The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer.

PURPOSE: To investigate SGI-110 as a "chemosensitizer" in ovarian cancer and to assess its effects on tumor suppressor genes (TSG) and chemoresponsiveness-associated genes silenced by DNA methylation in ovarian cancer. EXPERIMENTAL DESIGN: Several ovarian cancer cell lines were used for in vitro and in vivo platinum resensitization studies. Changes in DNA methylation and expression levels of TSG and other cancer-related genes in response to SGI-110 were measured by pyrosequencing and RT-PCR. RESULTS: We demonstrate in vitro that SGI-110 resensitized a range of platinum-resistant ovarian cancer cells to cisplatin (CDDP) and induced significant demethylation and reexpression of TSG, differentiation-associated genes, and putative drivers of ovarian cancer cisplatin resistance. In vivo, SGI-110 alone or in combination with CDDP was well tolerated and induced antitumor effects in ovarian cancer xenografts. Pyrosequencing analyses confirmed that SGI-110 caused both global (LINE1) and gene-specific hypomethylation in vivo, including TSGs (RASSF1A), proposed drivers of ovarian cancer cisplatin resistance (MLH1 and ZIC1), differentiation-associated genes (HOXA10 and HOXA11), and transcription factors (STAT5B). Furthermore, DNA damage induced by CDDP in ovarian cancer cells was increased by SGI-110, as measured by inductively coupled plasma-mass spectrometry analysis of DNA adduct formation and repair of cisplatin-induced DNA damage. CONCLUSIONS: These results strongly support further investigation of hypomethylating strategies in platinum-resistant ovarian cancer. Specifically, SGI-110 in combination with conventional and/or targeted therapeutics warrants further development in this setting.

Phase 1B study of amuvatinib in combination with five standard cancer therapies in adults with advanced solid tumors.

PURPOSE: Amuvatinib is an oral multi-kinase inhibitor that suppresses RAD51, inhibits mutant c-KIT and platelet-derived growth factor receptor alpha, and has synergistic activity with DNA-damaging agents and topoisomerase inhibitors such as etoposide, doxorubicin, and topotecan. We conducted a phase 1B study to estimate the maximum tolerated dose (MTD) levels of amuvatinib with standard chemotherapy regimens and to define the safety profiles of specific amuvatinib + standard regimens. METHODS: Five therapies each co-administered with amuvatinib 100-800 mg/day every 21 days were evaluated in treatment-naïve or moderately pre-treated subjects: paclitaxel IV followed by carboplatin IV; carboplatin IV followed by etoposide; topotecan IV; docetaxel IV; and erlotinib by mouth. RESULTS: Among 97 treated subjects, no treatment arm reached the MTD. Dose-limiting toxicities included febrile neutropenia and diarrhea. No pharmacokinetic interactions of amuvatinib with any cancer regimens occurred. Of 12/97 (12 %) partial responses overall, 11 were seen in the amuvatinib and paclitaxel/carboplatin or carboplatin/etoposide arms and most commonly in the neuroendocrine (NE), non-small cell lung cancer (NSCLC), and small cell lung cancer (SCLC) tumors. Forty-four subjects (45 %) had stable disease. Adverse events reflected combination treatment and were primarily non-hematologic (fatigue, alopecia, diarrhea, nausea, anorexia) and hematologic (neutropenia, anemia, thrombocytopenia, leukopenia). Pharmacodynamic effects as measured by decreased levels of RAD51 and increased residual DNA damage (53BP1 foci) were seen in skin punch biopsies. CONCLUSION: Amuvatinib was well tolerated, modulated RAD51, and showed antitumor activity when combined with paclitaxel/carboplatin and carboplatin/etoposide in NE, NSCLC, and SCLC tumors.

A phase I, first-in-human dose-escalation study of amuvatinib, a multi-targeted tyrosine kinase inhibitor, in patients with advanced solid tumors.

