What is the mechanism of action of this treatment?

The most common treatments for Acute Myeloid Leukemia (AML) include chemotherapy agents like cytarabine and anthracyclines, which work by damaging the DNA of rapidly dividing cells, leading to cell death. Targeted therapies, such as PARP inhibitors like Olaparib, specifically inhibit the PARP enzyme involved in DNA repair, making cancer cells more susceptible to damage and death. This is particularly important for AML patients with specific genetic mutations, such as IDH mutations, as these targeted treatments can be more effective and less toxic than traditional chemotherapy. Understanding these mechanisms helps in tailoring treatment plans to improve outcomes and reduce side effects for AML patients.

What side effects are associated with this type of intervention?

Common treatments for Acute Myeloid Leukemia (AML) include hypomethylating agents such as azacitidine and decitabine, as well as PARP inhibitors like Olaparib. The known side effects of these treatments often include hematologic adverse effects such as neutropenia, anemia, and thrombocytopenia. Non-hematologic side effects can include nausea, fatigue, and gastrointestinal disturbances. Specifically, Olaparib and other PARP inhibitors may also cause differentiation syndrome and QT prolongation. It is important for patients to discuss these potential side effects with their healthcare provider to manage and mitigate them effectively.

What prior FDA approvals exist?

The FDA has approved several treatments for Acute Myeloid Leukemia (AML). Notably, hypomethylating agents (HMAs) such as azacitidine and decitabine have been approved for AML treatment, particularly in patients who are not candidates for intensive chemotherapy. Additionally, venetoclax, a BCL2 inhibitor, has been approved in combination with HMAs for AML, showing improved outcomes. While Olaparib, a PARP inhibitor, is being studied for relapsed/refractory AML with IDH mutations, it is not yet FDA-approved for AML. Other targeted therapies include ivosidenib and enasidenib for IDH1 and IDH2 mutations, respectively.

What other types of research exist?

Promising alternatives to Olaparib for AML patients include: 1) Hypomethylating agents (HMAs) such as azacitidine and decitabine, which have shown comparable efficacy and are well-tolerated. 2) Venetoclax combined with low-dose cytarabine, which has shown positive results in clinical trials. 3) Ivosidenib, an IDH1 inhibitor, especially effective in patients with IDH1-mutated AML when combined with azacitidine. These alternatives offer different mechanisms of action and have shown efficacy in clinical settings.

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PARP Inhibitor

Olaparib for Acute Myeloid Leukemia with IDH Mutation

Phase 2

Waitlist Available

Led By Thomas Prebet

Research Sponsored by National Cancer Institute (NCI)

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Karnofsky >= 60%)

Must not have

Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication

Patients receiving concurrent chemotherapy, radiation therapy, or immunotherapy for AML/MDS

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 12 months

Awards & highlights

No Placebo-Only Group

Summary

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.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Olaparib may cause side effects like nausea, fatigue, blood cell count changes leading to increased infection risk, shortness of breath, headaches and dizziness. Some people might experience more serious issues affecting their lungs or kidneys.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My hepatitis B virus is under control with treatment.

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

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My MDS is classified as intermediate, high, or very high risk with excess blasts.

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I am HIV-positive, on treatment, and my viral load is undetectable.

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I finished chemotherapy 3 weeks ago and radiotherapy 2 weeks ago.

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My cancer has a specific IDH2 mutation.

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My MDS is classified as intermediate, high, or very high risk with excess blasts.

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I am 18 years old or older.

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My cancer has a specific IDH1 mutation.

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My AML or MDS has not responded to the first treatment or has come back after it.

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I have been diagnosed with MDS or AML according to WHO 2016 guidelines.

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My AML or MDS has not responded to or has returned after initial treatment.

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I had a stem cell transplant over 6 months ago, have minimal GVHD, and stopped immunosuppressants 2 weeks ago.

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I had hepatitis C but am cured, or I'm being treated with no detectable virus.

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I have been diagnosed with MDS or AML according to WHO 2016 guidelines.

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I am 18 years old or older.

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My hepatitis B virus load is undetectable with treatment.

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I had hepatitis C but have been treated and cured.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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

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

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I have never been treated with a PARP inhibitor like olaparib.

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I do not have any other cancers that need treatment which would interfere with this study.

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I do not have any ongoing, untreated infections.

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I am not taking strong or moderate CYP3A inhibitor medications.

