A Study of HST-1011 Given as Monotherapy and in Combination With an Anti-PD1 Antibody

Study Overview
=================
Brief Summary
-----------------
This is a Phase 1/2 study of HST-1011, a CBL-B inhibitor, being developed for the treatment of patients with advanced solid tumors, who relapsed while on or are refractory to approved anti-PD(L)1 therapies or other standard of care.

Detailed Description
-----------------
This is a Phase 1/2 study of HST-1011, a CBL-B inhibitor, being developed for the treatment of patients with advanced solid tumors, who relapsed while on or are refractory to approved anti-PD(L)1 therapies or other standard of care. In Phase 1 patients will receive HST-1011 as either monotherapy (Parts A1 and A2) or in combination with the anti-PD1 antibody, cemiplimab (Part B). Part A1 is a monotherapy dose escalation in which cohorts of patients will receive increasing doses of HST-1011. Upon completion of Part A1, an HST-1011 monotherapy dose optimization will commence (Part A2). Part B is a dose escalation of HST-1011 given in combination with the standard dose/regimen of cemiplimab. Dosing in Part B may commence prior to the completion of Part A1. Phase 2 will evaluate the preliminary antitumor activity of HST-1011 in combination with anti-PD(L)1 antibody or other standard of care therapies.

Official Title
-----------------
An Open Label, Phase 1/2 Study of HST-1011 Given as Monotherapy and in Combination With an Anti-PD1 Antibody in Patients With Advanced Solid Tumors

Conditions
-----------------
Solid Tumor, Adult, Relapsed Cancer, Refractory Cancer

Intervention / Treatment
-----------------
* Drug: HST-1011
* Biological: Cemiplimab


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Patient is at least 18 years of age. Patient is capable of understanding and complying with protocol requirements. Patient has signed and dated ICF. Patient has a histologically confirmed, advanced solid tumor (metastatic, recurrent, and/or unresectable) in one of the following categories: 1) anti-PD-(L)1 relapsed/refractory; 2) platinum-resistant ovarian cancer; 4) anal cancer; 5) rectal cancer; or 6) castration-resistant prostate cancer Patient has failed prior standard of care therapies appropriate for their metastatic disease. Patient has at least 1 measurable non-central nervous system (CNS) lesions per RECIST 1.1. Patient has provided consent for pre- and on-treatment biopsies. Eastern Cooperative Performance Status of 0 or 1. Key Exclusion Criteria: Patient has active autoimmune disease or other medical conditions requiring chronic systemic steroid therapy at the time of screening. Patient has an unacceptable intolerance to anti-PD(L)1 monoclonal antibody (Part B Only). Patient has previously participated in a clinical study evaluating a CBL-B inhibitor. Patients has untreated and/or symptomatic metastatic CNS disease. Patient is currently taking any concomitant medications at Screening that have the potential to cause a clinically relevant drug-drug interaction with HST-1011. Patients with a history of gastrointestinal disease that may affect absorption of the study drug, or patients who are not able to take oral medications. Patient has an active infection requiring systemic therapy. Patient has known or suspected infection with SARS-CoV-2 virus.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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: HST-1011 Monotherapy Dose Escalation (Part A1)<br>Multiple dose levels of HST-1011 to be evaluated. | Drug: HST-1011<br>* Increasing doses of HST-1011 given orally as monotherapy.<br>* Other names: CBL-B inhibitor;|
| Experimental: HST-1011 Monotherapy Dose Optimization (Part A2)<br>Evaluation of HST-1011 monotherapy dose/dose regimen. | Drug: HST-1011<br>* Increasing doses of HST-1011 given orally as monotherapy.<br>* Other names: CBL-B inhibitor;|
| Experimental: HST-1011 Dose Escalation in Combination with cemiplimab (Part B)<br>Multiple dose levels of HST-1011 to be evaluated in combination with cemiplimab. | Drug: HST-1011<br>* Increasing doses of HST-1011 given orally as monotherapy.<br>* Other names: CBL-B inhibitor;Biological: Cemiplimab<br>* Cemiplimab administered via intravenous infusion in combination with increasing doses of HST-1011 given orally as monotherapy.<br>* Other names: anti-PD1 antibody;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the safety and tolerability of escalating doses of single-agent HST-1011 in Part A1 or in combination with cemiplimab in Part B. | Number of participants with DLTs, with Adverse Events (TEAEs, SAEs), with abnormal clinically significant vital signs, Electrocardiograms (ECGs), with abnormal physical examination findings, and abnormal laboratory test results. | 12 months | 
| Determine the Recommended Phase 2 Dose (RP2D) and schedule of HST-1011 monotherapy in Part A2. | Integration of safety, PD, PK, and preliminary efficacy endpoints. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the safety and tolerability of single-agent HST-1011 in Part A2. | Number of participants with Adverse Events (TEAEs, SAEs), with abnormal clinically significant vital signs, Electrocardiograms (ECGs), with abnormal physical examination findings and abnormal laboratory test results. | 12 months | 
| Measurement of plasma concentrations of HST-1011 after monotherapy in Part A1 and Part A2 or in combination with cemiplimab in Part B to derive summary pharmacokinetic (PK) parameters including Tmax, Cmax, AUC0-last, Ctrough. | Characterize pharmacokinetic parameters including Tmax, Cmax, AUC0-last, Ctrough after oral administration of HST-1011 or combination of orally administered HST-1011 and IV infused cemiplimab. | 12 months | 
| Characterize the concentration of peripheral blood cytokines/chemokines following HST-1011 monotherapy Part A1 and Part A2, or in combination with cemiplimab in Part B. | Measure of peripheral pharmacodynamic (PD) markers after oral administration of HST-1011 or combination of orally administered HST-1011 and IV infused cemiplimab. | 12 months | 
| Characterize global gene expression profiles following HST-1011 monotherapy Part A1 and Part A2, or in combination with cemiplimab in Part B. | Measure of peripheral pharmacodynamic (PD) markers after oral administration of HST-1011 or combination of orally administered HST-1011 and IV infused cemiplimab. | 12 months | 
| Evaluate intratumoral immune cells (number and phenotype) in tumor tissue of single-agent HST-1011 in Part A2. | Measure of intratumoral pharmacodynamic (PD) markers after oral administration of HST-1011. | 12 months | 
| Evaluate intratumoral gene expression changes of single-agent HST-1011 in Part A2. | Measure of intratumoral pharmacodynamic (PD) markers after oral administration of HST-1011. | 12 months | 
| Overall Response Rate (ORR) following HST-1011 monotherapy Part A1 and Part A2, or in combination with cemiplimab in Part B. | Defined as the percentage of subjects who have a complete response (CR) or partial response (PR), as determined according to RECIST v1.1, or to PCWG for CRPC, if applicable. | 12 months | 
| Duration of response (DOR) of single-agent HST-1011 in Part A2. | Defined as the time from when the criteria for RECIST 1.1, or to PCWG for CRPC, if applicable, CR or PR (whichever is recorded first) was first met until the date when progressive disease is documented. | 12 months | 
| Disease Control Rate (DCR) of single-agent HST-1011 in Part A2. | Defined as the percentage of subjects who have a CR or PR or stable disease (SD), as determined according to RECIST v1.1, or to PCWG for CRPC, if applicable. | 12 months | 
| Progression Free Survival (PFS) of single-agent HST-1011 in Part A2. | Defined as the time from first treatment to first occurrence of progressive disease or death from any cause. | 12 months | 
| Overall Survival (OS) of single-agent HST-1011 in Part A2. | Defined as the time from first treatment to death from any cause. | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
CBL-B, anti-PD(L)1