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

Study Overview
=================
Brief 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.

Official Title
-----------------
Phase II, Open Label Clinical Study to Investigate 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

Intervention / Treatment
-----------------
* Drug: PARP inhibitor 2X-121


Participation Criteria
=================
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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PARP inhibitor 2X-121<br>600 mg PARP inhibitor 2X-121 as single daily oral agent in mBC patients | Drug: PARP inhibitor 2X-121<br>* 600 mg PARP inhibitor 2X-121 as single daily oral agent in mBC patients<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-tumour efficacy after treatment with 600 mg 2X-121 as single oral agent in a 21-days cycle in mBC patients selected by the 2X-121 DRP | Overall tumor response according to RECIST | one year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival (PFS) after administration of 2X-121 in patients with mBC | Timespan | one year | 
| Duration of objective response after administration of 2X-121 in patients with mBC | Timespan | one year | 
| Overall survival (OS) after administration of 2X-121 in patients with mBC | Timespan | one year | 
| Performance status (ECOG) | To evaluate change in patient performance status by ECOG (Eastern Cooperative Oncology Group) Performance Status by a 6-step classification system | one year | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Adverse Events as assessed by CTCAE v4. to evaluate safety profile after administration of 2X-121 in patients with mBC | one year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PARP inhibitor, Drug Response Prediction (DRP), Tankyrase 1/2 inhibitor, mRNA biomarker