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I had major surgery more than 2 weeks ago and have recovered from it.

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My brain or spinal cord disease is causing symptoms and is not under control.

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I have heart issues that are not under control or I was born with a condition that affects my heart's rhythm.

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I have lasting side effects from cancer treatment, but not hair loss.

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I am not taking any strong or moderate drugs that affect liver enzymes.

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I do not have any serious, uncontrolled health conditions or infections.

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I have active leukemia in my brain or need ongoing chemotherapy in my spine.

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I haven't had chemotherapy or radiotherapy for 3 weeks, except for pain relief.

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I have been diagnosed with acute promyelocytic leukemia.

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I have had a double umbilical cord blood transplant before.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 12 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 12 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 12 months for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Cumulative overall response rate (ORR)

Secondary study objectives

Incidence of adverse events

ORR

Overall survival (OS)

+1 more

Other study objectives

Change in 2-hydroxyglutarate (2HG) levels

Minimal residual disease (MRD) assessment

Mutant allele frequency

Side effects data

From 2023 Phase 3 trial • 154 Patients • NCT02184195

49%

Nausea

47%

Fatigue

38%

Diarrhoea

29%

Abdominal pain

29%

Anaemia

28%

Constipation

27%

Decreased appetite

27%

Back pain

26%

Vomiting

21%

Arthralgia

19%

Pyrexia

18%

Asthenia

13%

Rash

13%

Nasopharyngitis

11%

Alanine aminotransferase increased

11%

Dyspnoea

10%

Neuropathy peripheral

10%

Cough

10%

Abdominal pain upper

10%

Dyspepsia

10%

Anxiety

10%

Pruritus

Hyperglycaemia

Dizziness

Aspartate aminotransferase increased

Thrombocytopenia

Oedema peripheral

Pain in extremity

Insomnia

Stomatitis

Dry mouth

Headache

Neutropenia

Blood creatinine increased

Weight decreased

Dysgeusia

Blood alkaline phosphatase increased

Neutrophil count decreased

Muscle spasms

Influenza

Influenza like illness

Myalgia

Peripheral sensory neuropathy

Gamma-glutamyltransferase increased

Hypertension

Platelet count decreased

Depression

Lymphopenia

Gastrooesophageal reflux disease

Abdominal distension

Musculoskeletal pain

Flank pain

Cholangitis

Flatulence

Paraesthesia

General physical health deterioration

Bladder papilloma

Pneumonia pneumococcal

Abdominal infection

Bartholinitis

Pneumonia

Cerebrovascular accident

Pneumothorax

Gastric varices haemorrhage

Large intestinal obstruction

Cholecystitis

Anastomotic haemorrhage

Device occlusion

Stent malfunction

Bronchiolitis

Empyema

Syncope

Incisional hernia

Device dislocation

Obstruction gastric

Cardiac failure

Vascular stenosis

Pleural effusion

Incarcerated inguinal hernia

Urinary tract infection

Hypothyroidism

Transient ischaemic attack

Infusion related reaction

Duodenal perforation

Melaena

Bile duct obstruction

Pancreatitis

100%

80%

60%

40%

20%

Study treatment Arm

Olaparib 300 mg Twice Daily (bd)

Placebo

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: Treatment (olaparib)Experimental Treatment3 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, or for up to 12 cycles. Patients also undergo bone marrow aspiration and collection of blood throughout the study.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Biospecimen Collection

2004

Completed Phase 3

~2030

Bone Marrow Aspiration

2011

Completed Phase 2

~1740

Olaparib

2007

Completed Phase 4

~2190

0 / 34Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Acute Myeloid Leukemia (AML) include chemotherapy agents like cytarabine and anthracyclines, which work by damaging the DNA of rapidly dividing cells, leading to cell death. Targeted therapies, such as PARP inhibitors like Olaparib, specifically inhibit the PARP enzyme involved in DNA repair, making cancer cells more susceptible to damage and death. This is particularly important for AML patients with specific genetic mutations, such as IDH mutations, as these targeted treatments can be more effective and less toxic than traditional chemotherapy. Understanding these mechanisms helps in tailoring treatment plans to improve outcomes and reduce side effects for AML patients.

Targeting ADP-ribosylation by PARP inhibitors in acute myeloid leukaemia and related disorders.Targeting phosphatidylinositol 3-kinase signaling in acute myelogenous leukemia.Childhood acute myeloid leukaemia.