Clinical Trials /

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

NCT03953898

Description:

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 treatment (refractory), or myelodysplastic syndrome. Patients must also have a change in the gene called the IDH gene (IDH mutation). Olaparib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. This study is being done to see if olaparib is better or worse in treating acute myeloid leukemia or myelodysplastic syndrome compared to the standard chemotherapy drugs.

Related Conditions:
  • Acute Myeloid Leukemia
  • Acute Myeloid Leukemia Arising from Previous Myelodysplastic Syndrome
  • Myelodysplastic Syndromes
  • Secondary Acute Myeloid Leukemia
  • Therapy-Related Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Using the Anticancer Drug Olaparib to Treat Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome With an Isocitrate Dehydrogenase (IDH) Mutation
  • Official Title: The PRIME Trial: PARP Inhibition in IDH Mutant Effectiveness Trial. A Phase II Study of Olaparib in Isocitrate Dehydrogenase (IDH) Mutant Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-03057
  • SECONDARY ID: NCI-2019-03057
  • SECONDARY ID: 10264
  • SECONDARY ID: 10264
  • SECONDARY ID: UM1CA186689
  • NCT ID: NCT03953898

Conditions

  • Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome
  • IDH1 NP_005887.2:p.R132H
  • IDH2 NP_002159.2:p.R140X
  • Myelodysplastic Syndrome
  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia
  • Therapy-Related Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
OlaparibAZD 2281, AZD-2281, AZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Treatment (olaparib)

Purpose

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 treatment (refractory), or myelodysplastic syndrome. Patients must also have a change in the gene called the IDH gene (IDH mutation). Olaparib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. This study is being done to see if olaparib is better or worse in treating acute myeloid leukemia or myelodysplastic syndrome compared to the standard chemotherapy drugs.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the overall response rate (ORR) to olaparib in subjects with isocitrate
      dehydrogenase (IDH)1/2 mutant myelodysplastic syndrome (MDS) or IDH1/2-mutant acute myeloid
      leukemia (AML).

      SECONDARY OBJECTIVES:

      I. To establish the progression free survival (PFS) of patients with IDH mutant AML or MDS
      treated with olaparib.

      II. To determine the overall survival (OS) of patients with IDH mutant AML or MDS treated
      with olaparib.

      III. To establish the duration of response (DOR) to treatment with olaparib. IV. To evaluate
      the safety and tolerability of olaparib in AML or MDS patients.

      EXPLORATORY OBJECTIVES:

      I. To establish a relationship between treatment response and correlative studies such as
      plasma and bone marrow 2-hydroxyglutarate (2HG) levels, and IDH variant allele frequency.

      II. To evaluate persistence of double strand breaks in IDH 1/2 mutant AML or MDS.

      III. To evaluate response to therapy in the different IDH mutant genotypes.

      IV. To perform molecular profiling assays on malignant and normal tissues, including, but not
      limited to, whole exome sequencing (WES), ribonucleic acid (RNA) sequencing (RNAseq) order
      to:

      IVa. Identify potential predictive and prognostic biomarkers beyond any genomic alteration by
      which treatment may be assigned.

      IVb. Identify resistance mechanisms using genomic deoxyribonucleic acid (DNA)- and RNA-based
      assessment platforms.

      IVc. Identify whether minimal residual disease (MRD) can be used to correlate mutational
      clearance with clinical outcome in IDH-mutated patients treated with olaparib.

      V. To contribute genetic analysis data from de-identified biospecimens to Genomic Data
      Commons (GDC), a well annotated cancer molecular and clinical data repository, for current
      and future research; specimens will be annotated with key clinical data, including
      presentation, diagnosis, staging, summary treatment, and if possible, outcome.

      VI. To bank blood and bone marrow aspirate obtained from patients at the Experimental
      Therapeutics Clinical Trials Network (ETCTN) Biorepository at Nationwide Children's Hospital.

      OUTLINE:

      Patients receive olaparib orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28
      days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for at least 90 days.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (olaparib)ExperimentalPatients receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Olaparib

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of MDS or AML per World Health Organization 2016 classification. AML may be
             de novo, or following a prior hematologic disorder, including MDS or Philadelphia
             chromosome-negative myeloproliferative neoplasm, and/or therapy-related.

