A phase 1 study of Olaparib, a poly ADP-ribose polymerase-1 (PARP) inhibitor, in combination with metronomic cyclophosphamide in patients with metastatic BRCA-associated cancer, triple negative breast cancer or serous ovarian cancer (ANZ 1103 SOLACE)

Funding

Other Collaborative groups,Breast Cancer Trials

Scientific enquiries

Dr Chee Khoon Lee

Brief Summary

This aim of this study is to determine the maximum tolerated dose of Olaparib combined with cyclophosphamide in patients with breast cancer or ovarian cancer. Who is it for? You may be eligible to join this study if you are aged 18 years or above and have been diagnosed with either metastatic BRCA-associated breast cancer, triple negative breast cancer or serous ovarian cancer. Trial details Olaparib is a highly active agent when used as a single therapy in a standard dose of 400mg twice a day. .... This aim of this study is to determine the maximum tolerated dose of Olaparib combined with cyclophosphamide in patients with breast cancer or ovarian cancer. Who is it for? You may be eligible to join this study if you are aged 18 years or above and have been diagnosed with either metastatic BRCA-associated breast cancer, triple negative breast cancer or serous ovarian cancer. Trial details Olaparib is a highly active agent when used as a single therapy in a standard dose of 400mg twice a day. However, olaparib frequently results in suppression of the immune system when combined with chemotherapy. Cyclophosphamide is a DNA-damaging agent widely used in breast cancer and epithelial ovarian cancer in metronomic (low dose, continuous therapy) doses and does not have significant suppression of the immune system. It is suggested that combining full-dose olaparib with metronomic cyclophosphamide might result in better treatment of cancers without causing extra difficulties with the immune system. In this study, participants will be administered olaparib as 300mg tablets twice per day in combination with Cyclophosphamide, which will be administered as 50mg tablets at a pre-specified schedule (the schedule will differ slightly for each dose level). Patients will enter the study as a cohort of 3 patients per dose level. Each dose level cohort will be assessed for toxicity until the maximum tolerated dose (MTD) is determined. Two extension cohorts will be treated at the MTD. Each cohort will consist of nine or more patients: one cohort of patients with breast cancer, the other cohort of patients with ovarian cancer. Treatment duration will be up to a maximum of 8 x 21 day cycles. All participants will be regularly monitored throughout treatment to evaluate toxicity, and to assess response rate, progression free survival, and overall survival.
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Key Inclusion Criteria

1. All patients must be aged >= 18 years and: a) Male or female with histologically confirmed, metastatic triple negative breast cancer: ER-negative, PR-negative (for ER- and PR-negative: <1% tumour staining by IHC), and HER-2 non-overexpressing (IHC score 0 or 1 or ISH-negative) OR b) Male or female with histologically confirmed, metastatic breast cancer and documented BRCA1 or BRCA2 germline mutation, regardless of tumour steroid hormone receptor or HER-2 status OR c) Female with histologicall .... 1. All patients must be aged >= 18 years and: a) Male or female with histologically confirmed, metastatic triple negative breast cancer: ER-negative, PR-negative (for ER- and PR-negative: <1% tumour staining by IHC), and HER-2 non-overexpressing (IHC score 0 or 1 or ISH-negative) OR b) Male or female with histologically confirmed, metastatic breast cancer and documented BRCA1 or BRCA2 germline mutation, regardless of tumour steroid hormone receptor or HER-2 status OR c) Female with histologically confirmed high grade serous epithelial ovarian cancer (EOC) (including fallopian tube cancer or primary peritoneal cancer) with or without a documented BRCA1 or BRCA2 germline mutation 2. Patients can have disease that is measurable or non-measurable. *Patients with high grade EOC with CA125 elevation alone are eligible if they meet the criteria of disease progression from previous systemic treatment as according to Gynecologic Cancer InterGroup (GCIG) criteria for tumour response and progression 3. Patients meeting eligibility criteria 1a or 1b (breast cancer cohort): * must have received prior treatment with an anthracycline and taxane in either the adjuvant or metastatic setting *must not have received more than 3 prior chemotherapy regimens for metastatic/recurrent disease *may have received prior platinum-based regimens 4. Patients meeting eligibility 1c (ovarian cancer cohort): * must not have received more than 3 lines of subsequent chemotherapy regimens for metastatic/recurrent disease * must have received at least one prior platinum-based regimen for their disease * may have platinum ‘sensitive’ (disease relapse more than 6 months after last platinum based chemotherapy) or platinum ‘resistant or refractory’ disease (disease relapse less than 6 months after last platinum based chemotherapy or primary progressive disease during first line platinum based chemotherapy) 5. The last dose of systemic treatment, inclusive of chemotherapy or hormonal agents must have been administered more than 14 days prior to registration into the study. The last dose of bevacizumab must have been administered 6 weeks or more before registration 6. Prior radiation therapy must be limited to <30% of bone marrow producing areas. Radiation therapy with curative intent must be completed at least 14 days prior to registration 7. Patients must have normal organ and bone marrow function measured within 7 days prior to administration of study treatment as defined below: a) Haematological function, as follows: * Haemoglobin >= 100 g/L * White blood cells (WBC) > 3x109/L or absolute neutrophil count (ANC) >= 1.5 x 109/L * Platelet count >= 100 x 109/L * Peripheral blood smear must not show any features suggestive of MDS/AML b) Hepatic function, as follows: * Total bilirubin <= 1.5 x institutional upper limit of normal (ULN) * Alkaline phosphatase (ALP), AST (SGOT)/ALT (SGPT) <= 2.5 x ULN unless liver metastases are present in which case it must be <= 5 x ULN. In the presence of bone metastases, ALP <= 5 x ULN is allowed. c) Renal function, as follows: * Serum creatinine <= 1.5 x ULN, or * creatinine clearance > 60mL/min 8. Within 28 days of registration, patients must have two ECG assessments within a 24 hour period. Patients must not have a resting ECG with a QTc interval of >470 msec or a family history of long QT syndrome 9. Patients on study with reproductive potential must use an effective barrier contraceptive method during the trial and for 3 months after the last dose of study drugs 10. Evidence of non-childbearing status for women of childbearing potential, or postmenopausal status: * negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on day 1 of cycle 1. Postmenopausal status is defined as: - Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments, - LH and 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, - or surgical sterilisation (bilateral oophorectomy or hysterectomy) 11. ECOG Performance Status <=2 12. Estimated life expectancy of at least 16 weeks 13. Patients have signed informed consent and are willing and able to comply with the protocol for the duration of the study, including undergoing treatment and scheduled visits and examinations. * Patients must also consent for donation of archival diagnostic tumour specimens, if available, for further correlative science research as specified in the protocol and Participant Information Sheet and Consent Form * Patients will also have the opportunity to consent to additional, optional tissue collection (blood and serum for DNA testing, fresh tissue and ascitic fluid [if applicable]) for further correlative science research as specified in the protocol and Participant Information Sheet and Consent Form 14. Patients must be treated and followed at the institution where they are registered, unless otherwise agreed by the Trial Management Committee
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Key Exclusion Criteria

