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

• ClinicalTrials.gov Identifier: NCT05431270
• Recruitment Status: Recruiting
• First Posted: June 24, 2022
• Last Update Posted: December 2, 2022
• Sponsor: Phanes Therapeutics
• Information provided by (Responsible Party): Phanes Therapeutics

Tracking Information

• First Submitted Date: May 25, 2022
• First Posted Date: June 24, 2022
• Last Update Posted Date: December 2, 2022
• Actual Study Start Date: June 23, 2022
• Estimated Primary Completion Date: November 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 21, 2022)

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 21, 2022)

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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Dose Escalation/Expansion Study of PT199 (an Anti-CD73 mAb) Administered Alone and in Combination With a PD-1 Inhibitor
• Official Title: 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
• Brief Summary: 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: 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.
• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention 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)
Primary Purpose: Treatment

Condition

• Advanced Solid Tumor
• Metastatic Cancer
• Refractory Cancer
• Non Small Cell Lung Cancer
• Pancreatic Adenocarcinoma
• Pancreatic Neoplasms
• Gastric Adenocarcinoma
• Gastric Cancer
• Esophageal Cancer
• Hepatic Carcinoma
• Ovarian Cancer
• Head and Neck Cancer
• Head-and-neck Squamous Cell Carcinoma
• Colo-rectal Cancer
• Colon Adenocarcinoma
• Breast Adenocarcinoma
• Triple Negative Breast Cancer
• Thyroid Cancer
• Lung Cancer

Intervention

• Drug: PT199
  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
• Drug: Anti-PD-1 monoclonal antibody
  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.

Study Arms

• Experimental: Part A Monotherapy Dose Escalation
  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.
  Intervention: Drug: PT199
• Experimental: Part B Combination Therapy Dose Escalation
  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).
  Interventions:

  • Drug: PT199
  • Drug: Anti-PD-1 monoclonal antibody
• Experimental: Part C Combination Therapy Dose Expansion
  Approximately 8 additional patients will be treated in a dose expansion cohort at the MTD/DRDE
  Interventions:

  • Drug: PT199
  • Drug: Anti-PD-1 monoclonal antibody

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 28, 2022): 41
• Original Estimated Enrollment (submitted: June 21, 2022): 38
• Estimated Study Completion Date: January 2024
• Estimated Primary Completion Date: November 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. 18 years or older and able to sign informed consent and comply with the protocol
2. At least one measurable lesion as defined by RECIST V1.1 criteria for solid tumors
3. 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.

4. 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).
5. ECOG performance status of 0 or 1

6. 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)
7. 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)
8. 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)
9. 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:

1. Women who are pregnant or lactating
2. Women of child-bearing potential (WOCBP) who do not use adequate birth control
3. Autoimmune disease requiring systemic treatment within the past twelve months
4. 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.
5. Patients with a history of (non-infectious) pneumonitis that required steroids, current pneumonitis, or has a history of interstitial lung disease.
6. 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.
7. 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.
8. Patients who have received an investigational product, < 5 half-lives duration.
9. Patients who have previously received immune checkpoint inhibitor therapy and discontinued treatment because of immune-related adverse events
10. Patients who have allergies or hypersensitivity reactions to immune checkpoint inhibitor therapy or any of the inactive ingredients
11. Prior T-cell, NK cell, or CD73 inhibitor therapy (Prior Checkpoint inhibitor anti PD-1 and anti PD-L1 therapies are allowed)
12. Patients that have received a live-virus vaccination within 30 days of planned treatment start (exception Janssen JNJ-78436735 COVID-19 vaccine).

13. 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
14. Patients with uncontrolled hypertension or blood pressure of ≥ 150 mmHg systolic and/or ≥ 90 mmHg diastolic at Screening.
15. 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
16. 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
17. Patients who have ≥ Grade 3 neuropathy
18. 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
19. Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from adverse events of prior therapy
20. 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).
21. 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
22. 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.)
23. 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Phanes Therapeutics; 858-766-0852; clinical-trials@phanestx.com

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT05431270
• Other Study ID Numbers: PT199X1101
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Phanes Therapeutics
• Original Responsible Party: Same as current
• Current Study Sponsor: Phanes Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Phanes Therapeutics
• Verification Date: November 2022