          -  Patients must have a documented IDH1 or IDH2 mutation within 30 days of inclusion
             based on mutational testing by polymerase chain reaction (PCR) by a Clinical
             Laboratory Improvement Amendments (CLIA) certified laboratory. Only specific mutations
             that lead to a neomorphic phenotype will be eligible for enrollment, and include those
             listed below:

               -  IDH1: R132V, R132G, R132S, R132L, R132C and R132H

               -  IDH2: R140W, R140L, R140Q, R172W, R172G, R172S, R172M, R172K.

          -  Patients with AML should have disease that has relapsed after, or is refractory to,
             first-line therapy, with or without subsequent additional therapy, or are currently
             considered unfit for, or unlikely to respond to, conventional therapy.

          -  Patients with MDS should have at least a MDS-excess blasts (EB)1 at the inclusion and
             have a revised International Prognostic Symptom Score risk stratification of
             intermediate, high, or very high risk. Patient may have received prior lines of
             therapy before entering the trial.

          -  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
             therapy with undetectable viral load within 6 months are eligible for this trial.

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

          -  Patients with a history of hepatitis C virus (HCV) infection must have been treated
             and cured. For patients with HCV infection who are currently on treatment, they are
             eligible if they have an undetectable HCV viral load.

          -  Patients may or may not have been previously treated with IDH targeted therapies.

          -  Patients who have undergone allogeneic stem cell transplant (alloSCT) are eligible if
             they are >= 180 days from stem cell infusion, have no evidence of graft versus host
             disease (GVHD) > grade 1, and are >= 2 weeks off all immunosuppressive therapy.

          -  Previous cytotoxic chemotherapy must have been completed at least 3 weeks and
             radiotherapy at least 2 weeks prior to Day 1 of treatment on the study, and all
             adverse events (AEs) (excluding alopecia) due to agents administered more than 4 weeks
             earlier should have recovered to < grade 1. Patients with hematologic malignancies are
             expected to have hematologic abnormalities at study entry. Hematologic abnormalities
             that are thought to be primarily related to leukemia are not considered to be
             toxicities (AEs) and do not need to resolve to < grade 1.

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

          -  Patient must have recovered from toxicities of any prior treatment regimen (no Common
             Terminology Criteria for Adverse Events [CTCAE] grading over 1 for non-hematological
             toxicities, return to baseline for hematological values).

          -  Ability to understand and the willingness to sign a written informed consent document.

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) unless considered
             due to Gilbert's syndrome (measured within 28 days prior to administration of study
             treatment).

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT])
             =< 2.5 x institutional upper limit of normal unless considered due to organ leukemic
             involvement (measured within 28 days prior to administration of study treatment). If
             liver metastases are present in which case they must be =< 5 x ULN.

          -  Serum creatinine =< 2 x the institutional ULN (measured within 28 days prior to
             administration of study treatment).

          -  Patients are eligible for this study if low blood count and transfusion support are
             due to the MDS/AML.

          -  Patients must have, in the best estimate of the treating physician, a life expectance
             of at least 12-16 weeks.

          -  Postmenopausal or evidence of non-childbearing status for women of childbearing
             potential: negative urine or serum pregnancy test within 28 days of study treatment
             and confirmed prior to treatment on day 1. Postmenopausal is defined as:

               -  Amenorrheic for 1 year or more following cessation of exogenous hormonal
                  treatments

               -  Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the
                  post menopausal range for women under 50

               -  Radiation-induced oophorectomy with last menses > 1 year ago

               -  Chemotherapy-induced menopause with > 1 year interval since last menses

               -  Surgical sterilization (bilateral oophorectomy or hysterectomy)

          -  Male patients must use a condom during treatment and for 3 months after the last dose
             of olaparib when having sexual intercourse with a pregnant woman or with a woman of
             childbearing potential. Female partners of male patients should also use a highly
             effective form of contraception if they are of childbearing potential.

        Exclusion Criteria:

          -  Patients with acute promyelocytic leukemia.

          -  Patients with active central nervous system (CNS) leukemia or requiring maintenance
             intrathecal chemotherapy.

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

          -  Patients actively receiving any other investigational agents.

          -  Management of treatment for patients with co-occurring mutations, like FLT3, will be
             prioritized by the treating physician after discussion of treatment options with the
             patient.

