A Study of PY314 in Subjects With Advanced Solid Tumors

Study Overview
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Brief Summary
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This is an open-label, multicenter, first in human, Phase 1a/1b study of PY314 in subjects with locally advanced (unresectable) and/or metastatic solid tumors that are refractory or relapsed to standard of care (including pembrolizumab, if approved for that indication).

Detailed Description
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Part A: Dose escalation of PY314 alone and in combination with pembrolizumab in a standard 3+3 design Part B: Dose expansion of one or more dose levels of PY314 administered alone and in combination with pembrolizumab for predefined tumor histology

Official Title
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A Phase 1a/1b Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PY314 as a Single Agent and In Combination With Pembrolizumab in Subjects With Advanced Solid Tumors

Conditions
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Advanced Solid Tumor, Gynecologic Cancer, Breast Cancer, Colorectal Cancer, Lung Adenocarcinoma, Renal Cell Carcinoma, Triple Negative Breast Cancer, Hormone Receptor/Growth Factor Receptor-Negative Breast Cancer, Ovarian Cancer

Intervention / Treatment
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* Drug: PY314
* Drug: Combination Therapy: PY314 + Pembrolizumab


Participation Criteria
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Eligibility Criteria
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KEY ELIGIBILITY CRITERIA Inclusion Criteria: Adults ≥18 years of age at the time of study consent Subjects with any of the following eligible solid tumor diagnoses as confirmed by cytology or histology: Escalation Cohorts (Part A): Subjects with advanced solid tumors from pre-specified tumor types (Gynecological cancers [including ovarian, fallopian, primary peritoneal, endometrial, cervical, vaginal, vulvar], gastric [adenocarcinoma], Colorectal ([MSIlow and CPI refractory MSIhigh]), lung [non-small cell lung adenocarcinoma and squamous cell carcinoma] who are recurrent or refractory to platinum-based chemotherapy in addition to prior treatment with CPI Programmed Cell Death-1 (PD-1)/Programmed Cell Death-Ligand 1 (PD-L1) or who give informed consent to forego such therapy, renal [clear cell and non-clear cell], breast [TNBC and HR+ HER-2-] with locally advanced or metastatic disease that is relapsed or refractory to at least one line of post-adjuvant therapy (including a CPI-either alone or in combination if approved for that indication, and not eligible for other targeted therapies specific for their tumor type). Expansion Cohorts (Part B): Subjects with advanced solid tumors selected from 5 prespecified cancers based on preclinical and Part A. Subjects must provide an original, diagnostic tumor sample to determine TREM2 expression (sites have verified source prior to screening and availability of archival tissue during screening). Subjects without an archival tissue sample will only be eligible if they choose and consent to provide a CNB of primary or a metastatic lesion required for part B, used in Part A only if an archival specimen unavailable. Subjects must have documented disease progression (including prior treatment with a CPI (alone or in combination), if approved for that indication. There is no limit to the number of prior treatments. Measurable disease by RECIST 1.1 All acute toxic effects of any prior antitumor therapy, including immunotherapy, have resolved to Grade < 2 before the start of study drug dosing (including Grade < 2 alopecia or peripheral neuropathy, or if controlled on thyroid replacement therapy). Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2 Coagulation: International Normalized Ratio (INR) ≤ 1.3, unless on a therapeutic anticoagulant Adequate hematologic function defined as follows: Platelets ≥ 100 x 10^9/L; Hemoglobin ≥ 8.0 g/dL; ANC ≥ 1.5 x 10^9/L (without granulocytic growth factors within the previous 7 days of obtaining the screening hematologic laboratory values) Adequate hepatic function defined as follows: AST / ALT ≤ 2.5 x upper limit of normal (ULN) (if liver metastases are present, ≤ 5 x ULN); Total or conjugated bilirubin ≤ 1.5 x ULN Adequate renal function defined as follows: Serum Creatinine ≤ 2 x ULN or creatinine clearance (CrCl) ≥45 mL/min as calculated by the Cockroft-Gault method Exclusion Criteria: Subject is a candidate for molecularly targeted therapy (e.g., drugs targeting EGFR, VEGF, ALK, ROS-1, NTRK, MET, RET and BRAF V600E, HER2). Applies to enrolled subjects on both Part A and Part B of the study. History of autoimmune disorder requiring ongoing or intermittent disease-modifying therapy excluding thyroid disease otherwise well controlled on replacement therapy Stable treated or asymptomatic brain metastases for at least 3 months documented by brain imaging prior to enrollment Uncontrolled intercurrent illness including, but not limited to, active SARS-CoV-2 infection, active or chronic bleeding event within 28 days prior to first dose of study drug, or psychiatric illness/social situation that would limit compliance with study requirements as judged by treating physician Decompensated liver disease as evidenced by hepatic encephalopathy or coagulopathy Active angina or Class III or IV CHF (NYHA CHF Functional Classification System) or clinically significant cardiac disease within 12 months of first dose of study drug, including MI, unstable angina, Grade 2 or greater peripheral vascular disease, CHF, uncontrolled HTN, or arrhythmias not controlled by medication Any anti-cancer therapy, including small molecules, immunotherapy, chemotherapy, monoclonal antibody therapy (except for bone-modifying agents as supportive care), radiotherapy, or any other agents to treat cancer within 21 days (dependent upon the agent and drug half-life), of first dose of study drug Refractory lung cancer subjects who have progressed within 3 months of initiating chemotherapy-doublet regimens or lung cancer subjects who have progressed within 6 months of initiation immunotherapy-chemotherapy combination treatment. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

