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

Phanes Therapeutics

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Pancreatic Ductal Adenocarcinoma; Gastric or Gastroesophageal Junction Adenocarcinoma

Treatments: Drug: FOLFIRINOX; Drug: KEYTRUDA® (pembrolizumab); Drug: Paclitaxel; Drug: Capecitabine; Drug: Oxaliplatin; Drug: Leucovorin; Drug: PT886; Drug: Abraxane; Drug: Gemcitabine; Drug: Fluorouracil

Study type: Interventional

Funder types: Industry

Identifiers

NCT05482893

PT886X1101

KEYNOTE-F58 (MK-3475-F58) (Other Identifier)

Details and patient eligibility

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: 135 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Key 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. 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.

   Part C, Cohort 1: 2L m/a GC/GEJ-C patients will receive PT886 in combination with Paclitaxel.

   Part C, Cohort 2: 1L m/a PDAC patients will receive PT886 in combination with Gemcitabine plus nab-Paclitaxel (Abraxane).

   Part C, Cohort 2b: 1L m/a PDAC patients will receive PT886 in combination with Gemcitabine plus FOLFIRINOX/mFFX.

   Part D, Cohort 3: 2L or 3L m/a GC/GEJ-C patients will receive PT886 in combination with KEYTRUDA® (pembrolizumab).

   Part D, Cohort 4: 1L HER2 negative m/a GC/GEJ-C patients will receive PT886 in combination with SOC chemotherapy and KEYTRUDA® (pembrolizumab).

   Part D, Cohort 5: Patients with m/a GC/GEJ-C, that have progressed under 1L SOC chemotherapy, and zolbetuximab, will receive PT886 in combination with KEYTRUDA® (pembrolizumab).

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. This biopsy may not be done if the biopsy poses a risk to the patient and/or per the Investigators discretion.

   Parts B, C and D: Patients must present with ≥ 50%; ≥ 2+ (Part B) or ≥ 10%; ≥ 2+ (Parts C and D) CLDN18.2 positive TC in their tumor tissue.

5. ECOG performance status of 0 or 1.

6. Adequate organ function confirmed at screening and within 96 hours of initiating treatment.

Key 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.
4. Condition requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days prior to study treatment.
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).
7. 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.
8. Impaired cardiac function or significant diseases.
9. Prior hemolytic anemia or Evans Syndrome in the last 3 months.
10. 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.
11. Patients who have experienced any thromboembolic event such as deep vein thrombosis (DVT) or pulmonary embolism in the past 6 months.

Additional inclusion and exclusion criteria will apply.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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135 participants in 4 patient groups

Dose Escalation

Experimental group

Description:

An accelerated titration design will be employed for early dose levels, followed by the standard 3+3 design at higher dose levels.

Treatment:

Drug: PT886

Dose Expansion

Experimental group

Description:

Two dose levels will be explored; the recommended dose for expansion (RDE) from Part A, and another dose level.

Treatment:

Drug: PT886

Combination Expansion with Chemotherapy

Experimental group

Description:

Part C, Cohort 1: 2L m/a GC/GEJ-C patients will receive PT886 in combination with Paclitaxel. Part C, Cohort 2: 1L m/a PDAC patients will receive PT886 in combination with Gemcitabine plus nab-Paclitaxel (Abraxane). Part C, Cohort 2b: 1L m/a PDAC patients will receive PT886 in combination with Gemcitabine plus FOLFIRINOX/mFFX.

Treatment:

Drug: Gemcitabine

Drug: Abraxane

Drug: PT886

Drug: Paclitaxel

Drug: FOLFIRINOX

Combination Expansion with KEYTRUDA® (pembrolizumab)

Experimental group

Description:

Part D, Cohort 3: 2L or 3L m/a GC/GEJ-C patients will receive PT886 in combination with KEYTRUDA® (pembrolizumab). Part D, Cohort 4: 1L HER2 negative m/a GC/GEJ-C patients will receive PT886 in combination with SOC chemotherapy and KEYTRUDA® (pembrolizumab). Part D, Cohort 5: Patients with m/a GC/GEJ-C, that have progressed under 1L SOC chemotherapy, and zolbetuximab, will receive PT886 in combination with KEYTRUDA® (pembrolizumab).

Treatment:

Drug: Fluorouracil

Drug: PT886

Drug: Leucovorin

Drug: Capecitabine

Drug: Oxaliplatin

Drug: KEYTRUDA® (pembrolizumab)