SBRT + Olaparib and Pembrolizumab + Olaparib for Gastric Cancer

Not currently recruiting at 3 trial locations

Overseen By Kebron Elias

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Colorado, Denver

Must not be taking: Live vaccines

Disqualifiers: Active infection, CNS metastases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatment combinations for individuals with metastatic gastric (stomach) or GEJ (gastroesophageal junction) cancers. It examines the effectiveness of combining olaparib (Lynparza, a targeted therapy), pembrolizumab (KEYTRUDA, an immunotherapy drug), and targeted radiation therapy (SBRT, Stereotactic Body Radiation Therapy). Participants will be grouped based on their genetic makeup, specifically the presence of certain DNA repair mutations, which may affect their response to the treatment. Candidates who have undergone at least one type of cancer treatment and can swallow pills may qualify for this study. The research aims to discover more effective methods for managing and treating advanced gastric cancer. As a Phase 2 trial, it focuses on assessing the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to advancements in cancer care.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on corticosteroids, you may continue as long as your dose is stable for at least 4 weeks before starting the trial. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that combining the drugs olaparib and pembrolizumab is generally safe. Common side effects include low red blood cell count (anemia), nausea, and fatigue, with no new safety issues identified.

Additionally, using stereotactic body radiation therapy (SBRT) with olaparib has proven safe, with patients typically tolerating these treatments well and few serious side effects reported.

Both treatment combinations have been tested in earlier studies, and results suggest they are generally well-tolerated by patients. However, each person's experience can vary, and side effects may still occur. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine cutting-edge approaches to tackling gastric cancer. Unlike standard chemotherapy and surgery, this trial uses a combination of olaparib, pembrolizumab, and stereotactic body radiation therapy (SBRT), which together offer a unique mechanism of action. Olaparib is a PARP inhibitor that targets cancer cells with specific DNA repair defects, while pembrolizumab is an immunotherapy drug that helps the immune system recognize and attack cancer cells. SBRT delivers high doses of radiation with precision, minimizing damage to surrounding healthy tissue. This multi-pronged approach aims to boost treatment efficacy and potentially offer a new avenue for patients who might not respond to traditional therapies.

What evidence suggests that this trial's treatments could be effective for gastric cancer?

This trial will evaluate the effectiveness of different treatment combinations for gastric cancer. Research has shown that olaparib, one of the treatments in this trial, can slow or stop the growth of stomach cancer cells, potentially preventing the cancer from spreading. Some studies found that combining olaparib with other cancer treatments was more effective than traditional treatments alone. Pembrolizumab, another treatment option in this trial, has helped stomach cancer patients live longer, with some studies reporting an increase in survival by several months. Stereotactic body radiation therapy (SBRT), also part of this trial, has effectively controlled cancer in the treated area, successfully stopping its growth. Together, these treatments have shown promise in managing stomach cancer, though individual results can vary. ^{6 7 8 9 10}

Who Is on the Research Team?

Sunnie Kim, MD

Principal Investigator

University of Colorado, Denver

Are You a Good Fit for This Trial?

Adults with metastatic gastric or gastroesophageal cancer who've had prior treatment including fluoropyrimidine and platinum drugs. They must be able to swallow pills, have good organ function, and a specific gene mutation related to DNA repair. Pregnant women can't join; men and women must agree to contraception.

Inclusion Criteria

I agree to have tumor biopsies during the study, but I understand I can stay in the study even if later biopsies are not possible.

My organs are functioning well.

My test shows a specific gene mutation affecting DNA repair.

Exclusion Criteria

I have an autoimmune disease treated with medication in the last 2 years.

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

I have been diagnosed with HIV.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Participants receive induction therapy with olaparib and stereotactic beam radiotherapy (SBRT)

4-6 weeks

Combination Treatment

Participants receive combination therapy with olaparib and pembrolizumab

4-6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 years

What Are the Treatments Tested in This Trial?

Interventions

• Olaparib
• Pembrolizumab
• Stereotactic Body Radiation Therapy

Trial Overview This phase II trial tests if olaparib combined with radiation therapy followed by olaparib plus pembrolizumab improves outcomes in patients with certain genetic mutations after previous treatments for their advanced stomach cancers.

