A Phase 1 and Pharmacokinetic Single Agent Study of Romidepsin in Patients with, Lymphomas, Chronic Lymphocytic Leukemia and Select Solid Tumors and Varying Degrees of Liver Dysfunction
Determine the safety and tolerability of romidepsin in patients with varying degrees of liver dysfunction (mild, moderate and severe).
histologically/cytologically confirmed (at original diagnosis or subsequent recurrence or progression) lymphoma, chronic lymphocytic lymphoma (CLL) or solid tumor*. Lymphoma/CLL patients must be refractory to standard therapy as defined by relapse within 6 months of last treatment (see note below). Patients with solid tumors must have radiologically evaluable disease that is metastatic, unresectable, progressive, or recurrent, and for which standard curative measures do not exist or are no longer effective. Patients with a liver mass, raised Î±-fetoprotein level (ï¿½500 ng/mL) and positive serology for hepatitis, consistent with a diagnosis of hepatocellular carcinoma will be eligible without the need for pathologic confirmation of the diagnosis. *excluding prostate cancer, renal cell cancer, neuroendocrine tumors, lung cancer, colorectal cancers, soft tissue sarcomas, glioma and thyroid cancer due to a lack of efficacy in these tumor types in phase 2 studies. Patients with breast, pancreatic, bladder, head and neck cancers, as well as melanoma and other malignancies are eligible. Note: As romidepsin is approved for patients with relapsed or refractory PTCL or CTCL, these patients would be eligible WITHOUT the requirement of having relapsed within 6 months of last treatment. Age greater than 18 years, Life expectancy of greater than 3 months, ECOG performance status less than 2 (Karnofsky greater than 60%, see Appendix B). Patients must have acceptable renal and marrow function, Women of childbearing potential and men must agree to use adequate contraception, Patients with abnormal liver function will be eligible and will be grouped according to severity/ Patients with active hemolysis should be excluded. Patients with brain metastases who require corticosteroids or anticonvulsants must be on a stable dose of corticosteroids and seizure free for 1 month prior to enrollment. Patients with known brain metastases should have completed brain irradiation (whole brain or gamma knife) more than 4 weeks before starting the protocol. Note that patients should have had their steroids tapered to low dose (i.e. less than 1.5 mg of dexamethasone/day) due to the potential for higher dexamethasone doses to induce CYP3A4. Patients with biliary obstruction for which a shunt has been placed are eligible, provided the shunt has been in place for at least 10 days prior to the first dose of romidepsin and the liver function has stabilized. Two measurements at least 2 days apart that put the patient in the same hepatic dysfunction stratum will be accepted as evidence of stable hepatic function. There should be no evidence of biliary sepsis. HIV-positive patients who are not receiving: 1) agents with the potential for PK interactions with romidepsin (see Appendix C) or 2) hepatotoxic antiretrovirals (Nucleoside reverse-transcriptase inhibitors (NRTIs): abacavir, didanosine, emtricitabine, lamivudine, stavudine, and zidovudine), dual PI-based regimens except low-dose boosting with ritonavir, atazanavir, indinavir, maraviroc, and nevirapine) may be eligible. Additionally, the HIV-positive patients should have a CD4 count greater than 250/mm3. If the specific cause of hepatic dysfunction is unknown, the patient should be worked up for other viral causes of hepatitis and their eligibility determined after consultation with the Principal Investigator Patients who have received prior romidepsin use are eligible. Patients must have completed radiation, major surgery, chemotherapy, or biological therapy 4 weeks prior to study. No Patients with current evidence of significant cardiovascular disease (New York Heart Association Class III or IV cardiac disease), symptomatic congestive heart failure, dilated/hypertrophic or restrictive cardiomyopathy, myocardial infarction (within the past 6 months), unstable angina, unstable arrhythmia or a need for anti-arrhythmic therapy (use of frequency adjusting medication for atrial fibrillation is allowed, if stable medication for at least last month prior to initiation of romidepsin treatment and medication not listed as causing Torsades de Points), or evidence of acute ischemia on ECG. Marked baseline prolongation of QT/QTc interval, e.g., repeated demonstration of a QTc interval greater than 450 msec*; Long QT Syndrome; the required use of concomitant medication that may cause Torsades de Pointes or may cause a significant prolongation of the QTc. Note: Due to difficulties assessing QTc in patients with heart block, they may be eligible if deemed safe by a cardiologist. Pregnant women are excluded
4 hour infusion given on days 1, 8, and 15 of a 28 day cycle after pre meds.
08/23/2014 04:02 AM