Olaparib With Cediranib or AZD6738 for the Treatment of Advanced or Metastatic Germline BRCA Mutated Breast Cancer

Exclusion Criteria27

• Patients who have had chemotherapy or RT within 3 weeks ( or less than 1 week if on weekly chemotherapy) prior to start of the study agents. or persisting \>/= Grade 2 CTCAE toxicity (except alopecia and Grade 2 peripheral neuropathy) from previous anti-cancer treatment(s), or those who have not recovered from adverse events due to agents administered more than 3 weeks earlier. No washout time period is needed for PARP inhibitors.
• Patients received any other investigational agents within the past 4 weeks.
• Patients with untreated brain metastases, spinal cord compression, or evidence of symptomatic brain metastases or leptomeningeal disease as noted on computed tomography (CT) or magnetic resonance imaging (MRI) scans should be excluded from this clinical trial. Patient with known and treated brain metastases is allowed in this study if they fulfil the following criteria: The lesions have improved or remained stable radiographically and clinically for at least 6 weeks after completion of brain irradiation or stereotactic brain radiosurgery. Patients can be on steroids not more than 10 mg/day if started 4 weeks prior to initiation of study drug).
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to Olaparib or ceralasertib.
• Participants receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 (See Appendix A) are ineligible, unless discontinues within the washout period (2 weeks for CYP3A4 inhibitors and 4weeks for CYP3A4 inducers) as described in Appendix A. Dihydropyridine calcium-channel blockers are permitted for management of hypertension. Other medications described in Appendix A should be discontinued within the washout period prior to the initiation of study drugs. In addition, patients enrolled in Olaparib+ ceralasertib arm, co-administration of study drug with substrates of OATP1B1 and Pgp (P-glycoprotein) inhibitor or inducer is prohibited.
• Current use of natural herbal products (see Appendix A) or other complementary alternative medications (CAM) or "folk remedies" should be discontinued 7 days prior to the initiation of study drugs.
• \) Patients with concomitant or prior invasive malignancies within the past 5 years. Subjects with treated limited stage basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the breast or cervix are eligible.
• \) Uncontrolled inter-current illness including, but not limited to, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements.
• \) History of myocardial infarction, stroke or transient ischemic attack within 6-12 months. Current condition requiring concurrent use of drugs or biologics with anti-arrhythmic or proarrhythmic potential 11) History of hypertensive crisis or hypertensive encephalopathy within 3 years.
• \) Clinically significant peripheral vascular disease or vascular disease (abdominal aortic aneurysm (\>5cm) or aortic dissection). If known history of abdominal aortic aneurysmwith
• cm in diameter, all the following criteria must be met:
• An ultrasound (US) within the last 6 months will be required to document that it is \</= 5cm
• Patient must be asymptomatic from the aneurysm.
• \) A major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to starting study drug (percutaneous/endobronchial biopsies are allowed). The patient must have recovered from any effects of any major surgery and surgical wound should have healed prior to starting treatment.
• \) Patients may not have current signs and/or symptoms of bowel obstruction within 3 months prior to starting study drugs, except if it was a temporary incident (improved within \< 24hrs with medical management).
• )History of haemoptysis or any significant bleeding within the last 1 month prior to enrolment. 16) Presence of cavitation of central pulmonary lesion 17) Intra-abdominal abscess within the 3 months prior to enrolment. Patient with history of GI perforation. History of abdominal fistula will be considered eligible, if the fistula was surgically repaired, there has been no evidence of fistula for at least 6 months prior to starting treatment, and patient is deemed to be at low risk of recurrent fistula.
• \) Patients may have current dependency on IV hydration or total parenteral nutrition (TPN).
• \) Patients may have features suggestive of myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) on peripheral blood smear or bone marrow biopsy, if clinically indicated. 20) As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, active bleeding diatheses, renal transplant, or active infection including any patient known to have hepatitis B, hepatitis C and human immunodeficiency virus (HIV).
• Screening for chronic conditions is not required 21) Any condition that, in the opinion of the treating investigator would interfere with evaluation of the investigational product or interpretation of subject safety or study results.
• \) Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
• \) Prior exposure to Ceralasertib 24) Patients with uncontrolled seizure 25) Any of the following cardiac criteria:
• Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation \>450 milli-second, or patients with congenital long QT syndrome or family history of unexplained sudden death under 40 years of age
• Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block).
• \) Patients at risk of brain perfusion problems, e.g., carotid stenosis 27) Patients with relative hypotension (\< 100/60 mm Hg) or clinically relevant orthostatic hypotension (\>/= 20 beats per minute change in pulse including a fall in blood pressure of
• \>/=20mm Hg associated with dizziness, syncope, and blurred vision, from lying down or sitting to standing). Uncontrolled hypertension requiring clinical intervention.
• \) Breast feeding/lactating/pregnant women. 29) Prior allogeneic bone marrow transplant or double umbilical cord blood transplantation.
• \) A diagnosis of ataxia telangiectasia 31) Major surgery within 3 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.