Clinical trial NCT02564614: A Study of Hypoxia-inducible Factor 1a (HIF1A) Messenger Ribonucleic Acid (mRNA) Antagonist (RO7070179), to Demonstrate Proof-of-mechanism in Adult Participants With Hepatocellular Carcinoma (HCC)
Official title: A Phase 1b, Proof of Mechanism, Open-label Study of RO7070179, a Hypoxia-inducible Factor 1a (HIF1A) mRNA Antagonist in Adult Subjects With Hepatocellular Carcinoma (HCC)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Carcinoma, Hepatocellular
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2015-10-01
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This open-label study will demonstrate proof-of-mechanism of HIF1A inhibition by a decrease of HIF1A mRNA after intravenous (IV) infusion of RO7070179 in participants with hepatocellular carcinoma (HCC) who have failed at least one line of systemic therapy. This will be a single arm study and all participants will receive RO7070179, 13 milligram per kilogram per week (mg/kg/week), 2-hour IV infusion on Days 1 and 4 during Week 1 of Cycle 1, followed by once weekly in 6 week cycle. Treatment with RO7070179 will be continued until disease progression or unacceptable toxicity.


Eligibility criteria: Inclusion Criteria:

* Male or female of \>=18 years of age with the Eastern Cooperative Oncology Group (ECOG) performance status 0-1, Child-Pugh score of 5-7, and Life expectancy of 3 months or greater.
* Confirmed to have HCC as described by the American Association for the Study of Liver Disease (AASLD).
* Participants who have failed at least one line of systemic therapy for advanced stage HCC or participants who are ineligible or unable to tolerate the standard of care treatment.
* Have measurable or evaluable disease.
* Participants with normal major organ functions as defined by hemoglobin (HgB) \>= 8.5 gram/decilitre (dL), absolute neutrophil count (ANC) \>= 1000/microliter (mcL), platelet \>= 60,000/micL, aspartate aminotransferase/alanine transaminase (AST/ALT) \<= 3 x Upper Limit of Normal (ULN), total Bilirubin \<= 2 x ULN, creatinine \<= 2 x ULN.
* Willingness to undergo two tumor biopsies: before and after administration of RO7070179.

Exclusion Criteria:

* Concurrent serious medical illness that could potentially interfere with protocol compliance (such medical illness will not include hepatitis or cirrhosis, as the degree of liver impairment caused by these diseases are covered by other exclusion criteria).
* Active hepatitis B or C, but participants on stable medications for hepatitis B or C.
* Bleeding esophageal or gastric varices within 2 months before enrollment.
* Participants who need to take therapeutic anti-coagulation or anti-platelet therapy.
* Presence of ascites that preclude biopsy of liver lesions.
* History of unstable angina or myocardial infarction within 12 months prior to Day 1 or ischemic heart disease.
* Known HIV positive and positive screening pregnancy test or is breast-feeding.
* Female or male of reproductive capacity unwilling to use methods of contraception to prevent pregnancy during this study. Participants unwilling to use methods of contraception to prevent pregnancy for 6 months after the last dose of RO7070179 due to the potential for prolonged half-life of RO7070179 in the liver.
* Known, clinically suspected, or history of CNS tumor involvement.
* Prior chemotherapy, immunotherapy, investigational therapeutic agent, or other therapy used to treat HCC within 4 weeks before the first scheduled administration of RO7070179.
* Participants who have not recovered from any reversible side effects (except alopecia) to Grade 0 or 1 toxicity attributed to the administration of an investigational therapeutic agent, chemotherapy, immunotherapy, radiotherapy, or other agents previously used to treat the cancer.
* Any condition that, in the opinion of the investigator or the Sponsor, makes the patients unsuitable for the study.
* Inability to comply with the study protocol.

Primary outcomes:
measure: Change From Baseline to Week 6 in HIF1A mRNA Level in Tumor Tissue
timeFrame: Pre-dose (baseline) and Week 6
Secondary outcomes:
measure: Change From Baseline to Week 6 in hypoxia-inducible factor 1a (HIF1A) Tumor Concentrations
timeFrame: Pre-dose (baseline) and Week 6
measure: Change From Baseline to Week 6 in HIF2 Tumor Concentrations
timeFrame: Pre-dose (baseline) and Week 6
measure: Change From Baseline to Week 6 in Vascular Endothelial Growth Factor (VEGF) Tumor Concentrations
timeFrame: Pre-dose (baseline) and Week 6
measure: Change From Baseline to Week 6 in Erythropoietin (EPO) Tumor Concentrations
timeFrame: Pre-dose (baseline) and Week 6
measure: Change From Baseline to Week 6 in Prolyl 4 Hydroxylase Tumor Concentrations
timeFrame: Pre-dose (baseline) and Week 6
measure: Change From Baseline to Week 6 in CD34/von Willebrand factor (VWF) Tumor Concentrations
timeFrame: Pre-dose (baseline) and Week 6
measure: Change in Blood Alpha-fetoprotein (AFP) Concentrations from Baseline
timeFrame: Week 1 and Week 4 for Cycle 1 and at Week 1 for subsequent treatment cycles
measure: Time to Progression (TTP) According to Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST)
timeFrame: Every 12 weeks upto 24 Months
measure: Percentage of Participants With Complete Response (CR) and Partial Response (PR) According to RECIST and mRECIST
timeFrame: Every 12 weeks upto 24 Months
measure: Duration of Response (DOR) According to RECIST and mRECIST
timeFrame: Every 12 weeks upto 24 Months
measure: Progression Free Survival (PFS) According to RECIST and mRECIST
timeFrame: Every 12 weeks upto 24 Months
measure: Overall Survival (OS) According to RECIST and mRECIST
timeFrame: Every 12 weeks upto 24 Months
measure: Percentage of Participants With Tumor Growth According to RECIST and mRECIST
timeFrame: Every 12 weeks upto 24 Months
measure: Maximum Observed Plasma Concentration (Cmax)
timeFrame: pre- and post-dose at Week 1, Week 6
measure: Time to Reach Maximum Observed Plasma Concentration (Tmax)
timeFrame: pre- and post-dose at Week 1, Week 6
measure: Area under the Concentration-Time Curve From Zero to 168 Hours [AUC (0-168 hours)]
timeFrame: pre- and post-dose at Week 1, Week 6
measure: Plasma Decay Half-Life (t1/2)
timeFrame: pre- and post-dose at Week 1, Week 6
Other outcomes:
Locations:
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: New York
country: United States
facility: Laura and ISAAC Perlmutter Cancer Center at NYU Langone.
state: New York
city: New York
country: United States
facility: NYU Langone Medical Center; Bellevue Hospital
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: