Clinical Trials /

A Study of PY314 in Subjects With Advanced Solid Tumors

NCT04691375

Description:

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).

Related Conditions:
  • Breast Carcinoma
  • Cervical Carcinoma
  • Clear Cell Renal Cell Carcinoma
  • Colon Carcinoma
  • Endometrial Carcinoma
  • Gastric Adenocarcinoma
  • Lung Adenocarcinoma
  • Non-Clear Cell Renal Cell Carcinoma
  • Ovarian Carcinoma
  • Vaginal Carcinoma
  • Vulvar Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study of PY314 in Subjects With Advanced Solid Tumors
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: PY314-1-01
  • NCT ID: NCT04691375

Conditions

  • Advanced Solid Tumor
  • Gynecologic Cancer
  • Breast Cancer
  • Colon Cancer
  • Lung Adenocarcinoma
  • Gastric Adenocarcinoma
  • Kidney Cancer

Interventions

DrugSynonymsArms
PY314Part A: PY314 Single agent dose level 1
Combination Therapy: PY314 + PembrolizumabPY314, PembrolizumabPart A: Combination dose level 1

Purpose

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

      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
    

Trial Arms

NameTypeDescriptionInterventions
Part A: PY314 Single agent dose level 1ExperimentalPY314 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.
  • PY314
Part A: PY314 Single agent dose level 2ExperimentalPY314 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.
  • PY314
Part A: PY314 Single agent dose level 3ExperimentalPY314 single agent dose level 3 to identify the maximum tolerated dose and/or to determine the recommended dose for expansion of PY314
  • PY314
Part A: PY314 Single agent dose level 4ExperimentalPY314 single agent dose level 4 to characterize the pharmacokinetic profile of PY314 as a single agent.
  • PY314
Part A: Combination dose level 1ExperimentalCombination 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.
  • Combination Therapy: PY314 + Pembrolizumab
Part A: Combination dose level 2ExperimentalPY314 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.
  • Combination Therapy: PY314 + Pembrolizumab
Part A: Combination dose level 3ExperimentalPY314 combination dose level 3 to characterize the pharmacokinetic profile of PY314 as a single agent and in combination with pembrolizumab.
  • Combination Therapy: PY314 + Pembrolizumab
Part A: Combination dose level 4ExperimentalPY314 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.
  • Combination Therapy: PY314 + Pembrolizumab
Part B: Single agent dose expansion dose level 1ExperimentalPY314 single agent dose expansion dose level 1 to define further the safety and tolerability of PY314 alone.
  • PY314
Part B: Single agent dose expansion dose level 2ExperimentalPY314 single agent dose expansion dose level 2 to further characterize the PK profile of PY314 as a single agent.
  • PY314
Part B: Combination dose expansion cohort 1ExperimentalPY314 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.
  • Combination Therapy: PY314 + Pembrolizumab
Part B: Combination dose expansion cohort 2ExperimentalPY314 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.
  • Combination Therapy: PY314 + Pembrolizumab
Part B: Combination dose expansion cohort 3ExperimentalPY314 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.
  • Combination Therapy: PY314 + Pembrolizumab
Part B: Combination dose expansion cohort 4ExperimentalPY314 in combination with pembrolizumab dose expansion cohort 4 to evaluate the incidence of ADA formation and TREM2 expression.
  • Combination Therapy: PY314 + Pembrolizumab

Eligibility Criteria

        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 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.

               -  Expansion Cohorts (Part B): Subjects with advanced solid tumors selected from
                  prespecified histologic subgroups identified in Part A.

          -  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 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 (Part A, including prior treatment
             with a CPI (alone or in combination), if approved for that indication

          -  Measurable disease by RECIST 1.1

          -  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

          -  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 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)

          -  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:

          -  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.

          -  History of autoimmune disorder requiring ongoing or intermittent disease-modifying
             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 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, radiotherapy, or any other agents to treat cancer within
             14 days, of first dose of study drug

          -  Part B: excluding 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of Adverse Events (AE)
Time Frame:36 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.

Secondary Outcome Measures

Measure:Measure PY314 concentration at the end of infusion (CEOI)
Time Frame:36 months
Safety Issue:
Description:Measure PY314 concentration at the end of infusion (CEOI) after the first dose.
Measure:Measure PY314 concentration at the trough level (Ctrough)
Time Frame:36 months
Safety Issue:
Description: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.
Measure:Determining PY314 time to maximum concentration (Tmax)
Time Frame:36 months
Safety Issue:
Description:Determining PY314 time to maximum concentration (Tmax) during Cycle 1.
Measure:Measure PY314 Area under the curve (AUC)0-t
Time Frame:36 months
Safety Issue:
Description: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.
Measure:Measure PY314 half-life (T1/2)
Time Frame:36 months
Safety Issue:
Description: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.
Measure:Measure PY314 Clearance (CL)
Time Frame:36 months
Safety Issue:
Description: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.
Measure:Measure PY314 Volume at Steady State (Vss)
Time Frame:36 months
Safety Issue:
Description: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.
Measure:Measure PY314 maximum concentration (Cmax)
Time Frame:36 months
Safety Issue:
Description: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.
Measure:Incidence of Anti-Drug Antibody (ADA) formation to PY314
Time Frame:36 months
Safety Issue:
Description:To evaluate the incidence of anti-drug antibody (ADA) formation to PY314
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:Clinical Benefit Rate (CBR)
Time Frame:36 Months
Safety Issue:
Description:Defined as the percentage of subjects who have achieved complete response, partial response and stable disease.
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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Pionyr Immunotherapeutics Inc.

Last Updated

June 16, 2021