SBRT + Olaparib and Pembrolizumab + Olaparib for Gastric Cancer

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

26 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a treatment for patients with advanced stomach and GEJ cancers who have not responded to previous treatments. It uses a drug called olaparib, precise radiation therapy, and a combination of olaparib and pembrolizumab to damage cancer cells' DNA, target them accurately, and help the immune system fight the cancer.

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.

What data supports the effectiveness of the treatment SBRT + Olaparib and Pembrolizumab + Olaparib for Gastric Cancer?

Olaparib combined with paclitaxel has shown improved survival in advanced gastric cancer, especially in patients with specific genetic markers. Additionally, pembrolizumab combined with radiotherapy has demonstrated safety and potential effectiveness in other cancers, such as lung cancer, suggesting possible benefits in gastric cancer as well. ^{1 2 3 4 5}

Is the combination of SBRT, Olaparib, and Pembrolizumab safe for humans?

Olaparib has been studied for safety in various cancers, including breast, ovarian, and gastric cancer, and is generally considered safe when used alone or with other treatments. Pembrolizumab has also been evaluated for safety in lung cancer treatments. While specific safety data for the combination of SBRT, Olaparib, and Pembrolizumab in gastric cancer is not provided, these drugs have been used safely in other cancer treatments. ^{1 2 3 6 7}

How is the treatment of SBRT + Olaparib and Pembrolizumab + Olaparib for gastric cancer different from other treatments?

This treatment is unique because it combines stereotactic body radiation therapy (SBRT), which precisely targets tumors with high-dose radiation, with olaparib, a drug that targets cancer cells with specific DNA repair weaknesses, and pembrolizumab, an immunotherapy that helps the immune system attack cancer cells. This combination aims to enhance the effectiveness of each component, potentially improving outcomes for gastric cancer patients. ^{1 3 4 5 8}

Research Team

Sunnie Kim, MD

Principal Investigator

University of Colorado, Denver

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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]

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]

References

1. England 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. [2022]

2. United States 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. [2022]

3. United States pubmed.ncbi.nlm.nih.gov

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

4. China 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. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Improved Survival Associated with Local Tumor Response Following Multisite Radiotherapy and Pembrolizumab: Secondary Analysis of a Phase I Trial. [2021]

6. Germany 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. [2020]

7. United States 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. [2022]

8. United States 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. [2022]