investigation of anti-tumour effect and tolerability of the parp inhibitor 2x-121 in patients with metastatic breast cancer selected by the 2x-121 drp

Conditions: Metastatic Breast Cancer

Summary: 2x-121 is a small molecule targeted inhibitor of poly adp ribose polymerase (parp), a key enzyme involved in dna damage repair in cancer cells. the parp inhibitor demonstrated clinical activity in a prior phase 1 study in a number of solid tumors. 2x-121 has a novel dual-inhibitory action against both parp 1/2 and tankyrase 1/2. the molecule is also active in p-glycoprotein expressing cells, suggesting it may overcome some of the parp inhibitor resistance. the phase 2 study is using 2x-121 drp® biomarker in metastatic breast cancer patients to identify patients likely to respond to and benefit from treatment with 2x-121.


Eligibility criteria:
inclusion criteria: * signed informed consent form. * age 18 years or older. * histologically or cytological documented mbc (independent of hormone receptor, her2 status and brca1 or 2 status) relapsed in 2 or more different prior therapies. * measurable disease by ct scan or mri. * with a drug response prediction (drp) for 2x-121 with an outcome measured as being in the upper 20% likelihood of response. * prior chemotherapy or hormone therapy for metastatic breast cancer is allowed. * performance status of ecog \<= 1 * recovered to grade 1 or less from prior surgery or from acute toxicities of prior radiotherapy, or from treatment with cytotoxic, hormonal or biologic agents). * \>= 2 weeks must have elapsed since any prior surgery or therapy with g-csf and gm-csf. * patients with intracranial disease must be on stable or decreased level of steroid therapy (e.g. dexamethasone) for at least 7 days prior to baseline mri. non-enzymatic inducing ant-epileptic drugs are allowed. * adequate conditions as evidenced by the following clinical laboratory values: * absolute neutrophils count (anc) \>= 1.5 x 10e9/l * haemoglobin is at least 4.6 mmol/l * platelets \>= 100 x 10e9 /l * alanine aminotransferase (alt) and aspartate aminotransferase (ast) \<= 2.5 x uln\* * serum bilirubin \<= 1.5 uln * alkaline phosphatase \<= 2.5 x uln\* * creatinine \<= 1.5 uln * blood urea within normal limits * creatinine clearance within normal limits. \*in case of known liver metastases with alt and ast \<= 5 x uln and/or alkaline phosphatase \<= 5 x uln. patients who do not conform to the transaminase and/or alkaline phosphatase inclusion criteria, but who by the pi are considered in good ps and otherwise eligible for inclusion, and where the transaminase and/or alkaline phosphatase levels are considered elevated due to other reasons than deteriorated lever capacity, may be considered for inclusion based on conferred agreement between pi and sponsor. * life expectancy equal or longer than 3 months. * sexually active females of child-producing potential must use adequate contraception (oral contraceptives, intrauterine device or barrier method of contraception) for the study duration and at least six months afterwards. exclusion criteria: * - concurrent chemotherapy, radiotherapy, hormonal therapy, or other investigational drug except non-disease related conditions (e.g. insulin for diabetes) during study period. * other malignancy with exception of curative treated non-melanoma skin cancer or cervical carcinoma in situ within 5 years prior to entering the study. * previous treatment with parp inhibitors * any active infection requiring parenteral or oral antibiotic treatment. * has known hiv positivity. * has known active hepatitis b or c. * has clinical significant (i.e. active) cardiovascular disease: * stroke within \<= 6 months prior to day 1 * transient ischemic attach (tia) within \<= 6 months prior to day 1 * myocardial infarction within \<= 6 months prior to day 1 * unstable angina * new york hart association (nyha) grade ii or greater congestive heart failure (chf) * serious cardiac arrhythmia requiring medication * mental status is not fit for clinical study or cns disease including symptomatic epilepsy. * other medications or conditions, including surgery, that in the investigator's opinion would contraindicate study participation of safety reasons or interfere with the interpretation of study results * inability to take oral medication, or malabsorption syndrome or any other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea, or vomiting) that might impair the bioavailability of 2x-121. * requiring immediate palliative treatment of any kind including surgery and/or radiotherapy. * female patients who are pregnant or breast-feeding (pregnancy test with a positive result before study entry)

Keywords: parp inhibitor drug response prediction (drp) tankyrase 1/2 inhibitor mrna biomarker