Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study.

BackgroundCabozantinib, an orally bioavailable inhibitor of tyrosine kinases including MET, AXL, and VEGF receptors, was assessed in patients with hepatocellular carcinoma (HCC) as part of a phase 2 randomized discontinuation trial with nine tumor-type cohorts.Patients and methodsEligible patients had Child-Pugh A liver function and ≤1 prior systemic anticancer regimen, completed ≥4 weeks before study entry. The cabozantinib starting dose was 100 mg daily. After an initial 12-week cabozantinib treatment period, patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 were randomized to cabozantinib or placebo. The primary endpoint of the lead-in stage was objective response rate (ORR) at week 12, and the primary endpoint of the randomized stage was progression-free survival (PFS).ResultsAmong the 41 HCC patients enrolled, the week 12 ORR was 5%, with 2 patients achieving a confirmed partial response (PR). The week 12 disease control rate (PR or SD) was 66% (Asian subgroup: 73%). Of patients with ≥1 post-baseline scan, 78% had tumor regression, with no apparent relationship to prior sorafenib therapy. Alpha-fetoprotein (AFP) response (>50% reduction from baseline) occurred in 9 of the 26 (35%) patients with elevated baseline AFP and ≥1 post-baseline measurement. Twenty-two patients with SD at week 12 were randomized. Median PFS after randomization was 2.5 months with cabozantinib and 1.4 months with placebo, although this difference was not statistically significant. Median PFS and overall survival from Day 1 in all patients were 5.2 and 11.5 months, respectively. The most common grade 3/4 adverse events, regardless of attribution, were diarrhea (20%), hand-foot syndrome (15%), and thrombocytopenia (15%). Dose reductions were utilized in 59% of patients.ConclusionsCabozantinib has clinical activity in HCC patients, including objective tumor responses, disease stabilization, and reductions in AFP. Adverse events were managed with dose reductions.Trial registration numberNCT00940225

Effect of radium-223 dichloride (Ra-223) on hospitalisation: An analysis from the phase 3 randomised Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial

Symptomatic skeletal events (SSEs) commonly occur in patients with bone metastases, often leading to hospitalisations and decreased quality-of-life. In the ALSYMPCA trial, radium-223 significantly improved overall survival (hazard ratio 0.70, 95% confidence interval [CI] 0.58e0.83, P < 0.001) and prolonged time to first SSE (hazard ratio 0.66, 95% CI 0.52 e0.83, P Z 0.00037) and subsequent SSE (hazard ratio 0.65, 95% CI 0.51e0.83, P Z 0.00039) versus placebo in patients with castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastases. Health care resource use (HCRU), including hospitalisation events and days, were prospectively collected in ALSYMPCA. We assessed health care resource use for the first 12 months post-randomisation. Significantly fewer radium-223 (218/589; 37.0%) versus placebo patients (133/292; 45.5%) had at least one hospitalisation event (P Z 0.016). However, mean number of hospitalisation events per patient was similar (radium-223 0.69 versus placebo 0.79, P Z 0.226), likely due to the significantly longer follow-up time for radium-223 (7.82 months versus 6.92 months for placebo;P < 0.001). There were significantly fewer hospitalisation days per patient for radium-223 (4.44 versus 6.68, respectively, P Z 0.004). The reduction in hospitalisation days with radium-223 was observed both before first SSE (2.35 days versus 3.36 days, respectively) and after SSE (7.74 days versus 9.19 days, respectively). Our data suggest that this reduced hospital days along with the survival benefit and reduction in time to SSEs with radium- 223 treatment may contribute to improvements in health-related quality-of-life in patients with castration-resistant prostate cancer with symptomatic bone metastases (ALSYMPCA ClinicalTrials.gov number, NCT00699751.)

Targeting DNA repair in Metastatic Castration-Resistant Prostate Cancer (mCRPC): Genomic Screening for a Clinical Trial of Rucaparib

