Description:
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
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
Recruiting
Phase 1
Drug | Synonyms | Arms |
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Dose of PY314 | Pembrolizumab | Combination dose expansion cohort 1 |
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
Name | Type | Description | Interventions |
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PY314 Single agent dose level 1 | Experimental | 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. |
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PY314 Single agent dose level 2 | Experimental | 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. |
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PY314 Single agent dose level 3 | Experimental | PY314 single agent dose level 3 to identify the maximum tolerated dose and/or to determine the recommended dose for expansion of PY314 |
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PY314 Single agent dose level 4 | Experimental | PY314 single agent dose level 4 to characterize the pharmacokinetic profile of PY314 as a single agent. |
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Combination dose level 1 | Experimental | 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. |
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Combination dose level 2 | Experimental | 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. |
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Combination dose level 3 | Experimental | PY314 combination dose level 3 to characterize the pharmacokinetic profile of PY314 as a single agent and in combination with pembrolizumab. |
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Combination dose level 4 | Experimental | 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. |
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Single agent dose expansion dose level 1 | Experimental | PY314 single agent dose expansion dose level 1 to define further the safety and tolerability of PY314 alone. |
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Single agent dose expansion dose level 2 | Experimental | PY314 single agent dose expansion dose level 2 to further characterize the PK profile of PY314 as a single agent. |
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Combination dose expansion cohort 1 | Experimental | 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. |
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Combination dose expansion cohort 2 | Experimental | 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. |
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Combination dose expansion cohort 3 | Experimental | 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. |
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Combination dose expansion cohort 4 | Experimental | PY314 in combination with pembrolizumab dose expansion cohort 4 to evaluate the incidence of ADA formation and TREM2 expression. |
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KEY ELIGIBILITY CRITERIA Inclusion Criteria: 1. Adults ≥18 years of age at the time of study consent 2. Subjects with any of the following eligible solid tumor diagnoses as confirmed by cytology or histology: 1. Escalation Cohorts (Part A): Subjects with solid tumors from pre-specified tumor types (gynecological cancers [including ovarian, endometrial, cervix, vagina, vulva], gastric [adenocarcinoma], colon [MSIlow],(MSIlow and CPI refractory MSIhigh) ], Colon (MSIlow and CPI refractory MSIhigh), lung [adenocarcinoma], renal [clear cell and non-clear cell], breast [TNBC and HR+ HER-2-] with metastatic disease that is relapsed or refractory to at least one line of metastatic 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)). Lung adenocarcinoma subjects who are relapsed or refractory to platinum-based chemotherapy in addition to prior treatment with PD-1/PD-L1 or who give informed consent to forego such therapy. 2. Expansion Cohorts (Part B): Subjects with advanced solid tumors selected from prespecified histologic subgroups identified in Part A, with TREM2 expression confirmed by IHC (of fresh CNB) prior to enrollment. Lung cancer subjects who are relapsed or refractory to prior treatment with an anti- PD-1/PD-L1 antibody and platinum-based chemotherapy or who give informed consent to forego such therapy. 3. Subjects must provide an original, diagnostic tumor sample to determine TREM2 expression (Investigators have verified source 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 core needle biopsy of a metastatic lesion. 4. Subjects must have documented disease progression 1. Part A, including prior treatment with a CPI (alone or in combination), if approved for that indication 2. Part B, excluding refractory lung cancer patients 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 5. Measurable disease by RECIST 1.1 6. All acute toxic effects of any prior antitumor therapy, including immunotherapy, resolved to Grade ≤ 1 or < 2 if controlled on medications (eg thyroid replacement therapy) before the start of study drug dosing 7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2 8. Coagulation: International Normalized Ratio (INR) ≤ 1.3, unless on a therapeutic anticoagulant 9. Adequate hematologic function defined as follows: Platelets ≥ 100 x 109/L; Hemoglobin ≥ 9.0 g/dL; ANC ≥ 1.5 x 109/L (without any granulocytic growth factors within previous 7 days of the screening hematologic laboratory values) 10. 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 11. 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: 1. Patient is a candidate for molecularly targeted therapy (e.g. drugs targeting EGFR, EGFR, ALK, ROS-1, NTRK, MET, RET and BRAF V600E, Her2neu)). Applies to enrolled subjects on both Part A and Part B of the study. 2. History of autoimmune disorder requiring ongoing or intermittent disease-modifying therapy 3. Known brain metastases for Part A only. (Treated, stable and asymptomatic metastases for at least 3 months prior to enrollment may be enrolled in Part B only) 4. Uncontrolled intercurrent illness including, but not limited to, 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 5. Decompensated liver disease as evidenced by hepatic encephalopathy or coagulopathy 6. 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 7. Any anti-cancer therapy, including small molecules, immunotherapy, chemotherapy, monoclonal antibody therapy, radiotherapy, or any other agents to treat cancer within 14 days, of first dose of study drug
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Measure: | Incidence of Adverse Events (AE) |
Time Frame: | 12 months |
Safety Issue: | |
Description: | 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. |
Measure: | Objective response rate (ORR) |
Time Frame: | 36 months |
Safety Issue: | |
Description: | 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. |
Measure: | Deceased control rate (DCR) |
Time Frame: | 36 months |
Safety Issue: | |
Description: | DCR will be measure per resists 1.1 criteria. DCR will be summarized descriptively. |
Measure: | Duration of response (DOR) |
Time Frame: | 36 months |
Safety Issue: | |
Description: | 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. |
Measure: | Progress free survival (PFS) |
Time Frame: | 36 months |
Safety Issue: | |
Description: | PFS will be measure from entry onto the study until disease progression or death from any cause. PFS will be assessed using KAPLAN-MEIER methods. |
Measure: | Overall survival (OS) |
Time Frame: | 36 months |
Safety Issue: | |
Description: | The duration of overall survival (OS) will be measured from the time of first study drug administration until the date of death. OS will be assessed using KAPLAN-MEIER methods. |
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | Pionyr Immunotherapeutics Inc. |
December 31, 2020