          -  Hyperleukocytosis with > 50,000 blasts/mcl. Hydroxyurea for blast count control is
             permitted before starting treatment and may be continued until day 28 of cycle 1. The
             maximum dose of hydrea will be 6 grams per day. Patients will be withdrawn from the
             study if > 50,000 blasts/mcl occur or recur > 14 days after starting treatment on the
             study.

          -  Active, uncontrolled infection. Patients with infection controlled with antibiotics
             are eligible.

          -  Patients considered a poor medical risk due to a serious, uncontrolled medical
             disorder, non-malignant systemic disease or active, uncontrolled infection. Examples
             include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3
             months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal
             cord compression, superior vena cava syndrome, extensive interstitial bilateral lung
             disease on high resolution computed tomography (HRCT) scan or any psychiatric disorder
             that prohibits obtaining informed consent.

          -  Patients who are pregnant or nursing. Pregnant women are excluded from this study
             because olaparib is a PARP inhibitor with the potential for teratogenic or
             abortifacient effects. Because there is an unknown but potential risk for AEs in
             nursing infants secondary to treatment of the mother with olaparib, breastfeeding
             should be discontinued if the mother is treated with olaparib. These potential risks
             may also apply to other agents used in this study.

          -  Resting electrocardiogram indicating uncontrolled, potentially reversible cardiac
             conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled
             symptomatic arrhythmia, congestive heart failure, corrected QT by Fridericia's formula
             (QTcF) prolongation > 500 ms, electrolyte disturbances, etc.), or patients with
             congenital long QT syndrome.

          -  Patients with symptomatic uncontrolled CNS disease. Imaging to confirm the absence of
             brain metastases is not required. Patients with spinal cord compression unless
             considered to have received definitive treatment for this and evidence of clinically
             stable disease for 28 days.

          -  The patient can receive a stable dose of corticosteroids, up to 20 mg by mouth (PO)
             prednisone daily, before and during the study as long as these were started at least 4
             weeks prior to treatment.

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

          -  Any previous treatment with PARP inhibitor, including olaparib.

          -  Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin,
             rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's wort) or
             moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil). The required washout
             period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3
             weeks for other agents.

          -  Major surgery within 2 weeks of starting study treatment and patients must have
             recovered from any effects of any major surgery.

          -  Patients with a known hypersensitivity to olaparib or any of the excipients of the
             product.

          -  Patient with active malignancies requiring active treatment that interferes with
             protocol therapy and/or with significant risk of clinical relapse within 12 months
             that would require treatment interfering with protocol therapy are excluded.

          -  Persistent toxicities (> Common Terminology Criteria for Adverse Event [CTCAE] grade
             2) caused by previous cancer therapy, excluding alopecia.

          -  Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
             reasons) within 3 weeks prior to study treatment.

          -  Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin,
             clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
             saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g.
             ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
             period prior to starting olaparib is 2 weeks. Patients without reasonable alternative
             may be included in the trial after discussion with the medical monitor.

          -  Previous double umbilical cord blood transplantation (dUCBT).

          -  Breast feeding women.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Up to 12 months
Safety Issue:
Description:The effectiveness of the drug in patients for each cohort will be independently assessed by ORR. The exact two-sided 95% confidence intervals (CI) for the ORR will be reported. The CI based on the Greenwoods variance will be reported.

Secondary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:From first day of therapy to the time of documentation of progression, death of any cause, or last follow-up, whichever comes first, assessed up to 12 months
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method with the 95% CIs. The CI based on the Greenwoods variance will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease on the survival data. The adjusted p-values of the odds ratios and the adjusted 95% confidence interval will be reported.
Measure:Overall survival (OS)
Time Frame:From first day of therapy to the time of death or last follow-up, whichever comes first, assessed up to 12 months
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method with the 95% CIs. The CI based on the Greenwoods variance will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease on the survival data. The adjusted p-values of the odds ratios and the adjusted 95% confidence interval will be reported.
Measure:Duration of response (DOR)
Time Frame:From first documentation of response to the time of documentation of progression, death of any cause, or last follow-up, whichever comes first, assessed up to 12 months
Safety Issue:
Description:
Measure:Incidence of adverse events
Time Frame:Up to 12 months
Safety Issue:
Description:Non-hematologic toxicity will be evaluated by Common Terminology Criteria for Adverse Events version 5 criteria.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

August 6, 2020