TMZ + Olaparib for MGMT Hypermethylated Colorectal Cancer
Condition: Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Intervention: Temozolomide + Olaparib
Intervention description: Temozolomide (75 mg/m2 orally on days 1-7 every 3 weeks) + Olaparib (150 mg orally twice daily days 1-21) in a 21-day cycle.
Intervention MeSH terms: Temozolomide; Olaparib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 11.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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.