Study of SBRT/Olaparib Followed by Pembrolizumab/Olaparib in Gastric Cancers

NCT05379972 | Active Not Recruiting Phase 2 Results DMC FDA Drug

• 2 other identifiers: 21-4129.ccMK3475-A53
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 4

Brief Summary

This study is an open-label, phase II study with a safety lead-in to assess the response rate of induction olaparib and stereotactic beam radiotherapy (SBRT) followed by combination olaparib/pembrolizumab in patients with metastatic gastric and GEJ cancers after at least one of therapy.

Conditions

Gastric Cancer; GastroEsophageal Cancer

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR) of Unirradiated Tumors

  The proportion of patients with a complete response or partial response to treatment according to Immune Response Evaluation Criteria in Solid Tumors (iRECIST 1.1)

  2 years

Secondary Outcomes (5)

• Overall Survival (OS) of Total Cohort and HRD (Homologous Recombination Deficiency) Versus HR (Homologous Recombination) Proficient.

  4 years

• Progression Free Survival (PFS) of Total Cohort and HRD (Homologous Recombination Deficiency) Versus HR (Homologous Recombination) Proficient.

  4 years

• Duration of Response (DOR) of Total Cohort and HRD (Homologous Recombination Deficiency) Versus HR (Homologous Recombination) Proficient.

  4 years

• Disease Control Rate (DCR) of Total Cohort and HRD (Homologous Recombination Deficiency) Versus HR (Homologous Recombination) Proficient.

  4 years

• Number of Participants With Treatment-Related Adverse Events as Assessed by CTCAE v5.0 During Concurrent SBRT/Olaparib

  4 years

Study Arms (2)

HR deficient cohort

EXPERIMENTAL

Pre-identified presence of somatic or germline deleterious mutation, as determined by NGS only, in at least one gene critical to DNA repair through homologous recombination, including but not limited to: ARID1A, ATM, ATRX, MRE11A, NBN, PTEN, RAD50/51/51B, BARD1, BLM, BRCA1, BRCA2, BRIP1, FANCA/C/D2/E/F/G/L, PALB2, WRN, CHEK2, CHEK1, BAP1, FAM175A, SLX4, MLL2 or XRCC.

Drug: Pembrolizumab; Drug: Olaparib; Radiation: Stereotactic Body Radiation Therapy

HR proficient cohort

EXPERIMENTAL

No identifiable somatic or germline deleterious mutation in DNA Response and Repair pathway

Drug: Pembrolizumab; Drug: Olaparib; Radiation: Stereotactic Body Radiation Therapy

Interventions

Pembrolizumab DRUG

Pembrolizumab 200mg IV every 3 weeks starting C2D1

Also known as: Keytruda

HR deficient cohort; HR proficient cohort

Olaparib DRUG

Olaparib 200mg orally twice daily starting C1D1 concurrently with radiation. Starting C2D1, Olaparib 300mg orally twice with Pembrolizumab

Also known as: Lynparza

HR deficient cohort; HR proficient cohort

Stereotactic Body Radiation Therapy RADIATION

Stereotactic Body Radiation Therapy Dose 25Gy in 5 fractions daily (M-F) for 5 days starting C1D1 with Olaparib