How Is the Trial Designed?

Group I: HR proficient cohort Experimental Treatment 3 Interventions

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

Group II: HR deficient cohort Experimental Treatment 3 Interventions

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.

Olaparib is already approved in European Union, United States for the following indications:

Approved in European Union as Lynparza for:

• Breast cancer
• Ovarian cancer
• Fallopian tube cancer
• Peritoneal cancer
• Pancreatic cancer
• Prostate cancer
• Endometrial cancer

Approved in United States as Lynparza for:

• Ovarian, fallopian tube, and primary peritoneal cancer
• Breast cancer
• Prostate cancer
• Pancreatic cancer

Who Is Running the Clinical Trial?

University of Colorado, Denver

Lead Sponsor

Trials

1,842

Recruited

3,028,000+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

The pharmacokinetic (PK) profile of olaparib in Chinese patients with advanced solid tumors is similar to that observed in Western and Japanese populations, confirming that the recommended dose of 300 mg twice daily is appropriate for this group.

When olaparib was combined with paclitaxel, there was a significant decrease in olaparib exposure, and while adverse events were rare, hematological side effects were more common in patients receiving the combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and safety of olaparib tablets as monotherapy and in combination with paclitaxel: results of a Phase I study in Chinese patients with advanced solid tumours. Yuan, P., Shentu, J., Xu, J., et al.[2020]

Stereotactic body radiotherapy (SBRT) is an effective standard treatment for patients with early non-small cell lung cancer (NSCLC) who cannot undergo surgery, as well as for those with oligometastatic NSCLC.

A case study in China demonstrated nearly 5 years of progression-free survival with pembrolizumab monotherapy following SBRT, highlighting the potential for enhanced efficacy of immunotherapy after targeted radiotherapy in metastatic NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A patient with metastatic non-small cell lung cancer who received pembrolizumab monotherapy after stereotactic body radiotherapy had progression-free survival of nearly 5 years: a case report. Ni, J., Yang, L., Zhu, H., et al.[2021]

Olaparib (Lynparza) is approved for treating adult patients with high-risk early breast cancer that has a germline BRCA mutation, following chemotherapy treatment.

This approval highlights Olaparib's role as an adjuvant therapy, which means it is used after initial treatments to help prevent cancer recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Adjuvant Treatment for High-Risk Early Breast Cancer. Aschenbrenner, DS.[2022]

The phase 3 GOLD study involving 525 patients with advanced gastric cancer found that the combination of olaparib and paclitaxel did not significantly improve overall survival compared to placebo plus paclitaxel, with median survival times of 8.8 months versus 6.9 months, respectively.

Safety analysis revealed that the most common severe adverse events were neutropenia and leucopenia, with similar rates in both treatment groups, indicating that while olaparib was not effective in improving survival, it had a manageable safety profile when combined with chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD): a double-blind, randomised, placebo-controlled, phase 3 trial. Bang, YJ., Xu, RH., Chin, K., et al.[2022]

The KEYLYNK-012 study is a phase III clinical trial evaluating the effectiveness of pembrolizumab combined with chemoradiotherapy in patients with stage III non-small-cell lung cancer (NSCLC), involving participants aged 18 and older with unresectable disease.

This study aims to determine if the addition of pembrolizumab, with or without olaparib, improves progression-free survival and overall survival compared to standard concurrent chemoradiotherapy, with enrollment ongoing at around 190 sites.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and Design of the Phase III KEYLYNK-012 Study of Pembrolizumab and Concurrent Chemoradiotherapy Followed by Pembrolizumab With or Without Olaparib for Stage III Non-Small-Cell Lung Cancer. Jabbour, SK., Cho, BC., Bria, E., et al.[2022]

The combination of olaparib and carboplatin was found to be safe and effective in treating breast and ovarian cancer in patients with germline BRCA1 or BRCA2 mutations, with 50% of patients showing a partial response and one patient achieving a complete response.

