Overview

PT886 For Treatment of Patients With Advanced Gastric, Gastroesophageal Junction and Pancreatic Adenocarcinomas

Status:
Not yet recruiting
Trial end date:
2024-01-01
Target enrollment:
0
Participant gender:
All
Summary
PT886 is a novel bispecific antibody that targets Claudin 18.2 and CD47. Claudin 18.2 is overexpressed in a significant proportion of gastric, esophageal, and pancreatic adenocarcinomas and its restricted expression makes it a promising therapeutic target for the treatment of these carcinomas. Moreover, studies have found that immunoglobulin superfamily CD47 is overexpressed widely across tumor types, and CD47 plays an important role in suppressing phagocytes activity through binding to the transmembrane protein SIRPα in phagocytic cells. Hence by targeting both pathways, one can direct macrophage-mediated phagocytotic activity to tumor cells by blocking the "don't eat me signal" mediated by CD47/ SIRPα interaction, potentially offering a better safety profile than anti-CD47 monoclonal antibodies. This is an open label, Phase I study to evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of PT886 in subjects with advanced or refractory cancers. 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) for which there is no available standard therapy.
Phase:
Phase 1
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
Phanes Therapeutics
Criteria
Inclusion Criteria:

1. 18 years or older and able to sign informed consent and comply with the protocol.

2. Measurable disease as defined by RECIST V1.1 criteria for solid tumors.

3. 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.

4. HER2 overexpressing gastric and GEJ adenocarcinoma patients must have experienced
anti-HER2 therapy (such as Trastuzumab) or anti-HER2 therapy is not tolerated.

5. Able to provide a formalin fixed, paraffin embedded (FFPE) tumor tissue sample
(archival tissue or fresh biopsy) to be assessed for Claudin 18.2 expression and other
biomarkers. Biopsy must be excisional, incisional, or core needle. Fine needle
aspiration is insufficient. Archival tissue is acceptable if biopsy was completed
within 6 months.

- For enrollment in the dose escalation phase, the assessment of Claudin 18.2
expression will not be part of the entry criteria; however, the assessment will
be carried out during the study to support the analysis of potential responders.

- For enrollment in the dose expansion phase of the study ONLY, patient's tumor
sample must express Claudin 18.2 in tumor cells as determined by central lab
immunohistochemistry (IHC) testing. The minimal level of Claudin 18.2 expression
is to be determined by assessment of tumor samples from the dose escalation
phase.

6. ECOG performance status of 0 or 1.

7. Adequate organ function confirmed at screening and within 96 hours of initiating
treatment, as evidenced by:

- Absolute neutrophil count (ANC) ≥ 1.5 × 109/L

- Hemoglobin (Hgb) ≥ 9.5 g/dl (RBC transfusions not permitted in the 4 week period
before enrollment).

- Platelets (plt) ≥ 100 × 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 without liver metastases (or < 3.0 x ULN if liver
metastases are present)

- Calculated creatinine clearance ≥ 30 mL/min (Cockcroft Gault formula)

8. 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).

9. 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).

10. 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 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, 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. History of
COVID-19 pneumonia with fibrotic changes.

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 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.

8. Patients who have received an investigational product, < 5 half-lives duration.

9. Prior T-cell, NK cell, Claudin 18 inhibitor therapy or CD47 inhibitor therapy, or
anti-SIRPα (signal regulatory protein alpha) targeting agents (Prior Checkpoint
inhibitor anti PD-1 and anti PD-L1 therapies are allowed).

10. Patients that have received a live-virus vaccination within 30 days of planned
treatment start (exception Janssen JNJ-78436735 COVID-19 vaccine).

11. 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 or stroke ≤ 3 months prior to starting study drug

12. Patients with uncontrolled hypertension (defined as blood pressure of ≥ 150 mmHg
systolic and/or ≥ 90 mmHg diastolic at Screening).

13. Prior hemolytic anemia or Evans Syndrome in the last 3 months.

14. 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.

15. Patients who have ≥ Grade 3 neuropathy.

16. 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.

17. 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

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. 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.

21. 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).

22. 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).

23. 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.)

24. 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 infarction
recovery period, etc.

25. Has allergies or hypersensitivity to polysorbate 80, L-Histidine, Sucrose,
L-arginine-HCl (PT886 inactive ingredients).