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
Interventional Model Description: Part A: Dose escalation of PY314 alone and in combination with pembrolizumab in a standard 3+3 design Part B: Dose expansion of one or more dose levels of PY314 administered alone and in combination with pembrolizumab for predefined tumor histology
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: PY314 Single agent dose level 1<br>PY314 single agent dose level will depend on any safety signal observed in this cohorts only. Following the determination of the safety and tolerability of at least two PY314 dose levels by the safety review committee. | Drug: PY314<br>* Dose of PY314 as a single agent given in a standard 3+3 design.<br>|
| Experimental: Part A: PY314 Single agent dose level 2<br>PY314 single agent dose level 2 dose escalation of PY314 as a single agent will continue in the absence of unacceptable dose limiting toxicity to the maximum administered dose as defined in the predefined dose escalation schema. | Drug: PY314<br>* Dose of PY314 as a single agent given in a standard 3+3 design.<br>|
| Experimental: Part A: PY314 Single agent dose level 3<br>PY314 single agent dose level 3 to identify the maximum tolerated dose and/or to determine the recommended dose for expansion of PY314 | Drug: PY314<br>* Dose of PY314 as a single agent given in a standard 3+3 design.<br>|
| Experimental: Part A: PY314 Single agent dose level 4<br>PY314 single agent dose level 4 to characterize the pharmacokinetic profile of PY314 as a single agent. | Drug: PY314<br>* Dose of PY314 as a single agent given in a standard 3+3 design.<br>|
| Experimental: Part A: Combination dose level 1<br>Combination dose level 1 to characterize the safety and tolerability of PY314 as a single agent and in combination with pembrolizumab in subjects with advanced refractory solid tumors including refractory to check point inhibitor. | Drug: Combination Therapy: PY314 + Pembrolizumab<br>* Dose of PY314 alone and given in combination with pembrolizumab<br>* Other names: Pembrolizumab;|
| Experimental: Part A: Combination dose level 2<br>PY314 combination dose level 2 to identify the maximum tolerated dose and/or to determine the recommended dose for expansion of PY314 administered alone and in combination with pembrolizumab. | Drug: Combination Therapy: PY314 + Pembrolizumab<br>* Dose of PY314 alone and given in combination with pembrolizumab<br>* Other names: Pembrolizumab;|
| Experimental: Part A: Combination dose level 3<br>PY314 combination dose level 3 to characterize the pharmacokinetic profile of PY314 as a single agent and in combination with pembrolizumab. | Drug: Combination Therapy: PY314 + Pembrolizumab<br>* Dose of PY314 alone and given in combination with pembrolizumab<br>* Other names: Pembrolizumab;|
| Experimental: Part A: Combination dose level 4<br>PY314 combination dose level 4 to describe, in subjects selected by pre-specified tumor histology, anti-tumor activity of PY314 administered alone and in combination with pembrolizumab. | Drug: Combination Therapy: PY314 + Pembrolizumab<br>* Dose of PY314 alone and given in combination with pembrolizumab<br>* Other names: Pembrolizumab;|
| Experimental: Part B: Single agent dose expansion dose level 1<br>PY314 single agent dose expansion dose level 1 to define further the safety and tolerability of PY314 alone. | Drug: PY314<br>* Dose of PY314 as a single agent given in a standard 3+3 design.<br>|
| Experimental: Part B: Combination dose expansion cohort 1<br>PY314 in combination with pembrolizumab dose expansion cohort 1 to define the safety and tolerability of PY314 alone and in combination with pembrolizumab over multiple treatment cycles in subjects with pre-defined tumor histologies and confirmed TREM2 expression. | Drug: Combination Therapy: PY314 + Pembrolizumab<br>* Dose of PY314 alone and given in combination with pembrolizumab<br>* Other names: Pembrolizumab;|
| Experimental: Part B: Combination dose expansion cohort 2<br>PY314 in combination with pembrolizumab dose expansion cohort 2 to further characterize the PK profile of PY314 as a single agent and in combination with pembrolizumab. | Drug: Combination Therapy: PY314 + Pembrolizumab<br>* Dose of PY314 alone and given in combination with pembrolizumab<br>* Other names: Pembrolizumab;|
