Time-to-event modelling of effect of codrituzumab on overall survival in patients with hepatocellular carcinoma.

AIMS: Codrituzumab (GC33) is a recombinant, humanized mAb that binds to glypican-3 (GPC3), an oncofetal protein highly expressed in hepatocellular carcinoma (HCC). This investigation aimed to identify clinically relevant factors that may affect the overall survival (OS) in HCC patients treated with codrituzumab and to quantitatively annotate their effects. METHODS: Codrituzumab exposure was estimated by a population pharmacokinetics model with a nonlinear elimination pathway. Analysis of OS was performed using a time-to-event model in 181 patients with advanced HCC. The model was tested with the addition of various covariates, including levels of immune biomarkers, such as CD16 (measured in terms of molecules of equivalent soluble fluorophore; CD16MESF ) and CD4, codrituzumab exposure and potential prognostic biomarkers of HCC such as baseline tumour size and soluble GPC3. RESULTS: The time-to-event model estimated a prolonged OS (>3 months) in patients with codrituzumab exposure of ≥230 µg ml-1 and high CD16MESF level (>5.26 × 105 MESF at least). The Weibull model was selected as the base hazard model. The baseline tumour size was included in the hazard model as a parameter independent of the drug effect. A logistic model was applied to explain the effects of drug exposure and CD16MESF level. CONCLUSIONS: The final model indicates that adequate drug exposure plus a favourable immune environment are associated with prolonged OS. This quantitative model should be further validated with emerging data so as to guide study design in future clinical trials.

Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study.

BACKGROUND: Patients with non-small-cell lung cancer (NSCLC) and ALK rearrangements generally have a progression-free survival of 8-11 months while on treatment with the ALK inhibitor crizotinib. However, resistance inevitably develops, with the brain a common site of progression. More potent ALK inhibitors with consistently demonstrable CNS activity and good tolerability are needed urgently. Alectinib is a novel, highly selective, and potent ALK inhibitor that has shown clinical activity in patients with crizotinib-naive ALK-rearranged NSCLC. We did a phase 1/2 study of alectinib to establish the recommended phase 2 dose of the drug and examine its activity in patients resistant or intolerant to crizotinib. METHODS: We enrolled patients with ALK-rearranged NSCLC who progressed on or were intolerant to crizotinib. We administered various oral doses of alectinib (300-900 mg twice a day) during the dose-escalation portion of the study (phase 1), to ascertain the recommended dose for phase 2. We used Response Evaluation Criteria in Solid Tumors criteria (version 1.1) to investigate the activity of alectinib in all patients with a baseline scan and at least one post-treatment scan (CT or MRI), with central radiological review of individuals with brain metastases. We assessed safety in all patients who received at least one dose of alectinib. Here, we present data for the phase 1 portion of the study, the primary objective of which was to establish the recommended phase 2 dose; phase 2 is ongoing. This trial is registered at ClinicalTrials.gov, number NCT01588028. FINDINGS: 47 patients were enrolled. Alectinib was well tolerated, with the most common adverse events being fatigue (14 [30%]; all grade 1-2), myalgia (eight [17%]; all grade 1-2), and peripheral oedema (seven [15%] grade 1-2, one [2%] grade 3). Dose-limiting toxic effects were recorded in two patients in the cohort receiving alectinib 900 mg twice a day; one individual had grade 3 headache and the other had grade 3 neutropenia. The most common grade 3-4 adverse events were increased levels of γ-glutamyl transpeptidase (two [4%]), a reduction in the number of neutrophils (two [4%]), and hypophosphataemia (two [4%]). Three patients reported four grade 4 serious adverse events that were deemed unrelated to alectinib: acute renal failure; pleural effusion and pericardial effusion; and brain metastasis. At data cut-off (median follow-up 126 days [IQR 84-217]), 44 patients could be assessed for activity. Investigator-assessed objective responses were noted in 24 (55%) patients, with a confirmed complete response in one (2%), a confirmed partial response in 14 (32%), and an unconfirmed partial response in nine (20%). 16 (36%) patients had stable disease; the remaining four (9%) had progressive disease. Of 21 patients with CNS metastases at baseline, 11 (52%) had an objective response; six (29%) had a complete response (three unconfirmed) and five (24%) had a partial response (one unconfirmed); eight (38%) patients had stable disease and the remaining two (10%) had progressive disease. Pharmacokinetic data indicated that mean exposure (AUC0-10) after multiple doses of alectinib (300-600 mg twice a day) was dose-dependent. INTERPRETATION: Alectinib was well tolerated, with promising antitumour activity in patients with ALK-rearranged NSCLC resistant to crizotinib, including those with CNS metastases. On the basis of activity, tolerability, and pharmacokinetic data, we chose alectinib 600 mg twice a day as the recommended dose for phase 2. FUNDING: Chugai Pharmaceuticals, F Hoffmann La-Roche.

Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy.

