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

Trial Summary

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.

What data supports the effectiveness of the drug Olaparib in treating solid tumors?

Olaparib has shown effectiveness in treating ovarian cancer, particularly in patients with BRCA mutations, by targeting cancer cells' DNA repair mechanisms. It is approved for use in ovarian cancer and has been studied for its potential benefits in other cancers with similar DNA repair issues. ^{1 2 3 4 5}

What safety data exists for Adagrasib + Olaparib in humans?

Olaparib (Lynparza) has been studied for safety in various cancers, including ovarian and breast cancer, and is generally considered safe for use in humans. It has been tested in different formulations and patient populations, showing a consistent safety profile. ^{3 6 7 8 9}

What makes the drug combination of Adagrasib and Olaparib unique for treating solid tumors?

The combination of Adagrasib and Olaparib is unique because it targets solid tumors by combining two different mechanisms: Adagrasib targets specific cancer mutations, while Olaparib inhibits enzymes (PARP-1 and PARP-2) that help repair DNA damage in cancer cells, potentially enhancing the treatment's effectiveness. ^{2 3 5 9 10}

What is the purpose of this trial?

This trial is testing a combination of two drugs, adagrasib and olaparib, in patients with advanced solid tumors that have specific genetic mutations. The goal is to find a safe dose and see if the combination can effectively block cancer growth and prevent cancer cells from repairing themselves. Olaparib has shown activity in various cancers, particularly those with certain genetic mutations.

Research Team

Timothy Yap

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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 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]

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]

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]

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 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 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]

References

1. England pubmed.ncbi.nlm.nih.gov

Candidate biomarkers of PARP inhibitor sensitivity in ovarian cancer beyond the BRCA genes. [2020]

2. England pubmed.ncbi.nlm.nih.gov

Olaparib maintenance monotherapy in platinum-sensitive, relapsed ovarian cancer without germline BRCA mutations: OPINION Phase IIIb study design. [2020]

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

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

4. England pubmed.ncbi.nlm.nih.gov

Safety evaluation of olaparib for treating ovarian cancer. [2015]

5. England pubmed.ncbi.nlm.nih.gov

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

6. Germany pubmed.ncbi.nlm.nih.gov

Safety and tolerability of the olaparib tablet formulation in Japanese patients with advanced solid tumours. [2022]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Systematic Review of Olaparib in the Treatment of Recurrent Platinum Sensitive Ovarian Cancer. [2022]

8. England pubmed.ncbi.nlm.nih.gov

PARP inhibitors in the treatment of ovarian cancer: a review. [2023]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Olaparib: first global approval. [2020]

10. New Zealand pubmed.ncbi.nlm.nih.gov

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