HCW9218 in Select Advanced Solid Tumors

Study Overview
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Brief Summary
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This is a single center, Phase I dose finding study of HCW9218 for the treatment of advanced/metastatic solid tumor cancer (except pancreatic and primary brain cancers). HCW9218 is a novel bi-functional fusion protein complex administered by subcutaneous (SC) injection. It is comprised of a soluble fusion of two human TGFβRII domains, human tissue factor, and human IL-15, and a second soluble fusion of two human TGFβRII domains and a sushi domain of human IL-15Rα. HCW9218 activates IL-15R signaling on effector immune cells and the dimeric TGFβRII functions as a trap for all three human TGF-β isoforms.

Official Title
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A Phase I Study of HCW9218, a Bifunctional TGF-B; Antagonist/IL-15 Protein Complex, in Select Advanced Solid Tumors After Failing at Least Two Prior Therapies

Conditions
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Solid Tumor

Intervention / Treatment
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* Drug: HCW9218


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed advanced/metastatic solid tumor cancer (except pancreatic and primary brain cancers), has failed at least 2 prior lines of therapy given either in the recurrent or metastatic setting and must be refractory to or intolerant of existing therapy(ies) known to provide clinical benefit for their condition. Measurable disease per RECIST v 1.1. Acute effects of any prior therapy must have resolved to baseline or Grade ≤1 NCI CTCAE v5 except for AEs not constituting a safety risk by enrolling Investigator judgment. Age 18 years or older at the time of consent. ECOG Performance Status 0 or 1. Evidence of adequate organ function within 14 days prior to enrollment as defined in Section 4.1.6. Adequate pulmonary function with PFTs >50% FEV1 if symptomatic or known impairment. Sexually active persons of child-bearing potential or with partners of childbearing potential must agree to use a highly effective form of contraception (refer to Section 4.1.10 for acceptable methods) for at least 28 days after the last dose of HCW9218. Provides voluntary written consent prior to the performance of any research related activity. Exclusion Criteria: Pregnant or breastfeeding. History of clinically significant vascular disease, including any of the following within 6 months prior to start of study treatment: MI or unstable angina, percutaneous coronary intervention, bypass grafting, ventricular arrhythmia requiring medication, stroke or transient ischemic attack, symptomatic peripheral arterial disease. Marked baseline prolongation of QT/QTc interval (e.g., demonstration of a QTc interval greater or equal to 470 milliseconds by Fridericia's correction). Known or suspected untreated CNS metastases. Anti-cancer treatment including surgery, radiotherapy, chemotherapy, other immunotherapy, or investigational therapy within 14 days before treatment start. Other prior malignancy except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the subject is currently in complete remission, or any other cancer from which the subject has been disease-free for 3 years after surgical treatment. Known hypersensitivity or history of allergic reactions attributed to compounds of similar chemical or biologic composition to the agents used in the study. Prior therapy with TGF-β antagonist, IL-15 or analogs. Concurrent use of St. John's wort and and/or other herbal CYP modulators within 7 days of Day 1. Must agree to not use during study treatment through the end of treatment visit to be eligible. Known autoimmune disease requiring active treatment. Persons with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment. Inhaled or topical steroids, and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. Active systemic infection requiring parenteral antibiotic therapy. All prior infections must have resolved following optimal therapy. Prior organ allograft or allogeneic transplantation. Known HIV-positive or AIDS. Psychiatric illness/social situations that would limit compliance with study requirements. Other illness or a medical issue that in the opinion of the Investigator would exclude the subject from participating in this 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Administer HCW9218<br>Administer HCW9218 as monotherapy at assigned dose by SC injection once every 3 weeks. Dose Level -1 - 0.1 mg/kg - (start) 0.25 mg/kg - 0.5 mg/kg - 0.8 mg/kg - 1.2 mg/kg | Drug: HCW9218<br>* HCW9218 at the assigned dose level is administered as a subcutaneous injection once every 3 weeks for a minimum of 2 treatment cycles unless medically contraindicated.<br>* Other names: Monotherapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary objective of the dose finding component is to determine the maximum tolerated dose (MTD) of HCW9218 | Given that little to no toxicity is expected, the MTD will be determined using an adaptation of the continual reassessment method (CRM) (O'Quigley, 1996) starting with 1 patient cohorts. | through study completion, an average of 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimate response rate (complete response (CR), partial response (PR) or stable disease (SD) | Response rate will be estimated by a simple proportion with 95% confidence limits if sufficient numbers exist | 3 months after 1st dose | 
| Estimate response rate (complete response (CR), partial response (PR) or stable disease (SD) | Response rate will be estimated by a simple proportion with 95% confidence limits if sufficient numbers exist | 6 months after 1st dose | 
| Estimate response rate (complete response (CR), partial response (PR) or stable disease (SD) | Response rate will be estimated by a simple proportion with 95% confidence limits if sufficient numbers exist | 12 months after 1st dose | 
| Estimate progression of overall survival (OS) | Estimated with Kaplan-Meier curves | 6 months after 1st dose | 
| Estimate progression free survival (PFS) | Estimated with Kaplan-Meier curves | 6 months after 1st dose | 
| Estimate progression free survival (PFS) | Estimated with Kaplan-Meier curves | 1 year after 1st dose | 
| Estimate progression of overall survival (OS) | Estimated with Kaplan-Meier curves | 1 year after 1st dose |