This is a Phase II, non-randomized, open-label study to evaluate temozolomide in combination
with olaparib in patients with MGMT promoter hypermethylated advanced colorectal cancer.
Patients will receive temozolomide orally daily on days 1-7 and olaparib twice daily
continuously. Cycles repeat every 21 days in the absence of disease progression or
unacceptable toxicity. After completion of study treatments patients are followed up at 30
days, and for patients that come off treatment for reasons other than disease progression,
clinical assessments will continue every 6 weeks for the first year and every 12 weeks after
the first year.
PRIMARY OBJECTIVES:
I. To determine the efficacy of TMZ in combination with olaparib in subjects with MGMT
promoter hypermethylated advanced colorectal cancer by the overall response rate.
SECONDARY OBJECTIVES:
I. To determine the safety of TMZ in combination with olaparib. II. To estimate the
progression free survival (PFS). III. To estimate overall survival (OS).
EXPLORATORY OBJECTIVES:
I. Characterize NGS profiling, patterns of DNA methylation, gene expression, and develop MGMT
expression assays.
II. Correlate molecular features with Gamma H2AX with response. III. Establish organoids for
MGMT promoter hypermethylated colorectal cancer.
Inclusion Criteria:
- Capable of giving signed informed consent which includes compliance with the
requirements and restrictions listed in the informed consent form (ICF).
- Provision of signed and dated, written informed consent form prior to any mandatory
study specific procedures, sampling, and analyses.
- For inclusion in i) the optional exploratory genetic research and ii) the optional
biomarker research, patients must fulfill the following criteria:
- Provision of informed consent for genetic research prior to collection of sample
- Provision of informed consent for biomarker research prior to collection of
sample **If a patient declines to participate in the optional exploratory genetic
research or the optional biomarker research, there will be no penalty or loss of
benefit to the patient. The patient will not be excluded from other aspects of
the study.
- Individuals who are healthy as determined by medical evaluation including medical
history, physical examination, laboratory tests, and cardiac monitoring.
- Individuals with histologically proven relapsed/refractory mismatch repair proficient
/ microsatellite stable metastatic colorectal adenocarcinoma.
- MGMT promoter hypermethylation on pre-screening.
- Patients must have had recurrence, progression or intolerance to standard therapy
consisting of at least 2 prior standard regimens (containing a fluoropyrimidine plus a
platinum analogue and/or irinotecan) for metastatic disease. In the case where all
chemotherapy agents are used concurrently (I.e. FOLFOXIRI +/- Bevacizumab) 1 prior
treatment regimen is acceptable after discussion with the principal investigator.
Relapse within 6 months of completing adjuvant chemotherapy is considered one line of
therapy in the metastatic setting.
- Patients must have normal organ and bone marrow function measured within 28 days prior
to administration of study treatment as defined below:
- Haemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
- Platelet count ≥ 100 x 109/L
- Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)
- 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 liver metastases are present in
which case they must be ≤ 5x ULN.
- Patients must have creatinine clearance estimated of ≥51 mL/min using the
Cockcroft-Gault equation or based on a 24 hour urine test :
- Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F)° / serum
creatinine (mg/dL) x 72
- where F=0.85 for females and F=1 for males.
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
- Patients must have a life expectancy ≥ 16 weeks.
- 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.
- 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 sterilisation (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 ([see appendix C for acceptable methods]) if they are
of childbearing potential.
Exclusion Criteria:
- Other malignancy unless curatively treated with no evidence of disease for ≥5 years
except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer
of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial
carcinoma.
- Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as
judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic
arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte
disturbances, etc.), or patients with congenital long QT syndrome.
- Persistent toxicities (Common Terminology Criteria for Adverse Event (CTCAE) grade 2)
caused by previous cancer therapy, excluding alopecia.
- Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features
suggestive of MDS/AML.
- Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence
of brain metastases is not required. The patient can receive a stable dose of
corticosteroids before and during the study as long as these were started at least 4
weeks prior to treatment. Patients with spinal cord compression unless considered to
have received definitive treatment for this and evidence of clinically stable disease
for 28 days.
- 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 unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study
medication.
- Immunocompromised patients, e.g., patients who are known to be serologically positive
for human immunodeficiency virus (HIV).
- Patients with known active hepatitis (i.e. Hepatitis B or C).
- Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen
(HBsAg) result. Patients with a past or resolved HBV infection (defined as the
presence of hepatitis B core antibody and absence of HBsAg) are eligible.
- Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase
chain reaction is negative for HCV RNA.
- Any previous treatment with PARP inhibitor, including Olaparib.
- Any previous treatment with temozolomide or other monofunctional alkylating agent.
- 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 (eg. itraconazole, telithromycin,
clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg.
ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
period prior to starting olaparib and temozolomide is 2 weeks.
- Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin,
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort ) or
moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout
period prior to starting olaparib and temozolomide 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.
- Previous allogenic bone marrow transplant or double umbilical cord blood
transplantation (dUCBT).
- Whole blood transfusions in the last 120 days prior to entry to the study (packed red
blood cells and platelet transfusions are acceptable, for timing refer to inclusion
criteria related to "Patients must have had recurrence, progression or intolerance to
standard therapy...").
- Participation in another clinical study with an investigational product administered
in the last 28 days.
- Subjects with a known hypersensitivity to temozolomide, olaparib, any of the
recipients of either product, or the combination.
- Patients with a known hypersensitivity to the combination/comparator agent.
- Involvement in the planning and/or conduct of the study
- Judgment by the investigator that the patient should not participate in the study if
the patient is unlikely to comply with study procedures, restrictions and
requirements.
- Previous enrollment in the present study.
- Breast feeding women.
