Dose Escalation/Expansion Study of PT199 (an Anti-CD73 mAb) Administered Alone and in Combination With a PD-1 Inhibitor

Study Overview
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Brief Summary
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This is a first-in-human, Phase I, open-label, dose-escalation and expansion study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of PT199 (an Anti-CD73 mAb) alone and in combination with a PD-1 inhibitor, in patients with locally advanced or metastatic solid tumors that have progressed after all available standard therapy or for which standard therapy has proven to be ineffective, intolerable, or is considered inappropriate.

Detailed Description
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PT199 is an anti-CD73 mAb with a differentiated mechanism of action. PT199 is designed to counter the adenosine-mediated immunosuppressive tumor microenvironment, rendering anti-tumor immune cells to be more responsive to checkpoint immunotherapies, such as PD-1/PD-L1 inhibitors. PT199 fully inhibits both soluble and membrane-bound CD73, unlike some other CD73 inhibitors which may inhibit only one form of enzyme or exhibit incomplete inhibition. Moreover, at higher concentrations no loss of inhibition or hook effect is observed with PT199. Hence, PT199 is expected to increase antitumor immune activation, especially in combination with PD-1 pathway inhibition, and thus offer a new treatment option for cancer patients.

Official Title
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A Phase I, First-in-Human, Open-Label, Dose Escalation and Expansion Study of PT199 Administered Alone and in Combination With a PD-1 Inhibitor in Adult Patients With Advanced Solid Tumors

Conditions
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Metastatic Cancer, Refractory Cancer, Non Small Cell Lung Cancer, Pancreatic Adenocarcinoma, Pancreatic Neoplasms, Lung Cancer

Intervention / Treatment
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* Drug: PT199
* Drug: Anti-PD-1 monoclonal antibody


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years or older and able to sign informed consent and comply with the protocol At least one measurable lesion as defined by RECIST V1.1 criteria for solid tumors Histologically or cytologically confirmed unresectable advanced or metastatic solid tumors previously treated with all available systemic standard therapy or for which treatment is not available or not tolerated, or for subjects enrolling in parts B and C (combination therapy groups) only anti PD-1 therapy is indicated as standard of care therapy. Able to provide a formalin fixed, paraffin embedded (FFPE) tumor tissue sample (archival tissue or fresh biopsy). To be assessed for CD73 and other biomarkers (PD-L1) expression. Biopsy must be excisional, incisional, or core. Needle aspiration is insufficient. Archival tissue is acceptable if biopsy was completed within 6 months. Biopsy is optional in part A (monotherapy dose escalation). ECOG performance status of 0 or 1 Adequate organ function confirmed at screening and within 7 days of initiating treatment, as evidenced by: Absolute neutrophil count (ANC) ≥ 1.5 × 109/L Hemoglobin (Hgb) ≥ 9 g/dl (RBC and Platelets transfusion are not allowed within 2 weeks of C1D1). Platelets (plt) ≥ 75 × 109/L AST/SGOT and ALT/SGPT ≤ 2.5 × Upper Limit of Normal (ULN) or ≤ 5.0 × ULN if liver metastases are present Total bilirubin ≤ 1.5 × ULN Calculated creatinine clearance ≥ 50 mL/min (Cockcroft Gault formula) Resolution of all acute adverse events resulting from prior cancer therapies to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE V5.0) Grade ≤ 1 or baseline (except alopecia or neuropathy) Negative serum pregnancy test within 72 hours before starting study treatment in all pre-menopausal women and women < 24 months after the onset of menopause (had a menstrual period in past 24 months) and are of childbearing potential (women who underwent hysterectomy or bilateral oophorectomy do not need a pregnancy test) Must agree to use effective contraceptive methods to avoid pregnancy (including male and female participants and partners of study subjects) during the study and until at least 6 months after ceasing study treatment. Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, established, proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception Exclusion Criteria: Women who are pregnant or lactating Women of child-bearing potential (WOCBP) who do not use adequate birth control Autoimmune disease requiring systemic treatment within the past twelve months Condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days prior to study treatment. Corticosteroids doses equivalent to Prednisone 10mg per day or less are allowed. Patients with a history of (non-infectious) pneumonitis that required steroids, current pneumonitis, or has a history of interstitial lung disease. Patients with untreated brain or central nervous system (CNS) metastases or brain/CNS metastases that have progressed (e.g., evidence of new or enlarging brain metastasis or new neurological symptoms attributable to brain/CNS metastases) Note: Patients with treated brain metastases that are off corticosteroids and have been clinically stable for 28 days are eligible for enrollment. Patients with a known concurrent malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, carcinoma in situ of the cervix or other noninvasive or indolent malignancy that has previously undergone potentially curative therapy. Patients who have received an investigational product, < 5 half-lives duration. Patients who have previously received immune checkpoint inhibitor therapy and discontinued treatment because of immune-related adverse events Patients who have allergies or hypersensitivity reactions to immune checkpoint inhibitor therapy or any of the inactive ingredients Prior T-cell, NK cell, or CD73 inhibitor therapy (Prior Checkpoint inhibitor anti PD-1 and anti PD-L1 therapies are allowed) Patients that have received a live-virus vaccination within 30 days of planned treatment start (exception Janssen JNJ-78436735 COVID-19 vaccine). Impaired cardiac function or significant diseases, including but not limited to any of the following: LVEF < 45% as determined by MUGA scan or ECHO Congenital long QT syndrome QTcF ≥ 480 msec on screening ECG Unstable angina pectoris ≤ 3 months prior to starting study drug Acute myocardial infarction ≤ 3 months prior to starting study drug Patients with uncontrolled hypertension or blood pressure of ≥ 150 mmHg systolic and/or ≥ 90 mmHg diastolic at Screening. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., uncontrolled hypertriglyceridemia [triglycerides > 500 mg/dL], or active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol Patients who have received chemotherapy, ≤ 5 half-lives or 3 weeks, whichever is shorter (6 weeks for nitrosourea or mitomycin-C), targeted therapy, or immunotherapy within 4 weeks prior to starting study drug Patients who have ≥ Grade 3 neuropathy Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug or who have not recovered from adverse events of prior therapy Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from adverse events of prior therapy Patients who are currently receiving treatment with therapeutic doses of warfarin sodium (Coumadin®) or any other coumarin-derivative anticoagulants (Other anticoagulants such as anti-thrombin or factor X are allowed). Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory; patients with well controlled HIV might be enrolled per investigator's discretion and Sponsor approval Evidence of active infection with Hepatitis B or Hepatitis C that is not adequately controlled. (For patients with known prior history of Hepatitis B or Hepatitis C, enrollment may be allowed per investigator's discretion and Sponsor approval.) Has a history or current evidence of any medical or psychiatric condition, therapy, or laboratory abnormality that, in the opinion of the investigator, might confound the results of the trial, interfere with the patient's safe participation and compliance in the trial. For example, conditions that depend on the establishment of collateral circulation, such as peripheral arterial vascular disease, myocardial infraction recovery period, etc