Objectives: The high prevalence of men with mCRPC carrying pathogenic mutations in DNA damage repair (DDR) genes may have implications for clinical treatment, as poly(ADP-ribose) polymerase (PARP) inhibitors, such as rucaparib, have shown preliminary evidence of activity in these patients. The ongoing phase 2 TRITON2 study (NCT02952534) is evaluating rucaparib in mCRPC patients harboring a deleterious germline or somatic mutation in BRCA1, BRCA2, ATM, or other DDR gene. Here we present results from genomic screening of tissue and plasma samples from mCRPC patients. Methods: Comprehensive genomic profiling was performed by Foundation Medicine, Inc., using FFPE tumor tissue and plasma circulating cell-free DNA (cfDNA) samples. These next-generation sequencing (NGS) assays detect germline and somatic genomic alterations (GAs), but do not distinguish between them. Results: By Jan 15, 2019, prostate or metastatic tumor tissue samples from 1050 mCRPC patients were processed. Sequencing was successful for 68% of prostate samples, 82% of soft-tissue metastatic samples, and 57% of bone metastatic samples. In total, tissue sequencing results were obtained for 774 (74%) patients. GAs in BRCA1, BRCA2, or ATM were observed in 16.7% of patients’ tissue. In parallel, plasma from 654 mCRPC patients was collected and sequenced: 96% of plasma samples had sufficient cfDNA to obtain sequencing results, and sequencing success was independent of the location of metastases (visceral, nodal, or bone). GAs in BRCA1, BRCA2, or ATM were observed in 21.4% of patients’ plasma. There was high concordance between the alterations detected by the tissue and plasma assays. For example, in 86% of patients the plasma assay detected the same BRCA2 alteration present in tissue. Conclusions: Genomic profiling may help guide clinical decision-making for mCRPC patients. Tumor and plasma testing successfully identified patients with eligible somatic or germline GAs for enrollment into TRITON2. These data continue to support the utilization of plasma genomic testing, particularly in patients without a lesion that can be biopsied. Source of Funding: Clovis Oncology, Inc

Replication-Deficient Lymphocytic Choriomeningitis Virus-Vectored Vaccine Candidate for the Induction of T Cell Immunity against Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb) represents a major burden to global health, and refined vaccines are needed. Replication-deficient lymphocytic choriomeningitis virus (rLCMV)-based vaccine vectors against cytomegalovirus have proven safe for human use and elicited robust T cell responses in a large proportion of vaccine recipients. Here, we developed an rLCMV vaccine expressing the Mtb antigens TB10.4 and Ag85B. In mice, rLCMV elicited high frequencies of polyfunctional Mtb-specific CD8 and CD4 T cell responses. CD8 but not CD4 T cells were efficiently boosted upon vector re-vaccination. High-frequency responses were also observed in neonatally vaccinated mice, and co-administration of rLCMV with Expanded Program of Immunization (EPI) vaccines did not result in substantial reciprocal interference. Importantly, rLCMV immunization significantly reduced the lung Mtb burden upon aerosol challenge, resulting in improved lung ventilation. Protection was associated with increased CD8 T cell recruitment but reduced CD4 T cell infiltration upon Mtb challenge. When combining rLCMV with BCG vaccination in a heterologous prime-boost regimen, responses to the rLCMV-encoded Mtb antigens were further augmented, but protection was not significantly different from rLCMV or BCG vaccination alone. This work suggests that rLCMV may show utility for neonatal and/or adult vaccination efforts against pulmonary tuberculosis

Interleukin-21 Is Critically Required in Autoimmune and Allogeneic Responses to Islet Tissue in Murine Models

OBJECTIVE-Type 1 diabetes is an incurable chronic autoimmune disease. Although transplantation of pancreatic islets may serve as a surrogate source of insulin, recipients are subjected to a life of immunosuppression. Interleukin (IL)-21 is necessary for type 1 diabetes in NOD mice. We examined the efficacy of an IL-21-targeted therapy on prevention of diabetes in NOD mice, in combination with syngeneic islet transplantation. In addition, we assessed the role of IL-21 responsiveness in islet allograft rejection in mouse animal models. RESEARCH DESIGN AND METHODS-NOD mice were treated with IL-21R/Fc, an IL-21-neutralizing chimeric protein. This procedure was combined with syngeneic islet transplantation to treat diabetic NOD mice. Survival of allogeneic islet grafts in IL-21R-deficient mice was also assessed. RESULTS-Evidence is provided that IL-21 is continually required by the autoimmune infiltrate, such that insulitis was reduced and reversed and diabetes inhibited by neutralization of IL-21 at a late preclinical stage. Recovery from autoimmune diabetes was achieved by combining neutralization of IL-21 with islet transplantation. Furthermore, IL-21-responsiveness by CD8+ T-cells was sufficient to mediate islet allograft rejection. CONCLUSIONS-Neutralization of IL-21 in NOD mice can inhibit diabetes, and when paired with islet transplantation, this therapeutic approach restored normoglycemia. The influence of IL-21 on a graft-mounted immune response was robust, since the absence of IL-21 signaling prevented islet allograft rejection. These findings suggest that therapeutic manipulation of IL-21 may serve as a suitable treatment for patients with type 1 diabetes. Diabetes 60:867-875, 20111151sciescopu