Adagrasib + Olaparib for Solid Tumors

Overseen By Timothy Yap, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Active brain metastases, MDS/AML, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 2

Duration: 8-12 weeks

52 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, adagrasib (Krazati or MRTX-849) and olaparib (Lynparza), to determine their safety and tolerability in people with advanced solid tumors. Researchers aim to find the right dose for individuals whose cancers have specific genetic changes, known as KRAS G12C and/or KEAP1 mutations, which may influence cancer growth. It targets those with solid tumors who have already tried at least one other unsuccessful treatment. This trial may suit individuals whose cancer continues to progress despite previous treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial requires a 2-week washout period (time without taking certain medications) for strong or moderate CYP3A inhibitors and a 5-week washout period for strong or moderate CYP3A inducers before starting the study treatment. If you are taking medications that fall into these categories, you may need to stop or switch them before participating.

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

Research has shown that adagrasib, when used alone, is generally easy for patients to handle. One study produced good results without causing any serious side effects. Another study found that many patients responded well to adagrasib, experiencing positive effects without major safety concerns.

Olaparib is also known to be safe. The FDA has approved it for treating certain cancers, indicating its safety for many patients.

Currently, researchers are studying the combination of adagrasib and olaparib to assess their joint efficacy and safety. This trial is in its early stages, focusing primarily on safety and determining the right doses. Research on each drug alone supports their safety, but the combination is being carefully monitored to ensure it is well-tolerated. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Adagrasib and Olaparib for treating solid tumors because it targets cancer in two innovative ways. Adagrasib inhibits a specific mutant form of the KRAS protein, which is a common driver of cancer cell growth in many tumors, while Olaparib blocks PARP enzymes, crucial for cancer cell repair. This dual approach could potentially halt tumor growth more effectively than current treatments that typically target only one pathway. By leveraging these two mechanisms, this combination aims to improve patient outcomes and offer a new hope for those with challenging solid tumors.

What evidence suggests that this trial's treatments could be effective for advanced solid tumors?

Research has shown that combining the drugs adagrasib and olaparib, which participants in this trial will receive, may help treat advanced solid tumors with certain genetic mutations. One study found that this combination increased the tumor shrinkage rate to 46% and extended the time patients lived without cancer worsening to 6.9 months for colorectal cancer, compared to using adagrasib alone. Adagrasib has proven effective in patients with KRAS G12C mutations. Patients also tolerated this combination treatment well, suggesting it could be a promising option for those with these types of tumors. ^{1 2 6 7 8}

Who Is on the Research Team?

Timothy Yap

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with advanced solid tumors that have specific mutations (KRAS G12C or KEAP1) can join this trial. They should be in good physical condition, not have major health issues that could affect the study, and agree to use effective contraception. People with certain gastrointestinal conditions, uncontrolled infections, recent significant bleeding or surgery, or those on strong CYP3A inhibitors/inducers are excluded.

Inclusion Criteria

Willing to comply with clinical trial instructions and requirements

Your recent lab test results need to meet certain standards.

I have another cancer type, but it won't affect this trial's treatment.

Exclusion Criteria

Pregnancy or planning to breastfeed

I have not had severe coughing up of blood or bleeding in the last 4 weeks.

I have been diagnosed with myelodysplastic syndrome or acute myeloid leukemia.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive adagrasib and olaparib by mouth twice daily to evaluate safety, tolerability, and establish the recommended dose

8-12 weeks

Weekly visits for monitoring and dose adjustments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Adagrasib
• Olaparib

Trial Overview The trial is testing a combination of two drugs: Adagrasib and Olaparib for patients with certain genetic mutations in their tumors. The goal is to find the safest dose level. Participants will receive both medications and be monitored for how well they tolerate them and any signs of tumor response.

How Is the Trial Designed?

Group I: Adagrasib+Olaparib Experimental Treatment 2 Interventions

Participants will take adagrasib and olaparib by mouth 2 times each day. Each dose should be taken at about 12 hours apart (1 dose in the morning, 1 dose in the evening). The study drugs should be swallowed whole with water. Do not chew, crush, dissolve, or divide the study drugs. If forget a dose and less than 2 hours have passed since the usual time participants take the study drug, take the dose as soon as participants remember. If more than 2 hours have passed, do not take the dose. Wait and take the next dose as scheduled

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

Approved in United States as Krazati for:

• KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC)
• KRAS G12C-mutated locally advanced or metastatic colorectal cancer

Approved in European Union as Krazati for:

• KRAS G12C mutation non-small cell lung cancer

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Mirati Therapeutics Inc.

Industry Sponsor

Trials

73

Recruited

8,900+

Dr. Charles M. Baum

Mirati Therapeutics Inc.

Chief Executive Officer since 2023

MD, PhD

Dr. Joseph Leveque

Mirati Therapeutics Inc.

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

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]

Olaparib significantly improves overall survival in patients with recurrent platinum-sensitive ovarian cancer, with a hazard ratio of 1.24 based on a meta-analysis of 7 randomized controlled trials involving 2406 patients.

However, the treatment is associated with a higher incidence of adverse events, particularly for grades 3 or higher, indicating that while olaparib is effective, it also carries a risk of significant side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic Review of Olaparib in the Treatment of Recurrent Platinum Sensitive Ovarian Cancer. Chen, Q., Li, X., Zhang, Z., et al.[2022]

In a Phase I study involving 28 Japanese patients with advanced solid tumors, olaparib tablets at doses of 200 and 300 mg twice daily were found to be tolerable, with no dose-limiting toxicities reported.