Any one of the following is regarded as criterion for exclusion from the trial: 1. Any previous treatment with a PARP inhibitor, including olaparib 2. Treatment with any investigational product during the last 14 days (or a longer period depending on the defined characteristics of the agents used). These cases must be referred to the study chair prior to patient registration 3. Patients receiving any systemic chemotherapy, radiotherapy (except for palliative reasons), within 14 days from the las .... Any one of the following is regarded as criterion for exclusion from the trial: 1. Any previous treatment with a PARP inhibitor, including olaparib 2. Treatment with any investigational product during the last 14 days (or a longer period depending on the defined characteristics of the agents used). These cases must be referred to the study chair prior to patient registration 3. Patients receiving any systemic chemotherapy, radiotherapy (except for palliative reasons), within 14 days from the last dose prior to study treatment (or a longer period depending on the defined characteristics of the agents used). The patient can receive a stable dose of bisphosphonates for bone metastases, before and during the study as long as these were started at least 4 weeks prior to study treatment 4. 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 for brain metastasis, before and during the study, as long as these were started at least 4 weeks prior to treatment 5. Patients who are pregnant or currently breast-feeding 6. Patients who are unable to swallow orally administered medication or have gastrointestinal disorders likely to interfere with absorption of the study medication (e.g. including but not limited to partial bowel obstruction or chronic malabsorption syndrome, Crohn’s disease and ulcerative colitis) 7. Patients with uncontrolled seizures 8. Patients with known interstitial lung disease 9. Patients with known haemorrhagic cystitis 10. Patients with another active second primary cancer, except: - adequately treated non-melanoma skin cancer - curatively treated in-situ cancer of the cervix, or - other solid tumours curatively treated with no evidence of disease for >= 5 years 11. Patients with prior diagnosis of myelodysplastic syndrome or acute myeloid leukaemia. Any abnormal blood films at baseline need to be reviewed to exclude these conditions 12. Patients must not have had a blood transfusion within 28 days prior to registration 13. Patients who are known to be serologically positive for human immunodeficiency virus (HIV), Hepatitis B and/or Hepatitis C 14. Patients receiving the following classes of inhibitors of CYP3A4: - Azole antifungals - Macrolide antibiotics - Protease inhibitors 15. Toxicities (>CTCAE grade 2) caused by previous cancer therapy 16. 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, or any psychiatric disorder that prohibits obtaining informed consent 17. If patient has a major surgery within 14 days of starting study treatment, patient must have recovered from any effects of major surgery 18. Patients with a known hypersensitivity to cyclophosphamide or any of the excipients of olaparib and cyclophosphamide
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