A Phase I, Multicenter Study of MRX34 Given Intravenously Two Times per Week for Three Weeks, Repeated Every Four Weeks in Patients with Unresectable Primary Liver Cancer or Advanced or Metastatic Cancer With Liver Involvement
This is a Phase I, open-label, multicenter, dose-escalation study to investigate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the micro ribonucleic acid (microRNA) MRX34, in patients with unresectable primary liver cancer or advanced or metastatic cancer with liver involvement.
This is a first-in-man dose escalation study. There has been no prior human exposure to this agent.
MRX34 will be administered IV twice a week for 3 weeks with 1 week off (total 28 days) as a single agent. To provide consistency in the number of days between doses, doses will be given twice a week on Monday and Thursday. This schedule will be maintained throughout treatment. Variation of this scheduling to Tuesday to Friday may be accommodated after approval by the sponsor.
The study will enter 3 patients per cohort Dose escalation will be according to a modified Fibonacci dose escalation schema increasing doses at 100%, 67%, 50%, 40%, and then in increments of 33%.
Dose Level Dose of
1 10 mg/m2
2 20 mg/m2
3 33 mg/m2
4 50 mg/m2
5 70 mg/m2
6 93 mg/m2
7 124 mg/m2
8 165 mg/m2
1. If a DLT is observed in 1 out of 3 patients at a given dose level, up to an additional 3 patients will be enrolled and treated at that dose level.
2. If 2 out of 3-6 patients at that dose level have DLTs, the dose will be decreased to the previous dose level and 3 additional patients will be enrolled at that dose level, if needed, to have a total of 6 patients.
Subjects who successfully complete treatment Cycle 1 (28 days) without evidence of significant treatment-related toxicities or clinical evidence of progressive disease may continue to receive treatment. Treatment cycles will be repeated every 4 weeks (28 days) based on toxicity and response. The schedule will continue as long as there is perceived benefit or until disease progression.
Participating patients must fulfill ALL of the following criteria:
1. Aged greater than or equal to 18 years.
2. Patients with histologically confirmed unresectable primary liver cancer or advanced metastatic cancer with liver metastasis including lymphoma.
3. Advanced tumors considered refractory to standard treatments or for which no standard treatment is available.
4. One or more measurable tumors by radiologial evaluation.
5. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.
6. Life expectancy of at least 3 months.
7. Signed, writtend Institutional Review Board (IRB) - approved informed consent.
8. Negative practy test for women of childbearing potential.
9. Acceptable liver function:
*Total bilirubin <=1.5 times the upper limit of normal (ULN)
*Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phasphatase (ALP) <=5 x ULN
10. Acceptable renal function:
*Serum Creatinin <=1.5 times the ULN, or calculated creatinine clearance >=60 mL/min/1.73m2 for patients with creatinine levels above institutional normal.
11. Acceptable heamtological status:
*Absolute Neutrophil Count (ANC) >=1500 cells/mm3
*Platelet count >=100,000 plts/mm3 (without transfusion)
*Hemoglobin >=9 g/dL
12. Urinalysis - no clinically significant abnormalities
13. Acceptable coagulation status:
*Prothrombin time (PT) or International Normalized Ratio (INR) <=1.25 X ULN
14. Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier meth of birth control; or abstinence) prior to study entry and for the duration of study participation including one month after the last dose of study drug.