Olaparib and Temozolomide in Treating Patients With Relapsed Glioblastoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2013 by Cancer Research UK
Sponsor:
Information provided by (Responsible Party):
Cancer Research UK
ClinicalTrials.gov Identifier:
NCT01390571
First received: July 7, 2011
Last updated: September 24, 2013
Last verified: September 2013
  Purpose

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.


Condition Intervention Phase
Brain and Central Nervous System Tumors
Drug: olaparib
Drug: temozolomide
Genetic: gene expression analysis
Genetic: protein expression analysis
Other: laboratory biomarker analysis
Other: pharmacological study
Procedure: diffusion-weighted magnetic resonance imaging
Procedure: dynamic contrast-enhanced magnetic resonance imaging
Procedure: therapeutic conventional surgery
Phase 1

Study Type: Interventional
Study Design: Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Cancer Research UK:

Primary Outcome Measures:
  • 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 [ Designated as safety issue: No ]
  • Maximum-tolerated dose of olaparib in combination with temozolomide (stage 2) [ Designated as safety issue: Yes ]
  • Toxicity profile and dose-limiting toxicity as assessed by NCI CTCAE Version 4.02 (stage 2) [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • 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) [ Designated as safety issue: No ]
  • 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) [ Designated as safety issue: No ]
  • Gene copy number analysis of DNA repair genes [ Designated as safety issue: No ]
  • Quantification of DNA repair gene expression [ Designated as safety issue: No ]
  • Measurement of methylation of the MGMT promoter gene by bisulfite modification of DNA and pyrosequencing [ Designated as safety issue: No ]
  • Measurement of microsatellite instability by Multiplex PCR [ Designated as safety issue: No ]
  • Measurement of mismatch repair (MMR) gene expression by quantitative real time polymerase chain reaction (QRT-PCR) analysis [ Designated as safety issue: No ]
  • Measurement of phosphatase and tensin homolog (PTEN) protein and gene expression [ Designated as safety issue: No ]
  • Quantification of global DNA strand breaks in tumour tissue by Immunostaining for γH2AX [ Designated as safety issue: No ]
  • Measurement of Rad51 foci and nuclear staining intensity as markers of homologous recombination (HR) repair activity [ Designated as safety issue: No ]
  • Plasma levels of olaparib measured by LC-MS [ Designated as safety issue: No ]
  • PARP inhibition measured by validated assays [ Designated as safety issue: No ]

Estimated Enrollment: 34
Study Start Date: July 2011
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Detailed Description:

OBJECTIVES:

Primary

  • To determine whether olaparib crosses the blood-brain barrier (BBB) and achieves tumor penetration in patients with relapsed glioblastoma. (Stage 1)
  • To determine the safety and tolerability of the combination of olaparib and temozolomide in patients with relapsed glioblastoma. (Stage 2)

Secondary

  • To assess BBB disruption and BBB permeability in patients with relapsed glioblastoma. (Stage 1 and stage 2 maximum-tolerated dose [MTD] expansion cohort)
  • To assess the possible anti-tumor activity of the combination of olaparib and temozolomide in patients with relapsed glioblastoma. (Stage 2)

Tertiary

  • To assess biological markers as possible predictors of olaparib efficacy in patients with glioblastoma.
  • To optimize techniques for measuring DNA damage responses to PARP inhibition in tumor tissue.
  • To determine plasma concentration of olaparib at the time of surgery in patients with glioblastoma.
  • To evaluate the PARP inhibition at the time of surgery in peripheral blood mononuclear cells (PBMCs).

OUTLINE: This is a multicenter, dose-escalation study.

  • Stage 1: Patients receive fixed-dose oral olaparib twice daily for 3 days prior to resection and then receive a dose of oral olaparib on the morning of the resection. After the surgical resection, patient receive standard of care treatment. Patients undergo dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) scans to assess the disruption and permeability of the blood-brain barrier (BBB).

