Olaparib and Temozolomide with or without Irinotecan Hydrochloride in Treating Patients with Recurrent or Metastatic Ewing Sarcoma Previously Treated with Chemotherapy

Status: Active


This phase I trial studies the side effects and best dose of olaparib and temozolomide in treating patients with Ewing sarcoma that has returned or spread to other places in the body after previous treatment with chemotherapy. Olaparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Irinotecan hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving olaparib and temozolomide with irinotecan may be a better treatment for Ewing sarcoma.

Eligibility Criteria

Inclusion Criteria

  • Participant must have histologically confirmed Ewing’s sarcoma
  • The Ewing’s sarcoma must have progressed following at least one standard prior chemotherapy regimen
  • Hemoglobin >= 10.0 g/dL (measured within 28 days prior to administration of study treatment)
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (measured within 28 days prior to administration of study) treatment:
  • Platelet count >= 100 x 10^9/L (measured within 28 days prior to administration of study treatment)
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (measured within 28 days prior to administration of study treatment)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal (unless liver metastases are present in which case it must be =< 5 x ULN) (measured within 28 days prior to administration of study treatment)
  • Serum creatinine =< 1.5 x institutional upper limit of normal (ULN) (measured within 28 days prior to administration of study treatment)
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Participant must have a life expectancy >= 16 weeks
  • Women of childbearing potential must have a negative urine or serum pregnancy test within 28 days of initial dose of olaparib and temozolomide, and again within 7 days prior to treatment on day 1; if screening occurs within 7 days of day 1, only one pregnancy test is required; 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 postmenopausal range for women under 50 * Radiation-induced oophorectomy with last menses > 1 year ago * Chemotherapy-induced menopause with > 1 year interval since last menses, or surgical sterilization (bilateral oophorectomy or hysterectomy)
  • Participant is willing to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
  • Presence of measurable disease: at least one lesion, not previously irradiated, that can be accurately measured at baseline as >= 10 mm in the longest diameter (except lymph nodes which must have short axis >= 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements
  • Any participant must obtain prior approval from insurance to reimburse for oral temozolomide for the duration of the study or agree to self-pay for oral temozolomide or obtain institutional commitment from the study site to provide temozolomide
  • Participant must have adequate venous or central access for irinotecan administration

Exclusion Criteria

  • Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
  • Participants who have previously enrolled and received study drugs on arm 1 of this study cannot re-enroll onto arm 1 after being removed from this study, but if they were removed from arm 1 for disease progression, they are eligible to re-register onto this study in order to enroll onto arm 2 of this study if they otherwise meet all of the eligibility criteria for this study; all participants who received an investigational product on a clinical trial, including arm 1 of this study, must wait 21 days prior to course 1 day 1 (C1D1) of this study
  • Participants receiving any systemic chemotherapy, radiotherapy, or targeted anti-cancer therapy within 2 weeks or 3 half-lives from the last dose prior to study treatment (or a longer period depending on the half-life of the agents used); the patient can receive bisphosphonates or steroids
  • Participants are to discontinue the use of the following classes of inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4); patients who are on these drugs are eligible if a washout period of a minimum of 7 days occurs before start of olaparib and temozolomide * Azole antifungals * Macrolide antibiotics * Protease inhibitors
  • Persistent clinically significant grade >= 2 toxicities (as per >= CTCAE v4) related to prior cancer therapy
  • Participants with a previously documented diagnosis of myelodysplastic syndrome (or any dysplastic leukocyte morphology suggestive of myelodysplastic syndromes [MDS]) or acute myeloid leukemia
  • Participants with symptomatic uncontrolled brain metastases; a scan to confirm the absence of brain metastases is not required
  • Major surgery within 14 days of starting study treatment and patients must have recovered from any effects of any major surgery
  • Participants 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, corrected QT interval (QTc) prolongation > 470 msec, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, unstable spinal cord compression (untreated and unstable for at least 28 days prior to study entry), superior vena cava syndrome, extensive bilateral lung disease with less than 20% predicted lung function by diffusion capacity of the lungs for carbon monoxide (DLCO) (lung diffusion capacity testing), or any psychiatric disorder that prohibits obtaining informed consent
  • Participants unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
  • Pregnant or breast feeding women are excluded; all patients (male and female) must agree to practice a medically acceptable method of contraception; should a woman become pregnant or suspect that she is pregnant while participating in this study, she should inform her treating physician immediately
  • Patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving antiviral therapy
  • Patients with known active hepatitis B or C
  • Patients with a known hypersensitivity to olaparib or any of the excipients of the product
  • Patients with uncontrolled seizures
  • Patients who need to continue treatment with any prohibited medications
  • Patients who have not completed the appropriate washout period for the prohibited medications

Locations & Contacts


Boston Children's Hospital
Status: Active
Contact: Steven G. DuBois
Phone: 617-632-5460
Email: Steven_Dubois@dfci.harvard.edu
Brigham and Women's Hospital
Status: Active
Contact: George Daniel Demetri
Phone: 617-632-3985
Email: gdemetri@partners.org
Dana-Farber Cancer Institute
Status: Active
Contact: George Daniel Demetri
Phone: 617-632-3985
Email: gdemetri@partners.org
Massachusetts General Hospital Cancer Center
Status: Active
Contact: Edwin Choy
Phone: 617-726-8748
Email: echoy@mgh.harvard.edu


St. Jude Children's Research Hospital
Status: Active
Contact: Sara Michele Federico
Phone: 901-595-4154
Email: sara.federico@stjude.org

Trial Objectives and Outline


I. Determine the maximum tolerated dose (MTD) of combined oral administration of olaparib with either temozolomide or with temozolomide and irinotecan (irinotecan hydrochloride).


I. Evaluate the safety and tolerability of combination olaparib/temozolomide and olaparib/temozolomide/irinotecan as defined by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

II. Estimate the objective response rate as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 to olaparib/temozolomide and olaparib/temozolomide/irinotecan.

III. Estimate the time of progression free survival (PFS) and overall survival (OS) of patients treated with olaparib/temozolomide or with olaparib/temozolomide/irinotecan.

IV. Explore variations in PARP activity and tumor deoxyribonucleic acid (DNA)/ribonucleic acid (RNA)/protein characteristics as potential biomarkers for olaparib activity.

V. Evaluate in vivo changes of tumor RNA/protein biomarkers in response to administration of olaparib and temozolomide, and +/- irinotecan to patients who sign consent to undergo the optional tumor biopsy.

OUTLINE: This is a dose-escalation study.

Arm I: Patients receive olaparib orally (PO) twice daily (BID) and temozolomide PO once daily (QD) on days 1-5 or 1-7. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Arm II: Patients receive olaparib and temozolomide as in Arm I. Patients also receive irinotecan hydrochloride intravenously (IV) on days 1-5 or 1-7. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then every 3 months.

Trial Phase & Type

Trial Phase

Phase I

Trial Type


Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Edwin Choy

Trial IDs

Primary ID 13-115
Secondary IDs NCI-2013-01821
Clinicaltrials.gov ID NCT01858168