A Phase I/Ib Trial of the CDK4/6 Antagonist Ribociclib And The HDAC Inhibitor Belinostat In Patients With Metastatic Triple Negative Breast Cancer And Recurrent Ovarian Cancer With Response Prediction By Genomics (CHARGE)
This is an open-label, multi-center, phase I study designed to assess the maximum tolerated dose of ribociclib and belinostat in combination. The trial will open with a dose escalation followed by an expansion cohort at the identified dose. Dose escalation will be open to the enrollment of patients diagnosed with triple-negative breast cancer or ovarian cancer. Dose expansion will only be open to patients diagnosed with triple-negative breast cancer.
∙ For dose escalation cohorts only:
∙ \- Pathologically confirmed breast cancer with the following features:
• Measurable disease by RECIST 1.1;
• ER and PR ≤ 1% by immunohistochemistry;
• Her-2/neu negative (0 or 1+ by immunohistochemistry OR not-amplified by CAP/ASCO standards);
• Metastatic or unresectable and locally advanced and not amenable to treatment with curative intent, in the opinion of the enrolling investigator.
∙ OR --Pathologically confirmed serous ovarian cancer that is recurrent and is unresectable, in the opinion of the enrolling investigator.
∙ For dose expansion cohort only:
∙ \- Pathologically confirmed breast cancer with the following features:
• Measurable disease by RECIST 1.1;
• ER and PR ≤ 1% by immunohistochemistry;
• Her-2/neu negative (0 or 1+ by immunohistochemistry OR not-amplified by CAP/ASCO standards);
• Metastatic or unresectable and locally advanced and not amenable to treatment with curative intent, in the opinion of the enrolling investigator.
∙ For all patients:
• Age ≥ 18.
• ECOG performance Status ≤ 2.
• Able to swallow pills.
• Adequate organ function as defined as:
‣ Hematologic:
• ANC \> 1,500/mm3
∙ Platelets \> 100,000/mm3
∙ Hemoglobin \> 9g/dL
⁃ Hepatic:
• Serum bilirubin levels ≤1.5 mg/dL. Higher levels are acceptable if these can be attributed to active hemolysis or ineffective erythropoiesis. Bilirubin above 1.5mg/dL due to Gilbert's is still excluded.
∙ Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) ≤ 2.5 X upper limit of normal.
∙ AST(SGOT)/ALT(SGPT) ≤ 5 × institutional ULN for patients with liver metastasis.
∙ Alkaline phosphatase \< 2.5 X upper limit of normal, unless bone metastasis is present in the absence of liver metastasis
⁃ Renal:
• Serum creatinine levels ≤1.5 mg/dL
∙ Patient must have the following laboratory values within normal limits or corrected to within normal limits with supplements before the first dose of study medication:
‣ Potassium
⁃ Magnesium
⁃ Total Calcium (corrected for serum albumin)
⁃ Coagulation ---INR ≤1.5 (unless the patient is receiving anticoagulants and the INR is within the therapeutic range of intended use for that anticoagulant within 7 days prior to the first dose of study drug)
• Presence of ≥ 1 metastatic sites of disease that can be safely accessed for biopsy and patient willingness to undergo fresh tissue biopsies of up to 3 lesions. (Safely accessible means risk of mortality or major morbidity \< 1.5%, such as core needle biopsy of breast, superficial lymph node, subcutaneous nodule, peripheral liver nodule, pleural nodule, omental nodule, etc. or per investigator discretion)
• Negative serum or urine pregnancy test at screening for women of childbearing potential.
• Agrees to continue use of approved birth control for at least 6 months after receiving the last dose of study drugs. See section 7.3 for list of approved birth control methods.
• Able to provide informed consent and have signed an approved consent form that conforms to federal and institutional guidelines.