Proteomic analysis indicated that high levels of FOXO3a expression before treatment may predict a better response to the therapy, suggesting a potential biomarker for future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses. Lee, JM., Hays, JL., Annunziata, CM., et al.[2022]

In a phase II study involving 124 patients with recurrent or metastatic gastric cancer, the combination of olaparib and paclitaxel significantly improved overall survival compared to paclitaxel alone, with a median overall survival of 13.1 months versus 8.3 months.

Patients with low levels of ataxia telangiectasia mutated (ATM) showed even greater benefits from the olaparib/paclitaxel treatment, indicating that low ATM expression may predict better clinical outcomes in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, Double-Blind Phase II Trial With Prospective Classification by ATM Protein Level to Evaluate the Efficacy and Tolerability of Olaparib Plus Paclitaxel in Patients With Recurrent or Metastatic Gastric Cancer. Bang, YJ., Im, SA., Lee, KW., et al.[2022]

In a study of 68 patients with advanced solid tumors, the combination of stereotactic body radiotherapy (SBRT) followed by pembrolizumab showed a high one-year treated metastasis control rate of 89.5%, indicating effective tumor response regardless of whether the tumors received complete or partial radiation coverage.

The study found that treated metastasis control (TMC) was significantly associated with improved overall survival, and SBRT altered tumor gene expression by increasing immune-related genes while decreasing those related to cell cycle and DNA repair, suggesting a mechanism for enhanced immune response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved Survival Associated with Local Tumor Response Following Multisite Radiotherapy and Pembrolizumab: Secondary Analysis of a Phase I Trial. Luke, JJ., Onderdonk, BE., Bhave, SR., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12185624/

Olaparib Combined with Anti-PD1 Enhances ... Olaparib Exhibits Significant Inhibitory Effects on Gastric Cancer Cells. Using the CCK-8 assay, we investigated the effects of 867 drugs on ...

2. nature.com nature.com/articles/s41416-023-02534-1

NCI10066: a Phase 1/2 study of olaparib in combination ... Conclusions. Olaparib and ramucirumab is well-tolerated with efficacy that exceeds historical controls with ramucirumab single agent for gastric ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.4_suppl.427

Single agent olaparib in advanced oesophago-gastric cancer Conclusions: In SOlar, Olaparib met its primary endpoint with 28% DCR in this heavily pre-treated group. No new safety concerns were observed.

4. astrazeneca.com astrazeneca.com/media-centre/press-releases/2016/astrazeneca-provides-top-line-results-from-lynparza-gold-trial-in-advanced-gastric-cancer-1805206.html

AstraZeneca provides top-line results from Lynparza GOLD ... AstraZeneca today announced that Lynparza (olaparib) in combination with paclitaxel chemotherapy, compared with paclitaxel chemotherapy alone, did not meet the ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT01063517

NCT01063517 | Efficacy Study of Olaparib With Paclitaxel ... To assess the efficacy of olaparib when given in combination with paclitaxel compared with paclitaxel alone as defined by progression-free survival (PFS),

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05379972

Study of SBRT/Olaparib Followed by Pembrolizumab ... 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 ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12238646/

A phase II single-arm study of combination pembrolizumab ... All BTC patients do not appear to benefit from pembrolizumab plus olaparib, but those with HRR deficiencies and/or IDH mutations may benefit ...

8. merck.com merck.com/news/merck-announces-keylynk-008-trial-evaluating-keytruda-pembrolizumab-plus-lynparza-olaparib-for-patients-with-metastatic-squamous-non-small-cell-lung-cancer-to-stop-for-futility/

Merck Announces KEYLYNK-008 Trial Evaluating ... Merck is discontinuing the study based on the recommendation of an independent Data Monitoring Committee (DMC), which reviewed data from a ...

9. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.5597

A phase II trial of pembrolizumab plus olaparib for the ... The combination of PEM + OLA has promising activity with durable responses observed in pts with persistent/recurrent TP53-mutant EC, including carcinosarcomas.

10. onclive.com onclive.com/view/olaparib-plus-pembrolizumab-shows-efficacy-in-hrr-gene-mutated-advanced-tumors-with-without-hrd-positivity

Olaparib Plus Pembrolizumab Shows Efficacy in HRR ... The combination therapy demonstrated a manageable safety profile, with common adverse effects including anemia, nausea, and fatigue, and no new ...