PURPOSE: Aberrant mammalian target of rapamycin (mTOR) signaling is common in sarcomas and other malignancies. Drug resistance and toxicities often limit benefits of systemic chemotherapy used to treat metastatic sarcomas. This large randomized placebo-controlled phase III trial evaluated the mTOR inhibitor ridaforolimus to assess maintenance of disease control in advanced sarcomas. PATIENTS AND METHODS: Patients with metastatic soft tissue or bone sarcomas who achieved objective response or stable disease with prior chemotherapy were randomly assigned to receive ridaforolimus 40 mg or placebo once per day for 5 days every week. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), best target lesion response, safety, and tolerability. RESULTS: A total of 711 patients were enrolled, and 702 received blinded study drug. Ridaforolimus treatment led to a modest, although significant, improvement in PFS per independent review compared with placebo (hazard ratio [HR], 0.72; 95% CI, 0.61 to 0.85; P = .001; median PFS, 17.7 v 14.6 weeks). Ridaforolimus induced a mean 1.3% decrease in target lesion size versus a 10.3% increase with placebo (P < .001). Median OS with ridaforolimus was 90.6 weeks versus 85.3 weeks with placebo (HR, 0.93; 95% CI, 0.78 to 1.12; P = .46). Adverse events (AEs) more common with ridaforolimus included stomatitis, infections, fatigue, thrombocytopenia, noninfectious pneumonitis, hyperglycemia, and rash. Grade ≥ 3 AEs were more common with ridaforolimus than placebo (64.1% v 25.6%). CONCLUSION: Ridaforolimus delayed tumor progression to a small statistically significant degree in patients with metastatic sarcoma who experienced benefit with prior chemotherapy. Toxicities were observed with ridaforolimus, as expected with mTOR inhibition. These data provide a foundation on which to further improve control of sarcomas.

Phase II study of the mitogen-activated protein kinase 1/2 inhibitor selumetinib in patients with advanced hepatocellular carcinoma.

PURPOSE Hepatocellular carcinoma (HCC) is a common and deadly malignancy with few systemic therapy options. The RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) pathway is activated in approximately 50% to 60% of HCCs and represents a potential target for therapy. Selumetinib is an orally available inhibitor of MEK tyrosine kinase activity. PATIENTS AND METHODS Patients with locally advanced or metastatic HCC who had not been treated with prior systemic therapy were enrolled on to the study. Patients were treated with selumetinib at its recommended phase II dose of 100 mg twice per day continuously. Cycle length was 21 days. Imaging was performed every two cycles. Biopsies were obtained at baseline and at steady-state in a subset of patients, and pharmacokinetic (PK) analysis was performed on all patients. Results Nineteen patients were enrolled, 17 of whom were evaluable for response. Most (82%) had Child-Pugh A cirrhosis. Toxicity was in line with other studies of selumetinib in noncirrhotic patients. PK parameters were also comparable to those in noncirrhotic patients. No radiographic response was observed in this group, and the study was stopped at the interim analysis. Of 11 patients with elevated α-fetoprotein, three (27%) had decreases of 50% or more. Median time to progression was 8 weeks. Inhibition of ERK phosphorylation was demonstrated by Western blotting. CONCLUSION In this study of selumetinib for patients with HCC, no radiographic responses were seen and time to progression was short, which suggests minimal single-agent activity despite evidence of suppression of target activation.

A multi-institutional phase II study of the efficacy and tolerability of lapatinib in patients with advanced hepatocellular carcinomas.

BACKGROUND: Hepatocellular carcinoma (HCC) is on the rise worldwide. HCC responds poorly to chemotherapy. Lapatinib is an inhibitor of epidermal growth factor receptor and HER2/NEU both implicated in hepatocarcinogenesis. This trial was designed to determine the safety and efficacy of lapatinib in HCC. METHODS: A Fleming phase II design with a single stage of 25 patients with a 90% power to exclude a true response rate of <10% and detect a true response rate of > or =30% was used. The dose of lapatinib was 1,500 mg/day administered orally in 28-day cycles. Tumor and blood specimens were analyzed for expression of HER2/NEU/CEP17 and status of downstream signal pathway proteins. RESULTS: Twenty-six patients with HCC enrolled on this study. Nineteen percent had one prior therapy. Most common toxicities were diarrhea (73%), nausea (54%), and rash (42%). No objective responses were observed. Ten (40%) patients had stable disease as their best response including six (23%) with stable disease lasting >120 days. Median progression-free survival was 1.9 months and median overall survival was 12.6 months. Patients who developed a rash had a borderline statistically significant longer survival. Tissue and blood specimens were available on >90% of patients. No somatic mutations in EGFR (exons 18-21) were found. In contrast to our previous findings, we did not find evidence of HER2/NEU somatic mutations. PTEN, P-AKT, and P70S6K expression did not correlate with survival. CONCLUSIONS: Lapatinib is well-tolerated but seems to benefit only a subgroup of patients for whom predictive molecular or clinical characteristics are not yet fully defined.

Development of a dedicated hepatopancreaticobiliary program in a university hospital system.