Also known as: SBRT

HR deficient cohort; HR proficient cohort

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision to sign and date the consent form.
• Participant must be ≥ 18 years of age
• Histologically confirmed metastatic gastric or GEJ adenocarcinoma that is amenable to biopsy either at primary or metastatic site.
• Patient must consent at initiation of study to serial tumor biopsies during study. Irradiated lesions will not be considered for biopsy. For baseline biopsy, available archived tumor tissue of a metastatic tumor collected up to 28 days prior to registration is acceptable. If, after patient consent, the tumor is deemed inaccessible, the biopsy is not in the subject's best interest per investigator discretion, or the patient refuses biopsy during course of the study, patients will be allowed to remain on study.
• Participant must have a primary tumor or a single metastatic site amenable to radiation in: the stomach, esophagus, liver, lungs, pancreas, thoracic/abdominal LNs, or soft tissues. Of note - sites of disease planned to be biopsied should not be radiated.
• Participant must have at least one radiographically-confirmed index lesion that will not undergo RT and is measurable based on RECIST v1.1.
• Homologous recombination deficiency cohort: pre-identified presence of somatic or germline deleterious mutation, as determined by NGS only, in at least one gene critical to DNA repair through homologous recombination, including but not limited to: ARID1A, ATM, ATRX, MRE11A, NBN, PTEN, RAD50/51/51B, BARD1, BLM, BRCA1, BRCA2, BRIP1, FANCA/C/D2/E/F/G/L, PALB2, WRN, CHEK2, CHEK1, BAP1, FAM175A, SLX4, MLL2 or XRCC.
• All patients must undergo NGS testing in a CLIA certified, CAP tested and bioinformatics-validated testing lab PRIOR to protocol treatment, to determine which cohort they are eligible for - HRD versus HR proficient. The testing may have been done at any time prior to enrollment.
• For patients within whom a deleterious mutation in the homologous recombination pathway is found, the determination of a deleterious mutation must be supported in the documentation included in the testing, and should include clinical, or pre-clinical literature to support the finding that a specific mutation results in impaired function of the gene, and thus impaired DNA repair through homologous recombination. Variants of unknown significance will not be eligible.
• Participants must have received at least one line of therapy including a fluoropyrimidine and platinum drug. For participants with HER2+ tumors, they must have received trastuzumab. Adjuvant therapy does not count toward first-line therapy unless patient recurs within 6 months of completion.
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Participants must have the ability to swallow whole pills and liquids at the Screening Visit and, in the investigator's judgement, for the duration of the study.
• Have adequate organ function as defined in Table 1:
• Table 1: Adequate Organ Function Laboratory Values:
• System: Laboratory Value:

You may not qualify if:

• An individual who meets any of the following criteria will be excluded from participation in this study:
• Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to allocation.
• Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.
• Note: If participant received major surgery within 4 weeks, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.
• Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids specifically for radiation toxicities, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
• Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. Note: Vaccines for SARS CoV- 2 will be permitted before and during the course of study.
• 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 treatment. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
• 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.
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded
• Has known active CNS metastases and/or carcinomatous meningitis that requires ongoing treatment or are found to be progressing. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
• Has severe hypersensitivity (≥Grade 3) to pembrolizumab or olaparib and/or any of its excipients.
• Participant must not have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
• Has 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 (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Has an active infection requiring systemic therapy.

Sponsors & Collaborators

• University of Colorado, Denver: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (4)

University of Colorado Health

Aurora, Colorado, 80045, United States

Location

UCHealth Memorial Hospital North

Colorado Springs, Colorado, 80909, United States

Location

UCHealth Memorial Hospital Central

Colorado Spring, Colorado, 80909, United States

Location

UCHealth Highlands Ranch Hospital

Highlands Ranch, Colorado, 80129, United States

Location

MeSH Terms

Conditions

Stomach Neoplasms

Interventions

pembrolizumab; olaparib; Radiosurgery

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases

Intervention Hierarchy (Ancestors)

Radiotherapy; Therapeutics; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques

Results Point of Contact

• Title: Sunnie Kim
• Organization: University of Colorado

Sunnie.kim@cuanschutz.edu

7208483532

Study Officials

• Sunnie S Kim, MD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 13, 2022
• First Posted: May 18, 2022
• Study Start: January 12, 2023
• Primary Completion: February 24, 2025
• Study Completion (Estimated): December 1, 2028
• Last Updated: May 4, 2026
• Results First Posted: May 4, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data requests can be submitted starting 9 months after article publication and the data will be made accessible for up to 24 months. Extensions will be considered on a case-by-case basis.
• Access Criteria: Access to trial IPD can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA).

Locations

US (4)