Chemotherapy and Pembrolizumab, Followed by Pembrolizumab and Olaparib As Firstline Therapy in Her-2 Negative Gastric/GEJ Adenocarcinoma

NCT05268510 | Completed Phase 2 DMC

• 1 other identifier: POLESTAR
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

Brief Summary

This is a multicenter, single arm, prospective, open-label phase II trial investigating the clinical activity of a first-line therapy consisting of induction chemotherapy plus pembrolizumab (12 weeks of mod. FOLFOX-6 plus pembrolizumab or 12 weeks of CAPOX plus pembrolizumab) followed by pembrolizumab plus olaparib.

Conditions

Esophagogastric Adenocarcinoma

Keywords

gastric adenocarcinoma; GEJ adenocarcinoma; Her-2 negative esophagogastric adenocarcinoma

Outcome Measures

Primary Outcomes (1)

• Overall survival (OS) rate at 1 year

  Overall survival (OS) rate at 1 year defined as the percentage of patients who remain alive one year after enrollment into the study

  1 year after enrolment

Secondary Outcomes (7)

• Progression-free survival (PFS)

  up to 55 months

• Objective response rate (ORR)

  up to 55 months

• Best Overall Response (BOR)

  up to 55 months

• Time to tumor progression (TTP)

  up to 55 months

• Overall Survival (OS)

  up to 55 months

Other Outcomes (3)

• Immune cell states (exploratory translational outcome)

  up to 55 months

• Predictive value of PD-L1 CPS (exploratory translational outcome)

  up to 55 months

• Other exploratory translational outcomes:

  up to 55 months

Study Arms (1)

Chemotherapy plus Pembrolizumab followed by Pembrolizumab and Olaparib

EXPERIMENTAL

Chemotherapy plus Pembrolizumab 2 cycles à 6 weeks: Pembrolizumab+mod FOLFOX-6: * Pembrolizumab 400 mg 30 min. day 1 * Oxaliplatin 85 mg/m² 2h day 1, 15, 29 * Leucovorin 400 mg/m² 2h day 1, 15, 29 * 5-FU 400 mg/m² bolus, followed by 2.400 mg/m² 46h day 1, 15, 29 or Pembrolizumab+CapOx: * Pembrolizumab 400 mg 30 min. day 1 * Oxaliplatin 130 mg/m² 2h day 1,22 * Capecitabine 1.000 mg/m² bid. day 1-14, 22-35 Consolidation phase Pembrolizumab and Olaparib max 16 cycles à 6 weeks: * Pembrolizumab 400 mg 30 min. day 1 * Olaparib 300 mg bid. cont. day 1 to 42

Drug: Pembrolizumab; Drug: Olaparib; Drug: mFOLFOX-6; Drug: CapOX

Interventions

Pembrolizumab DRUG

400 mg Pembrolizumab day 1 Q6W (max. 18 cycles)

Also known as: Keytruda

Chemotherapy plus Pembrolizumab followed by Pembrolizumab and Olaparib

Olaparib DRUG

300 mg Olaparib bid. cont. day 1 to 42 (max. 16 cycles)

Also known as: Lynparza

Chemotherapy plus Pembrolizumab followed by Pembrolizumab and Olaparib

mFOLFOX-6 DRUG

Oxaliplatin 85 mg/m² 2h day 1, 15, 29 plus Leucovorin 400 mg/m² 2h day 1, 15, 29 plus 5-FU 400 mg/m² bolus, followed by 2.400 mg/m² 46h day 1, 15, 29; Q6W, 2 cycles

Chemotherapy plus Pembrolizumab followed by Pembrolizumab and Olaparib

CapOX DRUG

Oxaliplatin 130 mg/m² 2h day 1,22 plus Capecitabine 1.000 mg/m² bid. day 1-14, 22-35; Q6W, 2 cycles

