MC# 20-41 - A Phase Ia/Ib Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of PY159 as a Single Agent and In Combination with Pembrolizumab in Subjects with Advanced Solid Tumors (PY159-2-01)

  • Agent(s): PY159
  • Disease Type(s): Breast, Cervical, Endometrial, Gastric, Head and Neck, Ovarian, Pancreatic, Lung-NSCLC, Vaginal, Vulva
  • Phase(s): I
  • Drug Classification(s): Targeted Therapy, Monoclonal Antibody
  • Molecular Target(s): TREML1 protein

Mechanism of Action

PY159 targets TREM1 to reprogram or repolarize suppressive myeloid cells to produce pro-inflammatory cytokines (including IFN-gamma, CXCL9, and CXCL10), as well as to upregulate immune-stimulatory cell surface proteins.

Purpose

In this study, the sponsor and investigators want to learn:

  • About the safety and tolerability of PY159 alone and in combination with Pembrolizumab
  • How proteins that indicate the status of your disease are affected with use of PY159
  • If PY159 prevents or delays tumor growth or shrinks existing tumors
  • How quickly PY159 is removed from the bloodstream
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 (head and neck cancer, gynecological cancers [including ovarian, endometrial, cervix, vagina, vulva], pancreatic [adenocarcinoma], lung [adenocarcinoma, squamous cell carcinoma], gastric (adenocarcinoma MSIlow and CPI refractory MSIhigh), breast [TNBC and Hormone Receptor Positive Breast Cancer (HR+) HER-2 Negative Breast Cancer (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 Programmed Cell Death-1 (PD-1)/Programmed Cell Death-Ligand 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 TREM1 expression confirmed by IHC (of fresh CNB) prior to enrollment.  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.
  3. Subjects must provide an original, diagnostic tumor sample to determine TREM1 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 (e.g. thyroid replacement therapy) before the start of study drug dosing, except for alopecia, peripheral neuropathy, or hypothyroidism
  7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2
  8. Life expectancy of ≥ 3 months, in the opinion of the Investigator
  9. Coagulation: International Normalized Ratio (INR) ≤ 1.3, unless on a stable dose of therapeutic anticoagulant
  10. Adequate hematologic function defined as follows: Platelets ≥ 100 x 109/L; Hemoglobin ≥ 9.0 g/dL; absolute neutrophil count (ANC) ≥ 1.5 x 109/L (without any granulocytic growth factors within previous 7 days of the screening hematologic laboratory values). Transfusions are allowed within 14 days of the first dose of PY159.
  11. 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
  12. 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
  13. Women of child-bearing potential must have a negative serum pregnancy test at screening and must agree to use an effective form of contraception from the time of consent and for up to 6 months after the last dose of study drug; Women of non-child-bearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥ 1 year
  14. Fertile men with partners of childbearing potential must agree to use an effective method of birth control during the study and for up to 6 months after the last dose of study drug
  15. Willingness and ability to provide written informed consent prior to any study-related procedures and to comply with all study requirements

Expansion Cohorts (Part B only)

  1. Tumor positive for TREM1 expression (pending H-score or IHC score inclusion criteria) using metastatic tumor tissue as measured by IHC
  2. Disease Specific Expansion Cohort Criteria

Ovarian Cancer - Subject must meet all the following

  • histologic diagnosis of epithelial ovarian, fallopian tube or primary peritoneal cancer
  • excludes germ cell, stromal cell, neuroendocrine and carcinosarcoma tumors
  • platinum refractory disease with or without prior maintenance therapy with biologic or targeted agent (e.g. maintenance bevacizumab, PARPi, or immunotherapy)

Metastatic Breast Cancer - Subject must meet one of the following:

  • Triple negative, defined as estrogen receptor (ER) negative, progesterone receptor (PR) negative, human epidermal growth factor receptor 2 (HER2) negative; HER2 negative defined as immunohistochemistry (IHC) 0 or 1+ or fluorescence in situ hybridization (FISH) negative
  • Refractory to at least one line of therapy for metastatic disease including a CPI containing regimen if approved for the subject’s clinical picture (per FDA approved label)
  • Hormone-refractory breast cancer (Histologically proven invasive breast carcinoma with hormone receptor+, HER2- status) with
    • Progression to endocrine therapy (e.g., tamoxifen, aromatase inhibitors, fulvestrant) unless contraindicated
    • Prior chemotherapy permitted provided progressive disease is documented

Lung Cancer - Subject must meet all of the following

  • metastatic NSCLC in which radiological progression has been demonstrated during or subsequent to prior therapy
  • prior therapy must include checkpoint blockade therapy with a PD-1/PD-L1 drug either alone or in combination with other agent(s).

