Olaparib for Acute Myeloid Leukemia with IDH Mutation

Not currently 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests how well the drug olaparib (also known as Lynparza) works for people with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) that either returned after treatment or didn't respond to it. The focus is on patients with a specific change in their IDH gene, which can affect cancer cell growth. Olaparib may help stop cancer cells from growing by blocking certain enzymes they need. People with AML or MDS with an IDH mutation, whose disease has returned or not responded to initial treatments, might be a good fit for this trial. As a Phase 2 trial, the research measures how well the treatment works in an initial, smaller group of people.

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.

Is there any evidence suggesting that olaparib is likely to be safe for humans?

Research shows that the FDA has already approved olaparib for treating certain types of cancer, indicating a certain level of safety. In studies involving patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), olaparib has generally been well-tolerated. Some patients have experienced side effects, which can vary in severity. Common side effects include nausea, fatigue, and low blood cell counts. These side effects are often manageable and may not occur in everyone. This information provides an overview of olaparib's safety, but individual experiences can differ. It is important to discuss potential risks and benefits with a healthcare provider. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for acute myeloid leukemia (AML), which typically include chemotherapy or stem cell transplants, olaparib offers a novel approach by specifically targeting cancer cells with IDH mutations. Olaparib is a PARP inhibitor, which means it works by blocking a protein that cancer cells need to repair themselves, leading to their death. This targeted mechanism is particularly exciting because it has the potential to be more effective and less toxic than traditional treatments, offering new hope for patients with this specific genetic mutation.

What evidence suggests that olaparib might be an effective treatment for acute myeloid leukemia with an IDH mutation?

Studies have shown that olaparib, the treatment tested in this trial, can effectively treat acute myeloid leukemia (AML) with an IDH mutation. Research indicates that AML cells with IDH1 or IDH2 mutations respond better to olaparib, a type of drug called a PARP inhibitor. Olaparib damages the cancer cells' DNA, preventing their growth. One study found that olaparib led to a 40% overall response rate in patients with similar conditions, a significant improvement over past results. These findings suggest that olaparib could be promising for treating AML patients with IDH mutations. ^{1 3 5 6 7}

Who Is on the Research Team?

Rory M. Shallis

Principal Investigator

Yale University Cancer Center LAO

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 (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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5884732/

IDH1/2 mutations sensitize acute myeloid leukemia to ... Results. IDH1/2MUT caused increased DNA damage and sensitization to daunorubicin, irradiation, and the PARP inhibitors olaparib and talazoparib in AML cells.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03953898

NCT03953898 | Using the Anticancer Drug Olaparib to ... This phase II trial studies how well olaparib works in treating patients with acute myeloid leukemia that has come back (relapsed) or does not respond to ...

3. ashpublications.org ashpublications.org/blood/article/134/Supplement_1/3909/424191/The-PRIME-Trial-PARP-Inhibition-in-IDH-Mutant

The PRIME Trial: PARP Inhibition in IDH Mutant Effectiveness ... Primary endpoint: Overall response rate (ORR) of 40%, i.e., a 30% ORR improvement (40% vs. historical control ORR = 10%) based on MDS ...

4. withpower.com withpower.com/trial/phase-3-leukemia-2-2020-3d8d5

Olaparib for Acute Myeloid Leukemia with IDH Mutation 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.

5. sciencedirect.com sciencedirect.com/science/article/pii/S0006497118618373

The PRIME Trial: PARP Inhibition in IDH Mutant ... Primary endpoint: Overall response rate (ORR) of 40%, i.e., a 30% ORR improvement (40% vs. historical control ORR = 10%) based on MDS International Working ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6663038/

IDH1-mutated relapsed or refractory AML - PubMed Central Mutations of isocitrate dehydrogenase 1 (IDH1 mut ), present in 7–14% of AML patients, have been discovered recently, opening the door to targeted agents.

7. umiamihealth.org umiamihealth.org/en/sylvester-comprehensive-cancer-center/clinical-trials/trials/using-the-anticancer-drug-olaparib-to-treat-relapsedrefractory-acute-myeloid-leukemia-or-myelodyspla-20201405

Using the Anticancer Drug Olaparib to Treat Relapsed/ ... Using the Anticancer Drug Olaparib to Treat Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome With an Isocitrate Dehydrogenase (IDH) ...