Paclitaxel + Pembrolizumab + Olaparib for Gastric Cancer

Overseen By Colleen Apostol, RN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must not be taking: CYP3A inhibitors

Disqualifiers: CNS metastases, Autoimmune disease, HIV, 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

Duration: Until treatment discontinuation or end of study

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three treatments—paclitaxel, pembrolizumab, and olaparib (also known as Lynparza)—to evaluate their safety and effectiveness for people with advanced stomach cancer. It includes two groups: one with measurable disease (tumors that can be measured) and another with unmeasurable disease. Participants should have advanced gastric cancer, have undergone only one previous unsuccessful therapy, and must agree to a biopsy. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Do I have to stop taking my current medications for the trial?

The trial does not specify if you need to stop taking your current medications, but you cannot take certain drugs like moderate or strong CYP3A inhibitors. It's best to discuss your current medications with the trial team.

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

Research shows that the combination of paclitaxel, pembrolizumab, and olaparib is generally safe for people with advanced stomach cancer. Studies have found that this combination has acceptable safety and manageable side effects.

Paclitaxel, a chemotherapy drug, has been used for a long time and is well-tolerated. Pembrolizumab, an immunotherapy, helps the immune system fight cancer and has been approved for several types of cancer, demonstrating its safety for those conditions. Olaparib is also used for other cancers, indicating a known safety profile.

While every treatment can have side effects, current data show that side effects from this combination are generally manageable. Doctors can help address any issues that arise. Always consult a healthcare provider for personalized information. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Paclitaxel, Pembrolizumab, and Olaparib for gastric cancer because it brings a novel approach to treatment by integrating three different mechanisms of action. Unlike traditional chemotherapy, which targets rapidly dividing cells, Pembrolizumab is an immunotherapy that helps the immune system recognize and attack cancer cells. Meanwhile, Olaparib is a PARP inhibitor, which disrupts cancer cell DNA repair processes, making it harder for the cancer to survive. This multi-pronged attack not only aims to enhance treatment effectiveness but also offers hope for patients whose cancer is resistant to conventional therapies.

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

Research has shown that using paclitaxel, pembrolizumab, and olaparib together may help treat advanced stomach cancer. In this trial, all participants will receive this combination of treatments. Studies have found that pembrolizumab, a type of immunotherapy, can effectively target cancer cells in some people with this condition. Paclitaxel, a chemotherapy drug, helps slow or stop the growth of cancer cells. Olaparib makes it harder for cancer cells to repair themselves, making them more vulnerable to treatment. Early results suggest that combining these treatments can lead to better outcomes for patients who have already tried other treatments. Overall, this combination aims to improve cancer treatment by using different approaches to fight the cancer. ^{1 2 3 5 6}

Who Is on the Research Team?

Katherine Bever, MD

Principal Investigator

Johns Hopkins Medical Institution

Are You a Good Fit for This Trial?

Adults over 18 with advanced gastric or gastroesophageal cancer, who have failed one prior therapy and have a measurable lesion. They must be in good physical condition (ECOG 0-1), not pregnant, willing to use birth control, and able to consent. Excluded are those with brain metastases, certain allergies, recent other treatments or vaccines, active infections like HIV/hepatitis B/C, severe illnesses or conditions that could affect study participation.

Inclusion Criteria

I agree to undergo a biopsy.

I am fully active or restricted in physically strenuous activity but can do light work.

My cancer is in an advanced stage in my stomach or where my esophagus meets my stomach.

Exclusion Criteria

Allergy to dexamethasone, diphenhydramine and famotidine

I have cancer spread to my brain or spinal cord and need treatment.

I am not pregnant or breastfeeding.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Paclitaxel, Olaparib, and Pembrolizumab

Until treatment discontinuation or end of study

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 years

What Are the Treatments Tested in This Trial?

Interventions

• Olaparib
• Paclitaxel
• Pembrolizumab

Trial Overview The trial is testing the combination of Paclitaxel (a chemotherapy drug), Olaparib (a PARP inhibitor) and Pembrolizumab (an immunotherapy drug) in patients who've had previous treatment for advanced Gastric Cancer. The goal is to assess safety and how well this combo works against the cancer.

How Is the Trial Designed?

Group I: Cohort 1 - Measurable Disease Experimental Treatment 3 Interventions

All Participants will receive Paclitaxel, Olaparib and Pembrolizumab.

Group II: Arm 2: Cohort 2-Unmeasurable Disease Experimental Treatment 3 Interventions

All Participants will receive Paclitaxel, Olaparib and Pembrolizumab.