If it is proven that olaparib can cross the BBB and achieve tumor penetration as measured by liquid chromatography mass spectrometry (LC-MS) in at least one out of six patients, then new patients are recruited to stage 2 of the study.

  • Stage 2: Patients receive escalating doses of oral olaparib once or twice daily for 3 days prior to resection and then receive a dose of oral olaparib on the morning of the resection. After recovery from surgery, patients receive oral olaparib once or twice daily and oral temozolomide once daily on days 1-42. Treatment repeats every 8 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients may receive 3 additional courses of treatment in the absence of disease progression.

Once the maximum tolerated dose (MTD) is established, 10 more patients are treated at the MTD as stage 2 MTD expansion cohort. These patients also undergo DCE-MRI and DWI scans.

All patients undergo blood collection periodically for pharmacokinetic and pharmacodynamic studies.

After completion of study treatment, patients are followed up for 28 days and then monthly until resolution of study drug-related adverse events.

Peer Reviewed and Funded or Endorsed by Cancer Research UK.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 ≥ 9.0 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

PRIOR CONCURRENT THERAPY:

  • 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

    • Patients in stage 1 of the study only may receive additional anticancer therapies as soon as the resection has been performed
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01390571

Locations
United Kingdom
Bristol Haematology and Oncology Centre Recruiting
Bristol, England, United Kingdom, BS2 8ED
Contact: Contact Person    01173423008    Kristen.Hopkins@UHBristol.nhs.uk   
Principal Investigator: Kristen Hopkins, Dr         
Addenbrooke's Hospital Recruiting
Cambridge, England, United Kingdom, CB2 0QQ
Contact: Contact Person    01223586705    sarah.jefferies@addenbrookes.nhs.uk   
Principal Investigator: Sarah Jefferies, Dr         
Christie Hospital Recruiting
Manchester, England, United Kingdom
Contact: Contact Person    0161 446 3495    catherine.mcbain@christie.nhs.uk   
Principal Investigator: Catherine McBain, Dr         
Royal Marsden Hospital Recruiting
Sutton, England, United Kingdom
Contact: Contact Person    020 8661 3988    Rhoda.molife@icr.ac.uk   
Principal Investigator: Rhoda Molife, Dr         
Beatson West of Scotland Cancer Centre Recruiting
Glasgow, Scotland, United Kingdom
Contact: Contact Person    0141 301 7097    anthony.chalmers@glasgow.ac.uk   
Principal Investigator: Anthony Chalmers, Prof         
Queen Elizabeth Hospital Recruiting
Birmingham, United Kingdom, B15 2TH
Contact: Contact Person    0121 697 8231    Garth.Cruickshank@uhb.nhs.uk   
Principal Investigator: Garth Cruikshank, Dr         
Western General Hospital Recruiting
Edinburgh, United Kingdom, EH4 2XU
Contact: Contact Person    0131 537 1052    serridge@staffmail.ed.ac.uk   
Principal Investigator: Sara Erridge, Dr         
Sponsors and Collaborators
Cancer Research UK
Investigators
Principal Investigator: Anthony Chalmers, Prof Beatson West of Scotland Cancer Centre
  More Information

Additional Information:
No publications provided

Responsible Party: Cancer Research UK
ClinicalTrials.gov Identifier: NCT01390571     History of Changes
Other Study ID Numbers: CDR0000702605, CRUK-CR0901-11, EUDRACT-2010-018615-15
Study First Received: July 7, 2011
Last Updated: September 24, 2013
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
United Kingdom: Research Ethics Committee

Keywords provided by Cancer Research UK:
adult glioblastoma
adult giant cell glioblastoma
adult gliosarcoma
recurrent adult brain tumor

Additional relevant MeSH terms:
Glioblastoma
Nervous System Neoplasms
Central Nervous System Neoplasms
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms by Site
Nervous System Diseases
Temozolomide
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 18, 2014