| Experimental: Part B: Combination dose expansion cohort 3<br>PY314 in combination with pembrolizumab dose expansion cohort 3 to characterize the anti-tumor activity of PY314 alone and in combination with pembrolizumab in subjects with selected prespecified tumor histologies and known TREM2 expression. | Drug: Combination Therapy: PY314 + Pembrolizumab<br>* Dose of PY314 alone and given in combination with pembrolizumab<br>* Other names: Pembrolizumab;|
| Experimental: Part B: Combination dose expansion cohort 4<br>PY314 in combination with pembrolizumab dose expansion cohort 4 to evaluate the incidence of ADA formation and TREM2 expression. | Drug: Combination Therapy: PY314 + Pembrolizumab<br>* Dose of PY314 alone and given in combination with pembrolizumab<br>* Other names: Pembrolizumab;|
| Experimental: Part B: Combination dose expansion cohort 5<br>PY314 in combination with pembrolizumab dose expansion cohort 5 to further explore and characterize the anti-tumor activity of PY314 alone and in combination with pembrolizumab in subjects with selected prespecified tumor histologies and known TREM2 expression. | Drug: Combination Therapy: PY314 + Pembrolizumab<br>* Dose of PY314 alone and given in combination with pembrolizumab<br>* Other names: Pembrolizumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events (AE) | Adverse Events will be summarized by MedDRA system organ class and preferred term. Separate tabulations will be produced for all treatment emergent AEs, treatment related AEs, Serious Adverse Events (SAEs), discontinuations due to AEs, and AEs of at least NCI CTCAE grade 3 severity. | 36 months | 
| (Part A only) Dose Limiting Toxicity of PY314 | Evaluation of dose-limiting toxicity (DLT). | Assessed during first 21 days of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measure PY314 concentration at the end of infusion (CEOI) | Measure PY314 concentration at the end of infusion (CEOI) after the first dose. | 36 months | 
| Measure PY314 concentration at the trough level (Ctrough) | Measure PY314 concentration at the trough level (Ctrough). All subjects who received at least 1 dose of PY314 and have at least 1 measured concentration at a scheduled PK time point after start of dosing. | 36 months | 
| Determining PY314 time to maximum concentration (Tmax) | Determining PY314 time to maximum concentration (Tmax) during Cycle 1. | 36 months | 
| Measure PY314 Area under the curve (AUC)0-t | Measure PY314 Area under the curve (AUC)0-t. All subjects who received at least 1 dose of PY314 and have at least 1 measured concentration at a scheduled PK time point after start of dosing for at least 1 PK analyte. | 36 months | 
| Measure PY314 half-life (T1/2) | Measure PY314 half-life (T1/2). All subjects who received at least 1 dose of PY314 and have at least 1 measured concentration at a scheduled PK time point after start of dosing for at least 1 PK analyte. | 36 months | 
| Measure PY314 Clearance (CL) | Measure PY314 Clearance (CL). All subjects who received at least 1 dose of PY314 and have at least 1 measured concentration at a scheduled PK time point after start of dosing for at least 1 PK analyte. | 36 months | 
| Measure PY314 Volume at Steady State (Vss) | Measure PY314 Volume at Steady State (Vss). All subjects who received at least 1 dose of PY314 and have at least 1 measured concentration at a scheduled PK time point after start of dosing for at least 1 PK analyte. | 36 months | 
| Measure PY314 maximum concentration (Cmax) | Measure PY314 maximum concentration (Cmax) at various time points during Cycle 1. All subjects who received at least 1 dose of PY314 and have at least 1 measured concentration at a scheduled PK time point after start of dosing. | 36 months | 
| Incidence of Anti-Drug Antibody (ADA) formation to PY314 | To evaluate the incidence of anti-drug antibody (ADA) formation to PY314 | 36 months | 
| Objective response rate (ORR) | The incidents of ORR is defined as either a complete or partial response per RECIST. Subjects with no baseline data will be considered no responders. ORR will be summarized by dose, tumor type, and overall. ORR will be summarized descriptively. | 36 months | 
| Clinical Benefit Rate (CBR) | Defined as the percentage of subjects who have achieved complete response, partial response and stable disease. | 36 Months | 
| Duration of response (DOR) | DOR will be calculated to determine durability. DOR will be measured from the time by which the criteria for CR or PR-whichever is recorded first-are met until the first date by which recurrent or progressive disease is objectively documented. DOR will be assessed using KAPLAN-MEIER methods. | 36 months |