Brain and Central Nervous System Tumors Clinical Trial
Official title:
A Cancer Research UK Phase I Trial of Olaparib (AZD2281), an Oral PARP Inhibitor, in Combination With Extended Low-Dose Oral Temozolomide in Patients With Relapsed Glioblastoma
Verified date | February 2018 |
Source | Cancer Research UK |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
RATIONALE: 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 or by stopping them from
dividing. Olaparib may help temozolomide kill more tumor cells by making tumor cells more
sensitive to the drug.
PURPOSE: This phase I trial is studying the side effects and best dose of olaparib and
temozolomide in treating patients with relapsed glioblastoma.
Status | Completed |
Enrollment | 34 |
Est. completion date | June 20, 2017 |
Est. primary completion date | June 20, 2017 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility |
DISEASE CHARACTERISTICS: - Histologically confirmed grade IV glioblastoma - Radiological diagnosis of recurrent or progressive disease according to Response Assessment in Neuro-Oncology Working Group (RANO) criteria, which is suitable for palliative resection - Must have an adequate amount of tumor tissue available - Previously received first-line treatment with radical radiotherapy, or chemoradiation followed by adjuvant chemotherapy - No prior chemotherapy for recurrent disease PATIENT CHARACTERISTICS: - WHO performance status 0-2 - Life expectancy > 12 weeks - Hemoglobin = 10.0 g/dL - Absolute neutrophil count = 1.5 x 10^9/L - Platelet count = 100 x 10^9/L - Serum bilirubin = 1.5 times upper limit of normal (ULN) - ALT or AST = 2.5 times ULN - Calculated creatinine clearance = 50 mL/min OR isotope clearance measurement = 50 mL/min (uncorrected) - Not pregnant or nursing - Negative pregnancy test - Fertile patients must use one (male) or two (female) highly effective forms of contraception 4 weeks prior to, during, and for 6 months after completion of study therapy - Able to swallow and retain oral medications - Not at high medical risk due to non-malignant systemic disease, including active uncontrolled infection - No known hepatitis B, hepatitis C, or HIV seropositivity - No concurrent congestive heart failure, prior history of NYHA class III-IV cardiac disease, prior history of cardiac ischemia, or prior history of cardiac arrhythmia within the past 12 months - No grand mal seizures occurring = 3 times per week over the past month - No gastrointestinal disorders likely to interfere with absorption of the study medication - No known hypersensitivity to any of the components of olaparib - No known hypersensitivity to temozolomide (TMZ) or any of its components, or to dacarbazine (DTIC) (for patients enrolled in stage 2 study only) - No known lactose intolerance (for patients enrolled in the stage 2 study only) - No metal fragments in the eyes (shrapnel or bullet injuries are excluded on the basis of their unsuitability to undergo MRI scans) - No other condition which, in the Investigator's opinion, would not make the patient a good candidate for the clinical trial EXCLUSION CRITERIA: - See Disease Characteristics - No ongoing toxic manifestations from previous treatments except for alopecia or grade 1 toxicities which, in the opinion of the Investigator and the Drug Development Office (DDO), should not exclude the patient - At least 12 weeks since prior radiotherapy, endocrine therapy, or immunotherapy - At least 6 weeks since prior major surgery - At least 4 weeks since prior chemotherapy - At least 4 weeks since prior immunizations with live vaccines (or expected to receive vaccines during the trial and up to at least 6 months after receiving last study treatment), including BCG and yellow fever vaccines - No prior PARP inhibitors, including olaparib - No prior major thoracic or abdominal surgery from which the patient has not yet recovered - No prior heart surgery - No pacemakers - No change to systemic steroids dose within 5 days prior to enrollment (i.e., must be on a stable dose at time of enrollment and remain on a stable dose throughout the treatment period) - No herbal supplements and/or ingestion of foods known to modulate CYP3A4 enzyme activity from time entered on screening period until 28 days after the last dose of study medication - No concurrent drugs known to be potent inducers of CYP3A4, including phenytoin, carbamazepine, phenobarbital, rifampicin, rifapentine, rifabutin, nevirapine, modafinil, or St. John wort (wash-out period for phenobarbital is 5 weeks, 3 weeks for all others) - No concurrent drugs known to be potent inhibitors of CYP3A4, including ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin, or nelfinavir (wash-out period is 1 week) - No concurrent or planned participation in another interventional clinical study - Participation in an observational study is acceptable - No concurrent warfarin (patients requiring anticoagulation should be given subcutaneous low molecular weight heparin) - No other concurrent anticancer therapy (including radiotherapy) or investigational drugs - No blood transfusions within 4 weeks prior to study start of features suggestive of myelodysplasia or AML |
Country | Name | City | State |
---|---|---|---|
United Kingdom | Queen Elizabeth Hospital | Birmingham | |
United Kingdom | Bristol Haematology and Oncology Centre | Bristol | England |
United Kingdom | Addenbrooke's Hospital | Cambridge | England |
United Kingdom | Western General Hospital | Edinburgh | |
United Kingdom | Beatson West of Scotland Cancer Centre | Glasgow | Scotland |
United Kingdom | Christie Hospital | Manchester | England |
United Kingdom | Royal Marsden Hospital | Sutton | England |
Lead Sponsor | Collaborator |
---|---|
Cancer Research UK |
United Kingdom,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Gene copy number analysis of DNA repair genes | |||
Other | Quantification of DNA repair gene expression | |||
Other | Measurement of methylation of the MGMT promoter gene by bisulfite modification of DNA and pyrosequencing | |||
Other | Measurement of microsatellite instability by Multiplex PCR | |||
Other | Measurement of mismatch repair (MMR) gene expression by quantitative real time polymerase chain reaction (QRT-PCR) analysis | |||
Other | Measurement of phosphatase and tensin homolog (PTEN) protein and gene expression | |||
Other | Quantification of global DNA strand breaks in tumour tissue by Immunostaining for ?H2AX | |||
Other | Measurement of Rad51 foci and nuclear staining intensity as markers of homologous recombination (HR) repair activity | |||
Other | Plasma levels of olaparib measured by LC-MS | |||
Other | PARP inhibition measured by validated assays | |||
Other | Detection of olaparib in tumour margin tissue using LC-MS | |||
Primary | Detection of olaparib in tumor tissue using liquid chromatography mass spectrometry (LC-MS) seen in at least 1 out of the 6 patients treated in stage 1 of the study | |||
Primary | Maximum-tolerated dose of olaparib in combination with temozolomide (stage 2) | |||
Primary | Toxicity profile and dose-limiting toxicity as assessed by NCI CTCAE Version 4.02 (stage 2) | |||
Secondary | Measurement of blood-brain barrier (BBB) disruption and permeability biomarkers by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) (stage 1 and stage 2 MTD expansion cohort) | |||
Secondary | Progression-free survival at 6 months post-surgery as assessed by the Response Assessment in Neuro-Oncology Working Group (RANO) criteria from conventional MRI and clinical assessment (stage 2) |
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