Inclusion Criteria:
- - Patients must have histologically confirmed glioblastoma multiforme that is
recurrent after primary treatment (surgery/radiation/temozolomide) (i.e. first
progression).
Patients may not have had disease progression while receiving adjuvant
temozolomide or radiation.
- - All patients must have an available formalin fixed paraffin embedded tissue block
(from their primary tumour) and must have provided informed consent for the release
of the block.
Patients participating in the pharmacodynamics study must have
provided consent for release of a representative sample of the resected tumour.
- - Presence of clinically and/or radiologically documented disease.
MRI scan must be
performed within 14 days prior to registration.
- - All patients enrolled to DL3 and the dose expansion cohort at RP2D must have
measurable disease according to RANO criteria as follows: At least one enhancing
lesion which is ≥ 10 mm x 10 mm.
- - Patients must be ≥18 years of age.
- - Patients must have an ECOG performance status of 0 or 1.
- - Patients must have received one prior temozolomide regimen, discontinued at least 16
weeks prior to registration.
Patients may have received one other cytotoxic regimen
(for example CCNU).
- - Patients may not have received immunotherapies, biologic and viral therapies,
angiogenesis inhibitors, mTOR, or PARP inhibitors.
- - Patients must have recovered from all reversible toxicity related to prior
chemotherapy and have adequate washout from prior chemotherapy, and investigational
agents as follows: longest of one of the following:
- two weeks,
- standard cycle length of prior regimen,
- 5 half-lives for investigational drugs.
- - Prior external beam radiation must have been completed at least 4 weeks prior to
registration.
- - Previous surgery is permitted provided that a minimum of 21 days have elapsed
between any major surgery (excluding resection for patients participating in the
Pharmacodynamic Study) and date of registration, and that wound healing has
occurred.
- - Patients must have recovered from any treatment related toxicities prior to
registration (unless grade 1, irreversible, or considered by investigator as not
clinically significant).
- - Hematology: Neutrophils ≥ 1.5 x 10^9/L; Platelets ≥ 100 x 10^9/L; INR ≤ 1.5.
- - Biochemistry:
Serum Creatinine or Creatinine Clearance* ≥ 50 ml/min (calculated by Cockcroft and Gault
equation) Total bilirubin ≤ 1.5 x ULN AST and ALT ≤ 2.5 x ULN (≤ 5x ULN in the presence
of liver metastases) Electrolytes within normal limits.
* Creatinine clearance to be measured directly by 24 hour urine sampling or as calculated
by appropriate formula below:
Females: GFR = 1.04 x (140-age) x weight in kg / serum creatinine in μmol/L.Males: GFR = 1.23 x (140-age) x weight in kg / serum creatinine in µmol/L.
- - Patient consent must be appropriately obtained in accordance with applicable local
and regulatory requirements.
Each patient must sign a consent form prior to
enrollment in the trial to document their willingness to participate. Patients who
cannot give informed consent (i.e. mentally incompetent patients, or those
physically incapacitated such as comatose patients) are not to be recruited into the
study. Patients competent but physically unable to sign the consent form may have
the document signed by their nearest relative or legal guardian. Each patient will
be provided with a full explanation of the study before consent is requested.
- - Patients must be accessible for treatment and follow up.
- - In accordance with CCTG policy, protocol treatment is to begin within 2 working days
of patient registration (exceptions will be made if surgical resection is delayed).
- - Women/men of childbearing potential must have agreed to use 2 methods of
contraception (1 highly effective method and 1 barrrier method) until 4 weeks after
the end of treatment.
Acceptable methods of highly effective contraception include:
- - Placement of an intrauterine device or intrauterine system.
- - Male partner's sterilization (with the appropriate post-vasectomy documentation
of the absence of sperm in the ejaculate).
- - Acceptable barrier methods of contraception include: condom or occlusive cap
(diaphragm or cervical/vault caps) with spermicidal
foam/gel/film/cream/suppository.
Please note: use of oral, injected, or implanted hormonal methods of contraception cannot
be considered highly effective as it is currently unknown whether AZD2014 may reduce
their effectiveness).
Exclusion Criteria:
- - Patients who have undergone any of the following procedures or experienced
conditions currently or in the preceding 12 months:
- Coronary artery bypass graft.
- - Myocardial infarction (MI)
- Angina pectoris.
- - Congestive heart failure New York Heart Association (NYHA) Grade 2.
- - Ventricular arrhythmias requiring continuous therapy.
- - Supraventricular arrhythmias including atrial fibrillation, which are uncontrolled.
- - Hemorrhagic or thrombotic stroke, including transient ischemic attacks or any other
central nervous system bleeding.
- - Patients with a baseline LVEF ≤ 50% by MUGA scan, and ≤ 55% by ECHO.
- - Patients with mean QT interval corrected for heart rate using Fridericia's formula
(QTcF) ≥ 470 msec in screening ECG measured using standard institutional method or
history of familial long QT syndrome or unexplained sudden death under 40 years of
age.
- - Any evidence of severe or uncontrolled systemic disease, active infection (including
any patient known to have hepatitis B, hepatitis C or human immunodeficiency virus
(HIV) or a prior history of tuberculosis), active bleeding or bleeding diathesis or
renal diseases such as nephritis or renal tubular acidosis.
- - Patients with history of pre-existing and/or clinically or radiologically active
interstitial lung disease.
- - History of hypersensitivity to protocol therapy or any excipient used in this study.
- - Patients who have significant gastrointestinal disease and who are unable to swallow
capsules.
- - Concurrent Medications.
- - Patients receiving other investigational agents.
- - Patients receiving other anti-cancer agents, or radiation therapy.
- - Patients receiving known QT/QTc-prolonging drugs.
- - Co-medications which are moderate or potent inhibitors or inducers of CYP3A4/5 and
CYP2C8, Pgp (MDR1) and BCRP or are sensitive or narrow therapeutic range substrates
of the drug metabolizing enzymes CYP2C8, CYP2C9, CYP2C19, CYP2D6 or the drug
transporters Pgp (MDR1), BCRP, OATP1B1, OATP1B3, OCT1 and OCT2 will be restricted.
These should be discontinued prior to registration unless in the opinion of the
investigator the risk/benefit is acceptable and no alternative medications are
available (see Appendix V for washout periods).
- - Patients taking corticosteroids must have been on a stable or decreasing dose for at
least 14 days prior to registration.
- - Patients who require oral anticoagulants should be switched to LMW heparin.
- - Patients on enzyme inducing anticonvulsants.
- - Patients who do not agree to avoid the ingestion of large amounts of grapefruit and
Seville oranges (and other products containing these fruits, e.g. grapefruit juice
or marmalade).
- - Pregnant or lactating women.
Women of childbearing potential must have a pregnancy
test proven negative within 7 days prior to registration. Men and women of
childbearing potential must agree to use adequate contraception.
- - Patients who do not agree to avoid excessive sun exposure and use adequate sunscreen
protection while on study and for three months after.
- - Patients with diabetes type I or uncontrolled type II as judged by the investigator.
- - Patients with meningeal or extracranial GBM involvement.
- - Live attenuated vaccination administered within 30 days prior to registration.