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?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

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

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Niraparib has been approved by the FDA for patients with complete or partial response to first-line platinum-based chemotherapy, regardless of their BRCAm or HRD status, expanding treatment options for more patients.

Olaparib, in combination with bevacizumab, has also received FDA approval for patients with epithelial ovarian cancer, indicating that PARP inhibitors are now beneficial not only for BRCAm and HRD-deficient patients but also for those with HRD-proficient tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PARP inhibitors in the treatment of ovarian cancer: a review. Washington, CR., Moore, KN.[2023]

In a phase 3 study involving 94 Asian patients with advanced PD-L1-positive gastric/GEJ cancer, pembrolizumab showed similar overall survival (OS) to paclitaxel, with a median OS of 8 months for both treatments, indicating comparable efficacy.

Pembrolizumab had a significantly better safety profile, with only 60% of patients experiencing any-grade treatment-related adverse events compared to 96% for paclitaxel, and fewer severe (grades 3 to 5) events (11% vs. 64%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus paclitaxel for previously treated advanced gastric or gastroesophageal junction cancer (KEYNOTE-063): A randomized, open-label, phase 3 trial in Asian patients. Chung, HC., Kang, YK., Chen, Z., 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]

In a study of 120 ovarian cancer patients, the combination of olaparib with paclitaxel and carboplatin significantly improved the objective remission rate and disease control rate compared to the standard treatment with paclitaxel and carboplatin alone.

The addition of olaparib also resulted in lower levels of tumor markers and a reduced rate of tumor metastasis after one year, all without increasing the incidence of adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib and paclitaxel in combination with carboplatin in treatment of ovarian cancer: influence on disease control. Zhang, H., Zhang, Y.[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]

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 phase 3 study involving 592 patients with advanced gastric or gastro-oesophageal junction cancer, pembrolizumab did not significantly improve overall survival compared to paclitaxel, with median survival times of 9.1 months and 8.3 months respectively.

However, pembrolizumab demonstrated a better safety profile, with only 14% of patients experiencing severe treatment-related adverse events compared to 35% in the paclitaxel group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Shitara, K., Özgüroğlu, M., Bang, YJ., et al.[2022]

In the GeparOLA trial involving 107 patients with early HER2-negative breast cancer and homologous recombination deficiency, the combination of olaparib and paclitaxel achieved a pathological complete response (pCR) rate of 55.1%, which is higher than the 48.6% pCR rate observed with paclitaxel and carboplatin.

The olaparib and paclitaxel combination was better tolerated than the carboplatin regimen, suggesting it may be a safer option for patients, particularly in younger and hormone receptor-positive subgroups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency (GeparOLA study). Fasching, PA., Link, T., Hauke, J., 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04209686

Paclitaxel, Pembrolizumab and Olaparib in Previously ... The purpose of this study is to evaluate the safety and clinical activity of paclitaxel plus olaparib and pembrolizumab in patients with previously treated ...

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2020-07517

Paclitaxel, Pembrolizumab, and Olaparib for the Treatment ... To estimate overall survival in patients with previously treated advanced gastric cancer (GC) who are treated with paclitaxel plus olaparib and pembrolizumab.

3. clinicaltrial.be clinicaltrial.be/en/details/20606?per_page=100&recruiting=1&enrolling_by_invitation=1&active_not_recruiting=1&not_yet_recruiting=0&completed=0&only_recruiting=0&only_eligible=0

Pembrolizumab, Olaparib, Recurrent/Advanced Gastric ... An Open Label, Single-Arm, Multi-center Phase Ib/II Study to Evaluate the Efficacy of Paclitaxel in Combination With Pembrolizumab and ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6031212/

Immunotherapy in Advanced Gastric Cancer - PubMed Central Results on safety and efficacy from pembrolizumab specifically in gastric cancer were first presented at ESMO Congress 2014 by Muro et al. (KEYNOTE-012) and ...

5. centerwatch.com centerwatch.com/clinical-trials/listings/NCT04209686/paclitaxel-pembrolizumab-and-olaparib-in-previously-treated-advanced-gastric-adenocarcinoma

Paclitaxel, Pembrolizumab and Olaparib in Previously ... The purpose of this study is to evaluate the safety and clinical activity of paclitaxel plus olaparib and pembrolizumab in patients with ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.4_suppl.452

Phase II study of combination pembrolizumab and olaparib ... Interim trial results indicate that combination olaparib and pembrolizumab has acceptable safety and manageable toxicity in pts with advanced ...