Cleveland BioLabs Inc. announced the achievement of all objectives in a Phase 1 clinical trial of CBL0102, or quinacrine, an orally administered small molecule. The study was performed in patients with advanced cancers for which no standard care exists or which had become resistant to conventional therapies. All patients had tumors involving the liver.
CBL0102 is the first of a group of compounds identified by CBLI scientists that act by blocking activity of the chromatin remodeling complex, FACT (FAcilitates Chromatin Transcription), resulting in simultaneous modulation of several signal transduction pathways (p53, PI3K/AKT/mTOR, NF-kappaB and heat shock response) that are commonly deregulated in cancer. CBL0102 is being developed by Incuron LLC, a joint venture between Bioprocess Capital Ventures and Cleveland BioLabs.
The primary objective of the study was to evaluate for a maximum tolerated dose and dose-limiting toxicities of CBL0102 in patients with advanced cancers. Secondary objectives were to characterize the drug’s safety and to profile its pharmacokinetics. The study also assessed for preliminary evidence of CBL0102 antitumor activity. In particular, the study was designed to explore potential effects related to CBL0102’s high relative biodistribution into the liver and therefore included only patients with primary or metastatic liver cancers. Patients were enrolled to receive sequentially higher starting doses of CBL0102 in seven cohorts. Study participants were treated with CBL0102 given orally daily. Patients could continue therapy for eight weeks (or longer if they appeared to be benefiting from therapy).
A total of 32 patients enrolled. Participants had cancers of breast, gastric, hepatic, pancreatic, and colorectal origin. The study successfully achieved both the primary and secondary objectives. CBL0102 was generally well-tolerated and a recommended Phase 2 dose of 400 mg/day was established. The most common adverse events were skin discoloration due to drug accumulation in skin, fatigue, upper abdominal pain, mild to moderate gastrointestinal disorders, and hepatic transaminase elevations, with most events being low grade. The analysis of pharmacokinetics showed that plasma exposures rose with increasing dose and that steady state had been achieved by 15 days of therapy. Liver biopsies were performed in two patients after four weeks of therapy and confirmed much higher liver concentrations of CBL0102 than were present in plasma.
By eight weeks of therapy, a partial tumor regression was recorded in one breast cancer patient, who experienced a 46% reduction in target lesion maximum dimensions. Disease stabilization was observed in four other patients (patients with breast cancer, hepatocellular carcinoma, salivary gland cancer, and rectal cancer). In the patient with hepatocellular carcinoma, long-term stabilization was observed for a period of 7.5 months, during which the patient remained on continuous CBL0102 treatment.
Professor Tyulyandin, deputy director of clinical oncology and director of clinical pharmacology and chemotherapy at the Russian Oncological Scientific Center in Moscow, a leading Russian oncology center was the national coordinator for the study. Tyulyandin commented: “I believe the favorable tolerability, pharmacological properties and initial signs of efficacy observed in several advanced cancer patients in the trial warrant serious consideration of advancing the development of CBL0102.”
Andrey Leonov, chief executive officer of Incuron said, “We are very encouraged by the outcome of this trial. We are looking to partner CBL0102 for further potential development, as well as support investigator-initiated trials. Moreover, the information derived from this trial of CBL0102 supports the development of our optimized proprietary FACT inhibitor, CBL0137, which is currently being evaluated in the United States and in Russia in ongoing Phase 1 trials assessing both oral and intravenous administration.”
A Phase 1/2 study evaluating the safety and efficacy of combination treatment with erlotinib and CBL0102 in Stage IIIB-IV non-small cell lung cancer was recently initiated by the Case Comprehensive Cancer Center in cooperation with the National Cancer Institute.
CBL0102 was granted Orphan Drug status by the U.S. Food and Drug Administration for the treatment of hepatocellular carcinoma in October 2012.
Date: April 16, 2014
Source: Cleveland BioLabs