental: WU-NK-101 /Cetuximab Combo<br>Patients will receive cetuximab dosed at 500 mg/m2 on Days 1 and 15, and WU-NK-101 on Days 2 and 16, in each 4-week cycle. Depending on response patients may receive up to 6 cycles of treatment. | Biological: WU-NK-101 - Cohort Expansion<br>* WU-NK-101 administered on Days 2 and 16<br>Biological: Cetuximab - Cohort Expansion<br>* Cetuximab 500mg/m2 administered on Days 1 and 15<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events of WU-NK-101 in combination with cetuximab as assessed by by CTCAE v5 | Safety is based on evaluation of adverse events (AEs) and serious adverse events (SAEs) from the time of consent until the end of the study visit or at the end of treatment visit. | 24 months | 
| Maximum Tolerated Dose | Maximum tolerated or administered dose of WU-NK-101 in combination with cetuximab | up to 56 days from first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response | Time of response to the time of disease relapse, progression or death due to any cause | 24 months | 
| Overall Response Rate | ORR is defined as the proportion of patients that achieve complete remission (CR) + partial response (PR) using modified Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NK cells, allogeneic NK cells, cetuximab