In 2001, a dedicated hepatopancreatobiliary (HPB) cancer program was established at a large, university hospital. Changes included recruitment of specialized HPB faculty, standardization of patient protocols, development of coordinated multidisciplinary research and clinical efforts, collection of prospective surgical outcomes data, and construction of a dedicated cancer hospital. The aim of this study was to evaluate the impact of this program on a university health system including effects on patient volume, surgical volume, outcomes, costs, resident education, and research productivity. Hospital and departmental databases were reviewed for all records pertaining to HPB surgical cases, diagnosis, and financial information over a 6-year period, including 2 years before (1999-2000) and 4 years after (2001-2004) HPB program development. A more than two-fold increase in the number of distinct patients who had HPB diagnosis was seen across all pertinent departments. A five-fold increase in surgical volume was observed. A multidisciplinary approach to care was implemented, leading to a four-fold increase in sharing of patients across departments. Improvements in operative mortality, hospital contribution margin, resident operative experience, and research productivity were observed. The implementation of a dedicated HPB cancer program with coordinated and standardized research, educational, and clinical efforts had measurable institutional benefit.

The synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid induces caspase-dependent and -independent apoptosis in acute myelogenous leukemia.

In acute myeloid leukemia (AML), resistance to chemotherapy is associated with defects in both the extrinsic and intrinsic pathways of apoptosis. Novel agents that activate endogenous apoptosis-inducing mechanisms directly may be potentially useful to overcome chemoresistance in AML. We examined the mechanisms of apoptosis induction by the novel synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) in AML cells. CDDO-induced apoptosis was associated with the loss of mitochondrial inner transmembrane potential, caspases activation, the translocation of apoptosis-inducing factor to the nucleus, and DNA fragmentation in AML cells. Apoptosis was equally evident in cells deficient in caspase-9 or caspase-8 after exposure to CDDO, suggesting caspase-independent cell death. The use of small interfering RNA to reduce the expression of apoptosis-inducing factor partially inhibited CDDO-induced apoptosis in AML cells. Cells overexpressing Bcl-2 were markedly resistant to CDDO-induced apoptosis. Moreover, CDDO promoted the release of cytochrome c from isolated mitochondria, suggesting that CDDO targets the mitochondria directly to trigger the intrinsic pathway of cell death in intact cells. Together, these results suggest that CDDO functions by activating the intrinsic pathway of apoptosis and initiates caspase-dependent and independent cell death. The direct modulation of mitochondrial-mediated, caspase-independent apoptosis by CDDO may be advantageous for overcoming chemoresistance in AML.

Role of Mtd/Bok in normal and neoplastic B-cell development in the bursa of Fabricius.

B-cell development in the bursa of Fabricius is accompanied by extensive apoptotic cell death. Apoptosis, however, is suppressed during c-myc-induced neoplasia. The experiments described here suggest that Mtd/Bok may drive apoptosis during normal development, and that this activity is blocked during myc-induced tumorigenesis. Bursal Mtd/Bok expression increases during development, correlating with the onset of intense, spontaneous apoptosis after hatching. Two isoforms of Mtd/Bok were characterized: WT-chMtd/Bok, found predominantly in the mitochondria and a less abundant form, lacking the presumptive transmembrane domain, Mtd/Bok deltaTM, found predominantly in the cytosol. Over-expression of Mtd/Bok deltaTM in a bursal lymphoma-derived cell line, DT40, reduced mitochondrial function and sensitized DT40 cells to apoptotic stimuli, while WT-chMtd/Bok had a diminished phenotype in these cells. In contrast, retroviral transduction of bursal stem cells with WT-chMtd/Bok ablated normal stem cell function in transplantation experiments, and produced extensive apoptosis in myc-induced pre-neoplastic bursal populations, but not in tumor cells.

The apoptotic effect of HA14-1, a Bcl-2-interacting small molecular compound, requires Bax translocation and is enhanced by PK11195.

HA14-1 is a small molecular compound that was identified based on the structure of Bcl-2. HA14-1 interacts with Bcl-2 and inhibits the antiapoptotic effect of Bcl-2. We investigated the mechanism of HA14-1-induced apoptosis and found that HA14-1 induces translocation of Bax from cytosols to the mitochondria. Cells deficient in Bax were much more resistant to HA14-1-induced apoptosis, suggesting that Bax is required for this process. A pan-caspase inhibitor failed to inhibit the apoptotic effect of HA14-1, indicating that this is through a caspase-independent pathway. To eliminate the effect of cytosolic Bax, we incubated cell-free mitochondria with HA14-1 to study its effect on cytochrome c release. HA14-1 was ineffective in causing cytochrome c release from the purified mitochondria. However, the combination of HA14-1 and PK11195, an antagonist of peripheral benzodiazepine receptor of the mitochondria, enhanced the cytochrome c release by HA14-1. The combination of PK11195 and HA14-1 could therefore serve as a potentially useful approach to enhance apoptosis in cancer.