A Phase 1b Dose Escalation Study of OMP-54F28 in Combination With Sorafenib in Patients With Hepatocellular Cancer
A Phase 1b Dose Escalation Study of OMP-54F28 in Combination With Sorafenib in Patients With Hepatocellular Cancer
This is an open-label Phase 1b dose-escalation study to assess the safety, tolerability, and PK of OMP-54F28 when combined with sorafenib. OMP-54F28 will be administered IV on Day 1 of each 21-day cycle. The planned dose levels of OMP-54F28 are 5 and 10 mg/kg. Depending on safety in this study, additional lower or intermediate dose levels may be evaluated.
Depending on emerging safety data from the Phase 1a study 54F28-001 with continuing dose escalation, additional higher dose levels of OMP-54F28 may be evaluated in this study. Alternative dosing schedules of OMP-54F28 may be explored based on emerging nonclinical and clinical data for safety, PD, PK and efficacy. The starting dose for a new dosing schedule will be chosen to result in an AUC equivalent to the highest dose level that cleared on the previously studied dosing schedule. No dose escalation of OMP-54F28 will be allowed within a dose cohort. Sorafenib 400 mg will be given orally twice daily (PO BID). Sorafenib dosing schedules with a total daily dose <800 mg (e.g. Sorafenib 400 mg once daily) may be evaluated in this study depending on emerging safety data from this study.
Inclusion Criteria:
Signed Informed Consent Form
Age ≥18 years
Histologically documented hepatocellular carcinoma
Locally advanced or metastatic disease
Availability of FFPE tumor tissue, either archival or obtained at study entry through fresh biopsy
o Tumor tissue from fine needle aspiration is not acceptable.
ECOG performance status of 0 or 1 (see Appendix C)
All acute treatment-related toxicity from prior therapy must have resolved to Grade ≤ 1 prior to study entry
Adequate hematologic and end-organ function
Child-Pugh Classification A (see Appendix D)
Evaluable or measurable disease per RECIST v1.1
For women of childbearing potential and men with partners of childbearing potential, agreement to use two effective forms of contraception
Exclusion Criteria:
Inability to take oral medications
Prior systemic therapy for locally advanced or metastatic hepatocellular cancer
Prior adjuvant therapy with sorafenib or another Raf/VEGF inhibitor
Prior history of allografts, including, but not limited to, liver and bone marrow transplants
Esophageal or gastric variceal bleeding within last 3 months
Risk for varices, based on known history of esophageal or gastric varices, evidence of hepatic cirrhosis and/or portal hypertension including biopsy-proven cirrhosis, hypersplenism, or radiographic findings of varices
Clinically evident ascites
Evidence of encephalopathy within last 3 months
Treatment with inducers of cytochrome P450 3A4 (CYP3A4) within 7 days prior to first dose of study treatment
Treatment with interferon within 4 weeks prior to first dose of study treatment
Treatment with any anti-cancer therapy, including radiotherapy, chemotherapy, biologic therapy, or herbal therapy within 3 weeks or 5 half-lives (for systemic agents), whichever is shorter
Known hypersensitivity to any component of study treatments that resulted in drug discontinuation
Uncontrolled seizure disorder or active neurologic disease
Untreated brain metastases
Leptomeningeal disease as a manifestation of cancer
Active infection requiring antibiotics
Bisphosphonate therapy for symptomatic hypercalcemia
Significant intercurrent illness including, but not limited to, unstable angina pectoris, and cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements
Pregnancy, lactation, or breastfeeding
Known HIV infection
Active Hepatitis B infection in the absence of adequate antiviral therapy
Uncontrolled hypertension, defined as systolic blood pressure >140 mm Hg or diastolic blood pressure >90 mm Hg, despite medical management
Pulmonary hemorrhage of Grade ≥2 within 28 days prior to first dose of study treatment
Any other hemorrhage or bleeding of Grade ≥3 within 28 days prior to first dose of study treatment
Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
Concurrent use of therapeutic warfarin
New York Heart Association Classification III or IV (see Appendix F)
Congenital long QT syndrome
Known clinically significant gastrointestinal disease including, but not limited to, inflammatory bowel disease
Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to the first dose of study treatment or anticipation of need for major surgical procedure during the course of the study
Osteoporosis based on a T-score of <-2.5 at the left or right total hip, left or right femoral neck or lumbar spine (L1-L4) as determined by DEXA scan
Bone metastases and one of the following:
Treatment with a thiazolidinedione PPAR gamma inhibitor; e.g. Actos® (pioglitazone) and Avandia® (rosiglitzone)
Active treatment with an oral or IV glucocortocoid for ≥4 weeks at a daily dose equivalent to or greater than 7.5 mg of oral prednisone
Fasting β-CTX of >1000 pg/mL
Metabolic bone disease, such as hyperparathyroidism, Paget's disease or osteomalacia