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

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Recruiting

CT.gov ID

NCT03953898

Collaborator

(none)

Enrollment

Locations

Arm

32.8

Anticipated Duration (Months)

9.4

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Recurrent Acute Myeloid Leukemia Recurrent Myelodysplastic Syndrome Refractory Acute Myeloid Leukemia Refractory Myelodysplastic Syndrome Therapy-Related Acute Myeloid Leukemia	Drug: Olaparib	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

To determine the rate of complete response (CR) to olaparib using a composite CR endpoint (CR + CR with incomplete hematologic response [CRi] + CR with partial hematologic response [CRh]) in subjects with isocitrate dehydrogenase (IDH)1/2 mutant myelodysplastic syndrome (MDS) or IDH1/2-mutant acute myeloid leukemia (AML).

SECONDARY OBJECTIVES:

To determine the overall response rate (ORR) to olaparib using a composite ORR endpoint (CR + morphologic leukemia-free state [MLFS] + partial response [PR]) in patients with IDH mutant AML or MDS treated with olaparib.
To establish the progression free survival (PFS) of patients with IDH mutant AML or MDS treated with olaparib.
To determine the overall survival (OS) of patients with IDH mutant AML or MDS treated with olaparib.
To establish the duration of response (DOR) to treatment with olaparib. V. To evaluate the safety and tolerability of olaparib in AML or MDS patients.

EXPLORATORY OBJECTIVES:

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.
To evaluate persistence of double strand breaks in IDH 1/2 mutant AML or MDS.
To evaluate response to therapy in the different IDH mutant genotypes.
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.

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.
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 for up to 12 cycles.

After completion of study treatment, patients are followed up at 90 days and then every 3 months until death.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

94 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Mar 9, 2020

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (olaparib) Patients receive olaparib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: Olaparib Given PO Other Names: AZD 2281 AZD-2281 AZD2281 KU-0059436 Lynparza PARP Inhibitor AZD2281

Arm

Intervention/Treatment

Experimental: Treatment (olaparib)

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

Drug: Olaparib

Given PO

Other Names:

AZD 2281

AZD-2281

AZD2281

KU-0059436

Lynparza

PARP Inhibitor AZD2281

Outcome Measures

Primary Outcome Measures

Overall response rate (ORR) [Up to 12 months]
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.
Cumulative ORR [Up to 6 cycles]
Will be evaluated by Myelodysplastic Syndrome International Working Group (IWG) 2006 criteria (Cheson et al., 2006) and acute myeloid leukemia (AML) IWG 2003 criteria (Cheson et al., 2003) after 6 cycles of treatment. Cumulative ORR will include complete remission (CR), complete remission with incomplete blood count recovery (CRi), partial response (PR), and bone marrow complete remission (marrow CR) achieved at least at one point during these 6 cycles.

Secondary Outcome Measures

Progression-free survival (PFS) [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]
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.
Overall survival (OS) [From first day of therapy to the time of death or last follow-up, whichever comes first, assessed up to 12 months]
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.
Duration of response (DOR) [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]
Incidence of adverse events [Up to 12 months]
Non-hematologic toxicity will be evaluated by Common Terminology Criteria for Adverse Events version 5 criteria.

Other Outcome Measures

Change in 2-hydroxyglutarate (2HG) levels [Up to 12 months]
The Mann-Whitney U test will be used to test for differences in post-treatment plasma 2HG concentrations between patients with a response to treatment and those without. Will also test for differences in Delta2HG (defined as pre-treatment minus post-treatment plasma concentration) between patients with a response to treatment and those without. Differences with p =< 0.05 will be considered significant. The area under the receiver operating characteristic curve (ROC AUC) will be calculated to determine the cutoff value of the Delta2HG difference. The optimal cutoff value will be determined at the point on the ROC curve at (sensitivity + specificity - 1) is maximized.
Minimal residual disease (MRD) assessment [Up to 12 months]
Will define MRD based on the variation of the variant allele frequency of the IDH1/2 mutation in the bone marrow of the patients before and during therapy. Will evaluate two different variables: MRD negativity (defined by the absence of detection of the IDH mutant in the sample) and the molecular response (defined by the log reduction of the frequency of the mutant allele). MRD negativity is a qualitative variable and will be reported as a percentage with 95% confidence interval for each time point and mutation. Will compare the different groups using a Chi-Square test. Molecular response is a quantitative variable reported as a median, min and max for each time point and we will use a student t test for the comparison of the different groups.
Mutant allele frequency [Up to 12 months]
Will be estimated using Poisson distribution model as the fraction of positive reads divided by total reads containing a target. The limit of detection will be defined for each mutation as the mean value of IDH1/2 wild-type controls plus three standard deviations.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age >= 18 years. Because no dosing or adverse event (AE) data are currently available on the use of olaparib in patients < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
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. 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 or MDS should have disease that has relapsed after, or is refractory to, first-line therapy, with or without subsequent additional 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.
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. Patients with impaired decision-making capacity may have a close relative, guardian, caregiver, or legally authorized representative consent on their behalf.
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.
Creatinine clearance of > 30 ml/min (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 white blood cell (WBC)/mcl. Hydroxyurea for WBC 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 WBC/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

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UC Irvine Health/Chao Family Comprehensive Cancer Center	Orange	California	United States	92868
2	Yale University	New Haven	Connecticut	United States	06520
3	UM Sylvester Comprehensive Cancer Center at Coral Gables	Coral Gables	Florida	United States	33146
4	UM Sylvester Comprehensive Cancer Center at Deerfield Beach	Deerfield Beach	Florida	United States	33442
5	University of Miami Miller School of Medicine-Sylvester Cancer Center	Miami	Florida	United States	33136
6	UM Sylvester Comprehensive Cancer Center at Plantation	Plantation	Florida	United States	33324
7	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
8	Wake Forest University at Clemmons	Clemmons	North Carolina	United States	27012
9	Wake Forest Baptist Health - Wilkes Medical Center	Wilkesboro	North Carolina	United States	28659
10	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157