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: This is a first-in-human, Phase I, open-label, dose-escalation and expansion study. The study will consist of 3 parts: Monotherapy Dose Escalation (Part A), Combination Therapy Dose Escalation (Part B), and Combination Dose Expansion (Part C). Patients may be eligible for intra-patient dose escalation as well as crossover from Monotherapy to Combination therapy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A Monotherapy Dose Escalation<br>A standard 3+3 dose escalation design will be employed, and 3 patients will be enrolled initially at each dose level. The starting dose of PT199 to be evaluated in the dose escalation study is 10 mg/kg weekly (QW). Additional provisional dose levels include: 20 mg/kg QW, and 30 mg/kg QW. | Drug: PT199<br>* PT199 is an anti-CD73 mAb with a differentiated mechanism of action. PT199 is designed to counter the adenosine-mediated immunosuppressive tumor microenvironment, rendering anti-tumor immune cells to be more responsive to checkpoint immunotherapies, such as PD-1/PD-L1 inhibitors. PT199 fully inhibits both soluble and membrane-bound CD73<br>|
| Experimental: Part B Combination Therapy Dose Escalation<br>A standard 3+3 dose escalation design will be employed, and 3 patients will be enrolled initially at each dose level. The starting dose of PT199 to be evaluated in the dose escalation study is 20 mg/kg weekly (QW). The dose level of PD-1 inhibitor in all provisional dose levels will be 200 mg once every 3 weeks (Q3W). | Drug: PT199<br>* PT199 is an anti-CD73 mAb with a differentiated mechanism of action. PT199 is designed to counter the adenosine-mediated immunosuppressive tumor microenvironment, rendering anti-tumor immune cells to be more responsive to checkpoint immunotherapies, such as PD-1/PD-L1 inhibitors. PT199 fully inhibits both soluble and membrane-bound CD73<br>Drug: Anti-PD-1 monoclonal antibody<br>* Anti-PD-1 monoclonal antibody 200 mg Q3W, inhibits the lymphocytes PD-1 receptors, blocking the ligands that would deactivate it and prevent an immune response.<br>|
| Experimental: Part C Combination Therapy Dose Expansion<br>Approximately 8 additional patients will be treated in a dose expansion cohort at the MTD/DRDE | Drug: PT199<br>* PT199 is an anti-CD73 mAb with a differentiated mechanism of action. PT199 is designed to counter the adenosine-mediated immunosuppressive tumor microenvironment, rendering anti-tumor immune cells to be more responsive to checkpoint immunotherapies, such as PD-1/PD-L1 inhibitors. PT199 fully inhibits both soluble and membrane-bound CD73<br>Drug: Anti-PD-1 monoclonal antibody<br>* Anti-PD-1 monoclonal antibody 200 mg Q3W, inhibits the lymphocytes PD-1 receptors, blocking the ligands that would deactivate it and prevent an immune response.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD), if reached. | Monitor grade 3 and higher related adverse events. | Start of the study drug till 90 days after last dose. | 
| RP2D of PT199 as a single agent and/or in combination with a PD-1 inhibitor. | Monitor for MTD, and minimal efficacious dose by monitoring responses at different dose levels. | Start of the study drug till 90 days after last dose. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preliminary Efficacy (assessed by the response rate by iRECIST and RECIST 1.1). | Objective Response Rate (ORR = PR+CR). | Through study completion, an average of 2 years. | 
| PK Parameters. | Half Life T1/2 | Start of the study drug till 90 days after last dose. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced, Metastatic, Refractory, Anti-CD73, Checkpoint immunotherapies, PD-1/PD-L1 inhibitors