Chemotherapy plus Pembrolizumab followed by Pembrolizumab and Olaparib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Metastatic or unresectable, histologically confirmed Her-2 negative (as assessed locally by a certified test) adenocarcinoma of the gastroesophageal junction (AEG I- III according to Sievert´s classification) or the stomach.
• Adjuvant/neoadjuvant or perioperative chemotherapy or chemoradiotherapy must have been finished at least 6 months before start of the study intervention.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Ability for oral intake of the study drug.
• Male/female\* participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of esophagogastric adenocarcinoma will be enrolled in this study.
• There are no data that indicate special gender distribution. Therefore, patients will be enrolled in the study gender-independently.
• Male participants: A male participant must agree to use a contraception during the treatment period and for at least 6 months after the last dose of study intervention and refrain from donating sperm during this period.
• Female participants: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
• Not a woman of childbearing potential (WOCBP) OR
• A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 6 months after the last dose of study intervention.
• The participant provides written informed consent for the trial.
• Have measurable or evaluable disease based on RECIST 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
• Have provided archival tumor tissue sample. FFPE tissue blocks are preferred to slides.
• Have adequate organ function as defined in the following table. Specimens must be collected within 14 days prior to the start of study intervention:
• Hematological:

You may not qualify if:

• A WOCBP who has a positive urine pregnancy test within 72 hours prior to start of study intervention. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137). Has received any previous treatment with a PARP inhibitor, including Olaparib.
• Persistent clinically relevant toxicities, CTCAE Grade \> 2 caused by previous cancer treatment.
• Has received prior radiotherapy within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.
• Participant received colony-stimulating factors (eg, granulocyte colony-stimulating factor \[G-CSF\], granulocyte-macrophage colony-stimulating factor \[GM CSF\] or recombinant erythropoietin) within 28 days prior to the first dose of study intervention.
• Participant is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption.
• Major surgery within 2 weeks of starting study intervention and patients must have recovered from any effects of any major surgery.
• Participant is currently receiving either strong (eg, itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil) inhibitors of cytochrome P450 (CYP)3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 2 weeks. Note: a current list of strong/moderate inhibitors of CYP3A4 can be found at the following website: https://www.fda.gov/drugs/drug-interactions-labeling/drug- development-and-drug-interactions-table-substrates-inhibitors-and-inducers
• Participant is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate (eg. bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be discontinued for the duration of the study. The required washout period prior to starting olaparib is 5 weeks for phenobarbital and 3 weeks for other agents.
• Note: a current list of strong/moderate inducers of CYP3A4 can be found at the following website: https://www.fda.gov/drugs/drug-interactions-labeling/drug- development-and-drug-interactions-table-substrates-inhibitors-and-inducers
• Concomitant use of drugs inhibiting DPD activity (including sorivudine, brivudine), the required wash out phase is 4 weeks before start of the study intervention.
• Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation \> 500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome.
• Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first dose of study drug. Administration of killed vaccines is allowed.
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.

Sponsors & Collaborators

• Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest: lead

Study Sites (1)

Universitätsklinikum Heidelberg

Heidelberg, Germany

Location

MeSH Terms

Interventions

pembrolizumab; olaparib

Study Officials

• Salah-Eddin Al-Batran, Prof. Dr.

  Institut für Klinische Krebsforschung IKF GmbH

  STUDY DIRECTOR

• Georg Martin Haag, PD Dr.

  National Center for Tumor Diseases, University Hospital Heidelberg

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Eligible subjects will receive 2 six-week (q42d) cycles of mod. FOLFOX-6 plus 400 mg pembrolizumab. Alternatively, subjects may receive 2 six-week (q42d) cycles of CAPOX plus 400 mg pembrolizumab. The decision for either mod. FOLFOX-6 or CAPOX is made at the sole discretion of the investigator taking into account the best interest of the patient. Following the chemotherapy induction phase, the subjects are scheduled to receive up to 16 six-week (q42d) cycles of pembrolizumab (400 mg) plus olaparib (300 mg bid.).

Study Record Dates

• First Submitted: February 15, 2022
• First Posted: March 7, 2022
• Study Start: September 15, 2022
• Primary Completion: August 27, 2024
• Study Completion: January 9, 2025
• Last Updated: February 20, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

DE (1)