The most common side effects included nausea, decreased appetite, anemia, and constipation, but no confirmed antitumor responses were observed, leading to the selection of 300 mg bid as the recommended dose for future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of the olaparib tablet formulation in Japanese patients with advanced solid tumours. Yonemori, K., Tamura, K., Kodaira, M., et al.[2022]

The OPINION study is evaluating the safety and efficacy of olaparib as a maintenance therapy for women with high-grade serous or endometrioid platinum-sensitive relapsed ovarian cancer who do not have BRCA mutations, involving patients who have undergone at least two prior lines of platinum-based chemotherapy.

The primary goal of the study is to assess progression-free survival, which will help determine how effective olaparib is in delaying cancer progression in this specific patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib maintenance monotherapy in platinum-sensitive, relapsed ovarian cancer without germline BRCA mutations: OPINION Phase IIIb study design. Poveda, AM., Davidson, R., Blakeley, C., et al.[2020]

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]

Olaparib is an effective treatment for patients with platinum-sensitive, relapsed BRCA-mutated high-grade serous ovarian cancer, showing significant improvement in progression-free survival compared to placebo in a study of 265 patients.

The treatment is generally well tolerated, with most side effects being mild to moderate, although fatigue, anemia, and neutropenia were noted as more severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: a review of its use as maintenance therapy in patients with ovarian cancer. Frampton, JE.[2016]

Olaparib is particularly effective for patients with BRCA-mutated ovarian cancer, but it also benefits a subset of patients with BRCA wild-type tumors that have loss-of-function mutations in DNA repair genes, showing similar treatment outcomes.

The study suggests that patients with specific HRR gene mutations, even without BRCA mutations, can be identified as a group that may respond well to olaparib, indicating a potential for broader use of this treatment in ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes. Hodgson, DR., Dougherty, BA., Lai, Z., et al.[2020]

Olaparib is an oral medication that inhibits poly (ADP-ribose) polymerase and is primarily developed for treating BRCA mutation-positive ovarian cancer, with its capsule formulation already approved in the EU and USA.

The drug is currently undergoing extensive clinical trials for various cancers, including breast, gastric, and pancreatic cancers, indicating its potential broad application in oncology beyond ovarian cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: first global approval. Deeks, ED.[2020]

Olaparib is an effective oral treatment for patients with BRCA mutation-positive ovarian cancer, approved for maintenance therapy after platinum-based chemotherapy, showing good tolerability with common side effects like nausea, fatigue, and anemia being mild to moderate.

Long-term monitoring is recommended due to a low risk of serious hematological complications, such as anemia and myelodysplastic syndrome, ensuring patient safety during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety evaluation of olaparib for treating ovarian cancer. Lheureux, S., Bowering, V., Karakasis, K., et al.[2015]

Olaparib is a powerful inhibitor of PARP-1 and PARP-2, showing effectiveness in treating ovarian cancer, particularly in patients with germline BRCA mutations.

Phase III trials are currently evaluating olaparib's efficacy as a maintenance therapy after initial treatment in patients with BRCA mutations, highlighting its potential role in long-term cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib: an oral PARP-1 and PARP-2 inhibitor with promising activity in ovarian cancer. Gunderson, CC., Moore, KN.[2016]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06130254

NCT06130254 | Phase Ib Trial of the KRAS G12C Inhibitor ... To evaluate the safety and tolerability of adagrasib in combination with olaparib in participants with KRAS G12C mutant advanced solid tumors. To establish the ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12323406/

Adagrasib in the treatment of colorectal cancer - PMC The study demonstrated enhanced efficacy compared to adagrasib monotherapy, with improved ORR of 46% and PFS of 6.9 months. The combination was well-tolerated, ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/35167329/

First-in-Human Phase I/IB Dose-Finding Study of Adagrasib ... Adagrasib 600 mg twice a day was well tolerated and exhibited antitumor activity in patients with advanced solid tumors harboring the KRAS G12C mutation.

4. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2022-0136.html

Phase Ib trial of the KRAS G12C inhibitor Adagrasib ... Phase Ib trial of the KRAS G12C inhibitor Adagrasib (MRTX849) in combination with the PARP inhibitor Olaparib in patients with KRAS G12C mutated advanced solid ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S104084282400297X

KRAS mutations in advanced non-small cell lung cancer Nowadays, sotarasib and adagrasib received the approval for the treatment of advanced NSCLC patients with KRASG12C mutation who progressed to chemotherapy and ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10852394/

Adagrasib in Advanced Solid Tumors Harboring a KRASG12C ... Adagrasib demonstrated an encouraging objective response rate of 35.1% in a biomarker-selected population who have declined or have no available standard-of- ...

7. asco.org asco.org/abstracts-presentations/ABSTRACT425082

KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in ... No grade 5 TRAE occurred. Conclusions: Adagrasib is well tolerated and demonstrates promising clinical activity in pretreated pts with PDAC, BTC, and other ...

8. krazatihcp.com krazatihcp.com/nsclc/efficacy

Efficacy | KRAZATI® (adagrasib) for NSCLC 58% HAD A RESPONSE DURATION OF ≥6 MONTHS2. 42% of patients (n=112) achieved a PR, and 0.9% of patients achieved a CR3.