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About
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.
Full 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. PT199 is a highly selective mAb, and thus far in development no off-target effects or dose limiting toxicities in cynomolgus monkey safety studies have been observed. Hence, PT199 addresses the limitations of current CD73 inhibitors and 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.
Enrollment
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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.
For Part A, a 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.
For Part B and C either:
(i) A histologically or cytologically confirmed diagnosis of NSCLC and radiological documentation of disease progression on standard of care, treatment may include a checkpoint inhibitor. (ii) NSCLC patients with confirmation that the tumor harbors an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) are eligible providing they have documented radiological progression after standard of care, including tyrosine kinase inhibitor (TKI) therapy, and are immune-checkpoint inhibitor (ICI) naive. (iii) A histologically or cytologically confirmed diagnosis of pancreatic ductal adenocarcinoma (PDAC) and documented radiological progression on standard of care treatment, with no more than 2 lines of treatment for metastatic disease.
In Part A, 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. In Parts B and C, fresh tumor biopsies are required if patients are clinically doing well, unless deemed by the Investigator to cause risk to the patient. If a fresh biopsy is not possible at baseline during Part B and C, archival tissue will be acceptable if the biopsy was collected within 6 months of screening.
ECOG performance status of 0 or 1.
Adequate organ function confirmed at screening and within 72 hours of initiating treatment, as evidenced by:
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 patients) 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.
Life expectancy > 3 months.
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. Active autoimmune disease or a history of autoimmune diseases that may relapse. Note: Patients with the following diseases are not excluded and may proceed to further screening:
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. Note: Patients who are currently or have previously been on any of the following steroid regimens are not excluded:
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 in part A (monotherapy arm). Patients who have received an investigational product at any time in parts B and C (combination therapy arms).
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.
Impaired cardiac function or significant diseases, including but not limited to any of the following:
Patients with uncontrolled hypertension, or with blood pressure of ≥ 150 mmHg systolic and/or ≥ 90 mmHg diastolic after triplicate measurements, each collection at least 10 minutes apart, at screening. The average from the triplicate measurements will be used for eligibility criteria. Patient must be in a stable condition with blood pressures controlled at < 150 systolic and < 90 diastolic, at least for the past 28 days, as evidence by records from the charts.
Patient must also be on a stable dose of antihypertensives.
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.
Primary purpose
Allocation
Interventional model
Masking
40 participants in 3 patient groups
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Central trial contact
Phanes Therapeutics
Data sourced from clinicaltrials.gov
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