PURPOSE: Amuvatinib is a novel orally administered tyrosine kinase inhibitor with in vitro pharmacological activity against mutant KIT, platelet-derived growth factor receptor alpha (PDGFRα), and Rad51. Amuvatinib was investigated in a first-in-human, single-agent, phase I, accelerated titration, dose-escalation trial ( clinicaltrials.gov identifier: NCT00894894) in patients with solid tumors refractory to prior therapies or for which no standard therapy existed. METHODS: Twenty-two patients received amuvatinib dry powder capsules (DPC) from 100 to 1,500 mg daily in 28-day cycles. Safety, preliminary efficacy, pharmacologic activity, and pharmacokinetics were investigated. RESULTS: No dose-limiting toxicities were reported with amuvatinib DPC up to 1,500 mg/day, given as one or in divided doses, for 1-6 cycles. No maximum tolerated dose was reached. Five patients had serious adverse events, all unrelated to treatment. Exposure levels were low and variable. One gastrointestinal stromal tumor (GIST) patient who previously failed imatinib and sunitinib had a 2-[18F]fluoro-2-deoxyglucose positron emission tomography response and clinical stable disease. A second GIST patient had decreased Rad51 expression in a skin punch biopsy on days 15 and 29. CONCLUSIONS: Amuvatinib shows in vitro inhibitory activity against multiple human tyrosine kinases including mutant KIT and PDGFRα and in vivo activity in human xenograft models in mice. Amuvatinib is also active as a DNA repair protein Rad51 inhibitor following chemotherapy. In this study, the amuvatinib DPC formulation was well tolerated up to 1,500 mg/day. While exposures were low and variable, a transient response in a refractory GIST patient warrants further investigation into single-agent amuvatinib in refractory GIST.

Safety, tolerability, and pharmacokinetics of amuvatinib from three phase 1 clinical studies in healthy volunteers.

PURPOSE: Amuvatinib is a multi-targeted tyrosine kinase inhibitor with activity that also disrupts DNA damage repair through suppression of homologous recombination protein Rad51. Amuvatinib dry-powder capsules (DPC) showed evidence of activity in early Phase 1 cancer studies but low systemic exposure. The purposes of the studies were to investigate the cause of low exposure, develop, and test an alternative formulation with improved exposure, and establish the dose to be tested in future studies in cancer patients. METHODS: Three studies were conducted in a total of 58 healthy subjects: a food-effect study using amuvatinib DPC, a single-dose pharmacokinetic study comparing amuvatinib DPC to a new lipid-suspension capsules (LSC), and a multiple-dose pharmacokinetic study using amuvatinib LSC. RESULTS: A high-fat meal administered with amuvatinib DPC increased the rate and extent of absorption compared to the Fasted state, a 183 and 118% increase in the mean C(max) and AUC(0-∞) of amuvatinib, respectively. The single-dose pharmacokinetics of amuvatinib LSC resulted in an approximately two-third-fold increased exposure (AUC) compared with amuvatinib DPC. The multiple-dose pharmacokinetics of the amuvatinib LSC 300 mg administered every 8 h exhibited improved accumulation compared with the 12-h regimens and achieved presumed therapeutic level safely with no serious or severe adverse events reported. No subject discontinued treatment due to an adverse event. CONCLUSION: Amuvatinib LSC, 300 mg every 8 h, is being studied in cancer patients based on the improved exposure and similar safety profile to amuvatinib DPC. A lipid-based formulation approach may be a useful tool for other low aqueous soluble compounds.

Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients.

Three-hundred and twenty-four patients were enrolled in an open-label, multicenter, international study in which pre- and post-liver transplantation (LT) patients with recurrent chronic hepatitis B (CHB) and evidence of lamivudine-resistant HBV were treated with adefovir dipivoxil 10 mg once daily. In the pre- and post-LT cohorts, 128 and 196 patients were treated for a median duration of 18.7 and 56.1 weeks, respectively. In patients who received 48 weeks of treatment, 81% of the pre-LT and 34% of the post-LT cohort achieved undetectable serum hepatitis B virus (HBV) DNA (Roche Amplicor Monitor polymerase chain reaction [PCR] assay lower limit of quantification [LLQ] < 400 copies/mL) with a median change in serum HBV DNA from baseline of -4.1 log(10) and -4.3 log(10) copies/mL, respectively. Serum alanine aminotransferase (ALT), albumin, bilirubin, and prothrombin time normalized in 76%, 81%, 50%, and 83% of pre-LT patients and 49%, 76%, 75%, and 20% of post-LT patients. The Child-Pugh-Turcotte (CPT) score improved in over 90% of patients in both cohorts. Genotypic analysis of 122 HBV baseline samples revealed that 98% of these patients had lamivudine-resistant mutant HBV. No adefovir resistance mutations were identified in patients after 48 weeks of therapy. One-year survival was 84% for pre-LT and 93% for post-LT patients (Kaplan-Meier analysis). Treatment-related adverse effects associated with adefovir dipivoxil in this setting were primarily mild to moderate in severity. In conclusion, 48 weeks of adefovir dipivoxil resulted in significant improvements in virologic, biochemical, and clinical parameters in CHB patients pre- and post-LT with lamivudine-resistant HBV.