PRIMARY OBJECTIVE:
I. 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:
I. 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.
II. To establish the progression free survival (PFS) of patients with IDH mutant AML or MDS
treated with olaparib.
III. To determine the overall survival (OS) of patients with IDH mutant AML or MDS treated
with olaparib.
IV. 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:
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.
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.
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. 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
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.
