Olaparib for Acute Myeloid Leukemia with IDH Mutation

Recruiting at 10 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inducers, CYP3A inhibitors

Disqualifiers: Acute promyelocytic leukemia, CNS leukemia, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: Up to 6 cycles

14 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial studies how well olaparib works in patients with AML or MDS that has come back or does not respond to treatment, and who have an IDH mutation. Olaparib is a pill that may help stop cancer cells from growing by blocking certain enzymes they need. The study aims to see if olaparib is better than other treatments. Olaparib has shown benefits in various cancers, including breast and ovarian cancers.

Will I have to stop taking my current medications?

The trial requires a washout period (time without taking certain medications) for strong or moderate CYP3A inducers and inhibitors before starting olaparib. If you are taking these types of medications, you may need to stop them for a few weeks before joining the trial. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Olaparib for treating acute myeloid leukemia with IDH mutation?

Research shows that Olaparib can kill leukemia cells in most acute myeloid leukemia (AML) samples while sparing healthy cells, suggesting it might be effective for AML patients. Additionally, Olaparib is already used successfully in treating certain types of ovarian and breast cancers, indicating its potential in other cancer treatments. ^{1 2 3 4 5}

Is Olaparib generally safe for humans?

Olaparib (also known as Lynparza) has been used in treating various cancers like ovarian, breast, pancreatic, and prostate cancer, and is generally considered safe. However, there are some concerns about rare side effects, such as myelodysplastic syndrome (a blood disorder) and acute myeloid leukemia, which have been reported in some cases. ^{1 4 6 7 8}

How does the drug Olaparib differ from other treatments for acute myeloid leukemia with IDH mutation?

Olaparib is unique because it is a PARP inhibitor that targets cancer cells with IDH mutations, which have a specific defect in DNA repair, making them more sensitive to this drug. Unlike standard chemotherapy, Olaparib is taken orally and specifically kills leukemic cells while sparing normal cells, offering a potential treatment for patients who do not respond to or relapse after other targeted therapies. ^{5 9 10 11 12}

Research Team

Rory M. Shallis

Principal Investigator

Yale University Cancer Center LAO

Eligibility Criteria

Adults diagnosed with relapsed or refractory Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) with an IDH mutation, who have tried first-line therapy without success. Participants must be in stable health otherwise, not pregnant, and willing to use contraception. Those with uncontrolled infections, other active cancers needing treatment, or known hypersensitivity to olaparib are excluded.

Inclusion Criteria

My cancer has an IDH1 or IDH2 mutation, confirmed within the last 30 days.

I can take care of myself but might not be able to do heavy physical work.

Creatinine clearance of > 30 ml/min

Exclusion Criteria

Hyperleukocytosis with > 50,000 white blood cell (WBC)/mcl

I cannot take pills by mouth or have stomach issues that affect medication absorption.

I am currently undergoing chemotherapy, radiation, or immunotherapy for AML/MDS.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive olaparib orally twice daily on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Up to 6 cycles

Monthly visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 90 days and then every 3 months until death.

Up to 12 months

Follow-up visits every 3 months

Treatment Details

Interventions

• Olaparib

Trial Overview The trial is testing the effectiveness of Olaparib for patients whose AML or MDS has returned after treatment or hasn't responded at all. The study aims to determine if Olaparib can block enzymes that cancer cells need to grow and whether it's better than standard chemotherapy.

Participant Groups

Group I: Treatment (olaparib) Experimental Treatment 3 Interventions

Patients receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity, or absence of remission after 6 cycles for patients without prior exposure to IDH inhibitors. Patients also undergo bone marrow aspiration and collection of blood throughout the study.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

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 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]

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]

PARP inhibitors significantly increase the risk of developing myelodysplastic syndrome and acute myeloid leukaemia compared to placebo, with a Peto odds ratio of 2.63, indicating more than double the risk.

In a review of 178 cases from a pharmacovigilance database, 45% of patients with these conditions related to PARP inhibitor therapy resulted in death, highlighting the serious nature of these delayed adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Myelodysplastic syndrome and acute myeloid leukaemia in patients treated with PARP inhibitors: a safety meta-analysis of randomised controlled trials and a retrospective study of the WHO pharmacovigilance database. Morice, PM., Leary, A., Dolladille, C., et al.[2021]

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]

In a study analyzing 8,450,009 reports from the FDA Adverse Event Reporting System, 6,402 reports of adverse events (AEs) related to olaparib were identified, confirming common AEs like anemia and nausea, as well as unexpected AEs such as interstitial lung disease and renal impairment.

The median onset time for olaparib-related AEs was 61 days, with most cases occurring within the first month of treatment, highlighting the importance of monitoring patients closely during this period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Real-World Disproportionality Analysis of Olaparib: Data Mining of the Public Version of FDA Adverse Event Reporting System. Shu, Y., He, X., Liu, Y., et al.[2022]

Olutasidenib, an oral IDH1mut inhibitor, received regular approval for treating relapsed/refractory IDH1mut acute myeloid leukemia (AML) on December 1, 2022, following its rapid development since 2016.

In clinical trials, olutasidenib showed high rates of durable remission and significant benefits like transfusion independence in patients with R/R IDH1mut AML, highlighting its efficacy as a targeted therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olutasidenib: from bench to bedside. Venugopal, S., Watts, J.[2023]

References

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

Olaparib: first global approval. [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. England pubmed.ncbi.nlm.nih.gov

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

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

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

5. Netherlands pubmed.ncbi.nlm.nih.gov

BRCA1, PARP1 and γH2AX in acute myeloid leukemia: Role as biomarkers of response to the PARP inhibitor olaparib. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Myelodysplastic syndrome and acute myeloid leukaemia in patients treated with PARP inhibitors: a safety meta-analysis of randomised controlled trials and a retrospective study of the WHO pharmacovigilance database. [2021]

7. Germany pubmed.ncbi.nlm.nih.gov

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

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

A Real-World Disproportionality Analysis of Olaparib: Data Mining of the Public Version of FDA Adverse Event Reporting System. [2022]

9. England pubmed.ncbi.nlm.nih.gov

In vivo anti-tumor effect of PARP inhibition in IDH1/2 mutant MDS/AML resistant to targeted inhibitors of mutant IDH1/2. [2022]

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

Clinical Efficacy of Olaparib in IDH1/IDH2-Mutant Mesenchymal Sarcomas. [2023]

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

Olutasidenib: from bench to bedside. [2023]

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

A Small-Molecule Inhibitor of WEE1, AZD1775, Synergizes with Olaparib by Impairing Homologous Recombination and Enhancing DNA Damage and Apoptosis in Acute Leukemia. [2020]