Status and phase
Conditions
Treatments
Study type
Funder types
Identifiers
About
This is a first-in-human, Phase 1/2, open-label, dose escalation and dose expansion and combination study designed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of PT886.
Patients with the following tumor types will be eligible for screening: unresectable or metastatic gastric adenocarcinoma, gastroesophageal junction (GEJ) adenocarcinoma, and pancreatic ductal adenocarcinoma (PDAC).
Enrollment
Sex
Ages
Volunteers
Inclusion and exclusion criteria
Inclusion Criteria
Patients are eligible to be included in the study only if all the following criteria apply:
18 years or older and able to sign informed consent and comply with the protocol.
Measurable disease as defined by RECIST V1.1 criteria for solid tumors. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Patients with measurable or non-measurable disease are allowed to participate in Part A of the study.
Part A and Part B: Histologically or cytologically confirmed unresectable advanced or metastatic solid gastric, gastroesophageal junction (GEJ), or pancreatic tumors (adenocarcinomas type) previously treated for advanced (metastatic or unresectable) disease or for which treatment is not available or not tolerated.
In Parts B, C and D, patients must present with ≥ 10% CLDN18.2 positive TC in their tumor tissue, with the exception of Cohort 2 (Part C) and Cohort 4 (Part D). For Cohorts 2 and 4. This cutoff may change based off emerging data. Archival tissue can be used to assess the expression level of CLDN18.2. For archival tissue older than 12 months, we recommend a fresh biopsy. For Part D, Cohort 5, patients must have ≥ 10% CLDN18.2 positive TC score in their tumor biopsy sample acquired after patients completed their prior zolbetuximab treatment.
Part C, Cohort 1: Patients with metastatic or advanced (m/a) GC/GEJ-C, that have progressed under 1L SOC chemotherapy +/- ICI, are treatment naïve to CLDN18.2 targeting agents, and are eligible for 2L SOC treatment. HER2+ patients are eligible. HER2+ patients may preferably continue with their HER2 targeted treatment due to the availability of a 2L targeted treatment option, such as trastuzumab deruxtecan if they are still HER2 positive. Patients who do not have access to 2L targeted treatment and are still HER2+ are eligible as long they present with ≥ 10% CLDN18.2 positive TC in their tumor tissue.
Part C, Cohort 2: PDAC patients, that are treatment naïve for their m/a disease and have no contra indication to receive Gemcitabine plus Abraxane (nab-paclitaxel).
Part D, Cohort 3: Patients with m/a GC/GEJ-C who have progressed under 1L or 2L SOC chemotherapy +/- ICI and are treatment naïve to CLDN18.2 targeting agents. Patients who were initially HER2+ and have exhausted their HER2 targeted therapy or where trastuzumab deruxtecan is not available, are equally eligible to be enrolled into this cohort and do not require a fresh biopsy. Patients will receive PT886 combined with pembrolizumab.
Part D, Cohort 4: Patients with m/a HER2 negative GC/GEJ-C, that are treatment naïve for their m/a disease.
Part D, Cohort 5: Patients with m/a GC/GEJ-C, that have progressed under 1L SOC chemotherapy, and zolbetuximab treatment, and are treatment naïve to pembrolizumab or other ICI therapy for their m/a disease. Patients must present with ≥ 10% CLDN18.2 positive TC in their tumor cells following their zolbetuximab treatment.
Biopsies:
Able to provide a formalin fixed, paraffin embedded (FFPE) tumor tissue sample (preferably fresh biopsy or if not possible, archival tissue) to be assessed for CLDN18.2 expression and other biomarkers. Biopsy must be excisional, incisional, or core needle. Fine needle aspiration is insufficient. This biopsy may not be done if the biopsy poses a risk to the patient and/or per the Investigators discretion.
ECOG performance status of 0 or 1.
Adequate organ function confirmed at screening and within 96 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 (< Grade 3)). Patients with endocrine-related AEs Grade ≤ 2 requiring treatment or hormone replacement may be eligible.
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 patients and partners of study patients) during the study and until at least 7 months after the last dose of 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, symptom-thermal, or post-ovulation methods) and withdrawal are not acceptable methods of contraception.
Life expectancy >3 months.
Exclusion Criteria
Patients are excluded from the study if any of the following criteria apply:
Women who are pregnant or lactating.
Women of child-bearing potential (WOCBP) who do not use adequate birth control.
Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
Condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days prior to study treatment. Corticosteroids doses equivalent to Prednisone 10 mg per day or less are allowed (see Criteria 3 for exceptions), or a single application of up to 8 mg dexamethasone i.v. over 30 minutes prior to dosing the first two PT886 doses, in individual cases.
Patients with a history of (non-infectious) pneumonitis that required steroids, current pneumonitis, or have a history of interstitial lung disease. History of COVID-19 pneumonia with fibrotic changes.
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 has required treatment for active disease within the previous 24 months. 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, 4 weeks or 5 half-lives, whichever is shorter, prior to start of study drug during Part A and Part B. Prior investigational treatment for m/a disease is not allowed during Part C and D, with the exception of Part D, Cohort 5, where prior zolbetuximab treatment is allowed.
Prior CLDN18.2 or CD47 targeting therapies, or SIRPα (signal regulatory protein alpha) targeting agents. For Part D, Cohort 5, prior treatment with zolbetuximab is 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 (defined as blood pressure of ≥ 150 mmHg systolic and/or ≥ 90 mmHg diastolic at Screening).
Prior hemolytic anemia or Evans Syndrome in the last 3 months.
RBC transfusion during the 4-week period prior to enrollment. RBC transfusions are not permitted during the screening period and prior to enrollment to meet the hemoglobin inclusion criteria.
Patients who have ≥ Grade 3 neuropathy.
Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., uncontrolled hypertriglyceridemia [triglycerides > 500 mg/dL], or active infection requiring parenteral treatment) 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 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 with a history of radiation pneumonitis are not eligible.
Note: Patients must have recovered from all radiation-related toxicities and not require corticosteroids. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.
Patients who have undergone major surgery ≤ 4 weeks prior to starting study drug or who have not recovered from adverse events of prior therapy.
Active gastric perforation, pyloric obstruction, complete biliary obstruction, complete or incomplete intestinal obstruction requiring clinical intervention, or pleural effusion or peritoneal effusion requiring clinical intervention.
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 inhibitors are allowed).
Patients who have experienced any thromboembolic event such as deep vein thrombosis (DVT) or pulmonary embolism in the past 6 months.
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). HIV-infected patients with a history of Kaposi sarcoma and/or Multicentric Castleman Disease are not eligible. HIV infected patients must be on antiretroviral therapy (ART) and have a well-controlled HIV infection/disease defined as:
Evidence of active infection with Hepatitis B or Hepatitis C that is not adequately controlled. (For patients with known prior history of Hepatitis B (defined as hBsAg reactive) or Hepatitis C (defined as HCV RNA [qualitative] is detected), enrollment may be allowed per Investigator's discretion). Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by a local health authority.
Has allergies or hypersensitivity (≥ Grade 3) to PT886 and/or any of its excipients (polysorbate 80, L-histidine, Sucrose, L-arginine-HCl), or to pembrolizumab and/or any of its excipients.
Has had an allogeneic tissue/solid organ transplant.
Primary purpose
Allocation
Interventional model
Masking
114 participants in 4 patient groups
Loading...
Central trial contact
Phanes Therapeutics
Data sourced from clinicaltrials.gov
Clinical trials
Research sites
Resources
Legal