PT886 For Treatment of Patients With Metastatic/Advanced Gastric, Gastroesophageal Junction and Pancreatic Adenocarcinoma (the TWINPEAK Study)

Pancreatic Ductal Adenocarcinoma Clinical Trial

Official title:

A Phase 1/2, Open-Label, Dose Escalation and Expansion Study With PT886 Followed by a Multi-cohorT Study in Patients With Advanced GastrIc, Gastroesophageal JuNction (GEJ), or Pancreatic Ductal AdEnocarcinomas of PT886, in Combination With Either ChemotherApy, and/or the ChecKpoint Inhibitor Pembrolizumab TWINPEAK Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05482893
• Other study ID #: PT886X1101
• Secondary ID: KEYNOTE-F58 (MK-
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: March 15, 2023
• Est. completion date: April 2026

Study information

• Verified date: April 2024
• Source: Phanes Therapeutics
• Contact: Phanes Therapeutics
• Phone: 858-766-0852
• Email: clinical-trials[@]phanestx.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 114
• Est. completion date: April 2026
• Est. primary completion date: December 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria

Patients are eligible to be included in the study only if all the following criteria apply:

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. 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.

3. 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.

4. 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.

• Archival tissue can be used to assess the expression level of CLDN18.2 for all Parts. In Part D for Cohort 5, a newly acquired fresh biopsy may be requested unless a biopsy was taken after completion of zolbetuximab treatment.
• If the archival tissue is older than 12 months, we recommend a newly acquired fresh biopsy. For Parts C and D, willingness to have an on-treatment biopsy in patients that have stable disease or partial response at week 16, if deemed clinically feasible by the Investigator.

5. ECOG performance status of 0 or 1.

6. 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) = 9.0 g/dL1 (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). 1 Criteria must be met without packed red blood cell (pRBC) transfusion within the prior 2 weeks. Participants can be on stable dose of erythropoietin (= approximately 3 months).

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 (< Grade 3)). Patients with endocrine-related AEs Grade = 2 requiring treatment or hormone replacement may be eligible.

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 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.

10. Life expectancy >3 months. Exclusion Criteria

Patients are excluded from the study if any of the following criteria apply:

1. Women who are pregnant or lactating.

2. Women of child-bearing potential (WOCBP) who do not use adequate birth control.

3. 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.

4. 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.

5. 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.

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, 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.

9. Prior CLDN18.2 or CD47 targeting therapies, or SIRPa (signal regulatory protein alpha) targeting agents. For Part D, Cohort 5, prior treatment with zolbetuximab is allowed.

10. Patients that have received a live-virus vaccination within 30 days of planned treatment start.

11. Impaired cardiac function or significant diseases, including but not limited to any of

the following:

1. LVEF < 45% as determined by MUGA scan or ECHO.

2. Congenital long QT syndrome.

3. QTcF = 480 msec on screening ECG.

4. Unstable angina pectoris = 3 months prior to starting study drug.

5. 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. 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.

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. Patients who have experienced any thromboembolic event such as deep vein thrombosis (DVT) or pulmonary embolism in the past 6 months.

23. 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:

1. Patients on ART must have a CD4+ T-cell count >350 cells/mm3 at time of screening.

2. Patients on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks prior to screening.

3. Patients on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks prior to study entry (Day 1).

24. 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.

• Patients who are hBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization. Patients should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post completion of study intervention.
• Patients with history of HCV infection are eligible if HCV viral load is undetectable at screening. Patients must have completed curative anti-viral therapy at least 4 weeks prior to randomization.

25. 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.

26. Has had an allogeneic tissue/solid organ transplant.

Related Conditions & MeSH terms

• Adenocarcinoma
• Gastric or Gastroesophageal Junction Adenocarcinoma
• Pancreatic Ductal Adenocarcinoma

Intervention

Drug:
• PT886
PT886 monotherapy, a novel bispecific antibody that targets Claudin 18.2 and CD47.
• Paclitaxel
Chemotherapy as a combination partner to PT886 in Part C: Cohort 1
• Gemcitabine
Chemotherapy as a combination partner to Abraxane and PT886 in Part C: Cohort 2
• Abraxane
Chemotherapy as a combination partner to Gemcitabine and PT886 in Part C: Cohort 2
• KEYTRUDA® (pembrolizumab)
Immune checkpoint inhibitor as a combination partner to PT886 in Part D: Cohort 3, 4, and 5.
• Oxaliplatin
Chemotherapy as a combination partner to KEYTRUDA® (pembrolizumab) and PT886 in Part D: Cohort 4
• Leucovorin
Chemotherapy as a combination partner to KEYTRUDA® (pembrolizumab) and PT886 in Part D: Cohort 4
• Fluorouracil
Chemotherapy as a combination partner to KEYTRUDA® (pembrolizumab) and PT886 in Part D: Cohort 4
• Capecitabine
Chemotherapy as a combination partner to KEYTRUDA® (pembrolizumab) and PT886 in Part D: Cohort 4

Locations

Country	Name	City	State
United States	Dana-Farber Cancer Institute (DFCI)	Boston	Massachusetts
United States	Sarah Cannon Research Institute (SCRI)	Denver	Colorado
United States	NEXT Oncology	Fairfax	Virginia
United States	MD Anderson Cancer Center, GI Medical Oncology Dept	Houston	Texas

Sponsors (2)

Lead Sponsor	Collaborator
Phanes Therapeutics	Merck Sharp & Dohme LLC

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Pharmacodynamic markers of PT886 biological activity		Through study completion, an average of 2 years.
Other	Pretreatment CLDN18.2 expression in correlation with primary endpoints		Through study completion, an average of 2 years.
Primary	To determine the dose-limiting toxicity (DLT) of PT886.	Monitor grade 3 and higher related adverse events.	Through study completion, an average of 2 years
Primary	To determine the maximum tolerated dose (MTD) of PT886.		Through study completion, an average of 2 years
Primary	To determine recommended Phase 2 dose (RP2D) of PT886.		Through study completion, an average of 2 years
Primary	To evaluate the safety and tolerability of PT886		Through study completion, an average of 2 years
Secondary	To evaluate the pharmacokinetics of PT886		Through study completion, an average of 2 years
Secondary	To evaluate the immunogenicity (ADA) of PT886		Through study completion, an average of 2 years
Secondary	Preliminary Efficacy (assessed by the response rate by iRECIST and RECIST 1.1).		Through study completion, an average of 2 years