A Multicenter Phase I Study of MRX34, MicroRNA miR-RX34 Liposomal Injection

Summary

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.

as of July 31, 2013, nine patients have been treated with MRX34, three at 10mg/m2 and six at 20mg/m2.

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.
3. When up to 3 additional patients are added to a given dose level, if 1 of 6 patients has a DLT then the dose will be increased to the next dose level.

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.

additional dose levels may be explored to better define the safety profile of MRX34.
Following the identification of the recommended Phase 2 dose (RPh2D) for the twice weekly regimen, an optional weekly dosing schedule for 4 weeks in 28-day cycles may be explored in additional cohorts of patients to identify the second RPh2D for the weekly dosing regimen. Study assessments and their frequencies may be modified for the weekly dosing cohorts. For HCC patients only, one to two doses below the intravenous RPh2D may be explored as directed by the Cohort Review Committee (CRC).

Participant Eligibility

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. After agreement between the sponsor, Medical Monitor, and investigators, if tumor responses are observed outside of the liver in the initial cohorts of patients, advanced metastatic cancer patients without liver metastasis may be included.
3. Advanced cancers considered refractory to standard treatments or for which no standard treatment is available.
4. One or more measurable tumors by radiologial evaluation. (See appendix IV) for patients with hepatocellular carcinoma only, one or more contrast-enhancing measurable tumors in arterial phase of 3-phase contrast CT/MRI.
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) ULN); for patients with hepatocellular carcinoma only, total bilirubin <= 3 mg/dL (i.e., Child-Pugh Score for bilirubin is no greater than 2)
*Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phasphatase (ALP) <=5 x ULN
10. Acceptable renal function:
*Serum Creatinin <=1.5 times the upper limit of normal (ULN), or calculated creatinine clearance >=60 mL/min/1.73 m2 for patients with creatinine levels above 1.5 times institutional upper limit of normal.
11. Acceptable heamtological status:
*Absolute Neutrophil Count (ANC) >=1500 cells/mm3
*Platelet count >=100,000 plts/mm3 (without transfusion); >= 75,000 plts/mm3 for patients with hepatocellular carcinoma only.
*Hemoglobin >=9 g/dL
12. Urinalysis - no clinically significant abnormalities
13. Acceptable coagulation and albumin status:
*Prothrombin time (PT) or International Normalized Ratio (INR) <=1.25 X ULN; for patients with hepatocellular carcinoma only, INR <1.7 or prothrombin time (PT) or < 4 seconds above ULN (i.e., Child-Pugh Score is no greater than 1 for the coagulation parameter);

* For patients with hepatocellular carcinoma only, serum albumin >=2.8 g/dL (i.e., Child-Pugh Score for albumin is no greater than 2).
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.
15. For patients with hepatocellular carcinoma only, Child-Pugh Class A (score 5-6) disease. Score for hepatic encephalopathy must be 1; the score for ascites must be no greater than 2 and clinically irrelevant; for the determination of the Child-Pugh Class (see Appendix II).
16. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures, including tumor biopsies as specified in the protocol.