Gastric Cancer - Subject must meet all the following

  • Has histologically confirmed non-resectable, metastatic gastric adenocarcinoma including adenocarcinoma of the gastroesophageal junction both MSIlow and CPI refractory MSIhigh
  • Has previously received at least 2 prior regimens for advanced disease including treatment with a CPI if indicated for their clinical picture (per FDA approved label)

Head and Neck Cancer - Subject must meet all the following

  • Must have pathologically confirmed squamous cell carcinoma of the head and neck (of the oral cavity, oropharynx, hypopharynx or larynx) with evidence of metastatic disease considered incurable by local therapies. Patients without pathologic or cytologic evidence of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation.
  • Patients must have progressed despite prior platinum containing chemotherapy (unless contraindicated in their care) and treatment with pembrolizumab

Pancreatic Cancer - Subject must meet all the following

  • metastatic pancreatic cancer in which radiological progression has been demonstrated during or subsequent to prior therapy
  • prior therapy must include either a gemcitabine or platinum-based chemotherapy regimen
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. Untreated and/or uncontrolled brain metastases.  (Treated, stable and asymptomatic metastases for at least 3 months prior to enrollment may be enrolled).  Stable patients with brain metastases receiving glucocorticoids must be on a stable dose for at least 3 months prior to enrollment.
  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 Congestive Heart Failure (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, 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. Subjects with a prior history of prostate cancer on LHRH agonist are eligible provided they have no evidence of metastatic disease.
  8. History of a concurrent or second malignancy, except for: adequately treated local basal cell or squamous cell carcinoma of the skin; cervical carcinoma in situ; superficial bladder cancer; breast carcinoma in situ; adequately treated Stage 1 or 2 cancer currently in complete remission; any other cancer that has been in complete remission for ≥ 5 years
  9. Known human immunodeficiency virus (HIV) infection or AIDS, except controlled and treated disease in Part B
  10. Known Positive Hepatitis B surface antigen test, except controlled and treated disease in Part B
  11. Known positive Hepatitis C antibody test, except treated disease resulting in cure in Part B
  12. History of long QT syndrome or whose corrected QT interval (QTc) measured (Fridericia method) at screening is prolonged (> 500 ms)
  13. Known sensitivity to any of the ingredients of the investigational product (refer to Section 5 of the IB for a list of ingredients)
  14. Has hypersensitivity to pembrolizumab or any of its excipients
  15. Major surgery, defined as any surgical procedure that involves general anesthesia and a significant incision (i.e., larger than what is required for placement of central venous access, percutaneous feeding tube, or biopsy) within 28 days of the first dose of study drug
  16. Minor surgical procedure(s) within 5 days of enrollment, or not yet recovered from prior surgery (placement of central venous access device, CNB, fine needle aspiration, or endoscopic biliary stent ≥ 1 day before enrollment is acceptable)
  17. Active infection requiring treatment within 7 days prior to 1st dose of study drug
  18. Active secondary malignancy unless the malignancy is not expected to interfere with the evaluation of safety and is approved by the Medical Monitor.  Examples of the latter include basal or squamous cell carcinoma of the skin, in-situ carcinoma of the cervix, and isolated elevation of prostate-specific antigen. (Subjects with a completely treated prior malignancy and no evidence of disease for ≥ 2 years are eligible)
  19. History or evidence of clinically significant disorder, condition, or disease that, in the opinion of the Investigator or Medical Monitor would pose a risk to subject safety or interfere with the study evaluations, procedures, or study completion
  20. Head and Neck Cancer
    • Metastatic disease impinging on the spinal cord or threatening spinal cord compression
    • Surgical fixation of bone lesion to be irradiated is required and indicated to provide mechanical stability

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT04682431

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Re: MC# 20-41