Patients with previously untreated BRAF V600E mutation-positive melanoma in BREAK-3 showed a median overall survival (OS) of 18.2 months for dabrafenib versus 15.6 months for dacarbazine (hazard ratio [HR], 0.76; 95% confidence interval, 0.48-1.21). Because patients receiving dacarbazine were allowed to switch to dabrafenib at disease progression, we attempted to adjust for the confounding effects on OS.
Rank preserving structural failure time models (RPSFTMs) and the iterative parameter estimation (IPE) algorithm were used. Two analyses, "treatment group" (assumes treatment effect could continue until death) and "on-treatment observed" (assumes treatment effect disappears with discontinuation), were used to test the assumptions around the durability of the treatment effect.
A total of 36 of 63 patients (57%) receiving dacarbazine switched to dabrafenib. The adjusted OS HRs ranged from 0.50 to 0.55, depending on the analysis. The RPSFTM and IPE "treatment group" and "on-treatment observed" analyses performed similarly well.
RPSFTM and IPE analyses resulted in point estimates for the OS HR that indicate a substantial increase in the treatment effect compared with the unadjusted OS HR of 0.76. The results are uncertain because of the assumptions associated with the adjustment methods. The confidence intervals continued to cross 1.00; thus, the adjusted estimates did not provide statistically significant evidence of a treatment benefit on survival. However, it is clear that a standard intention-to-treat analysis will be confounded in the presence of treatment switching-a reliance on unadjusted analyses could lead to inappropriate practice. Adjustment analyses provide useful additional information on the estimated treatment effects to inform decision making.
Treatment switching is common in oncology trials, and the implications of this for the interpretation of the clinical effectiveness and cost-effectiveness of the novel treatment are important to consider. If patients who switch treatments benefit from the experimental treatment and a standard intention-to-treat analysis is conducted, the overall survival advantage associated with the new treatment could be underestimated. The present study applied established statistical methods to adjust for treatment switching in a trial that compared dabrafenib and dacarbazine for metastatic melanoma. The results showed that this led to a substantially increased estimate of the overall survival treatment effect associated with dabrafenib.
©AlphaMed Press.

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On April 26, 2016 Celsion Corporation (NASDAQ: CLSN), an oncology drug development company, reported that the first patient in China has been enrolled in its ongoing global Phase III OPTIMA Study evaluating ThermoDox, Celsion’s proprietary heat-activated liposomal encapsulation of doxorubicin, in combination with radiofrequency ablation standardized to 45 minutes (sRFA) versus sRFA alone to treat newly diagnosed patients with primary liver cancer, also known as hepatocellular carcinoma (HCC) (Press release, Celsion, APR 26, 2016, View Source [SID:1234511405]).

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The pivotal, double-blind, placebo-controlled OPTIMA Study is expected to enroll up to 550 patients globally, and has been successfully enrolling patients at 50 clinical sites in 12 different countries in North America, Europe and Asia Pacific. In December 2015, the Company announced that it had received a Clinical Trial Application (CTA) approval from the China Food and Drug Administration (CFDA) to conduct the OPTIMA Study at up to 20 additional clinical sites in China. The Company aims to enroll more than 200 patients in the China territory, the minimum number required by the CFDA to file a New Drug Application (NDA), assuming positive clinical results.

"The enrollment of the first patient in China represents a significant milestone for the OPTIMA program," said Michael H. Tardugno, Celsion’s chairman, president and chief executive officer. "With the growing incidence of primary liver cancer in China, representing approximately 50% of the 850,000 cases diagnosed annually, this country is an important element of our global registration and commercialization strategy for ThermoDox, and we are committed to driving patient enrollment in this region as we execute our OPTIMA study."

"Survival data from the subgroup analysis in the HEAT study underscore the potential of ThermoDox in combination with sRFA to serve as a potentially curative treatment in primary liver cancer, where very limited treatment options currently exist," said Dr. Nicholas Borys, Celsion’s chief medical officer. "We look forward to working with our colleagues in China and the global research team to further explore ThermoDox in this setting."

The primary endpoint for the OPTIMA Study is overall survival (OS). The statistical plan calls for two preplanned interim efficacy analyses by an independent Data Monitoring Committee (iDMC). The design of the OPTIMA Study is supported by a retrospective analysis of a large subgroup of 285 patients in the Company’s previous 701 patient HEAT Study in primary liver cancer. In a subgroup of 285 HEAT Study participants, ThermoDox plus standardized RFA demonstrated a statistically significant improvement in survival of over two years compared to standardized RFA alone. In this large subgroup, the median overall survival in the ThermoDox plus standardized RFA arm was approximately 80 months (6 ½ years), which is considered a curative treatment for HCC.

Cardiovascular disease (CVD) is the leading cause of death worldwide and new approaches for both diagnosis and treatment are required. Autoantibodies directed against apolipoprotein A-I (ApoA-I) represent promising biomarkers for use in risk stratification of CVD and may also play a direct role in pathogenesis.
To characterize the anti-ApoA-I autoantibody response, we measured the immunoreactivity to engineered peptides corresponding to the different alpha-helical regions of ApoA-I, using plasma from acute chest pain cohort patients known to be positive for anti-ApoA-I autoantibodies.
Our results indicate that the anti-ApoA-I autoantibody response is strongly biased towards the C-terminal alpha-helix of the protein, with an optimized mimetic peptide corresponding to this part of the protein recapitulating the diagnostic accuracy for an acute ischemic coronary etiology (non-ST segment elevation myocardial infarction and unstable angina) obtainable using intact endogenous ApoA-I in immunoassay. Furthermore, the optimized mimetic peptide strongly inhibits the pathology-associated capacity of anti-ApoA-I antibodies to elicit proinflammatory cytokine release from cultured human macrophages.
In addition to providing a rationale for the development of new approaches for the diagnosis and therapy of CVD, our observations may contribute to the elucidation of how anti-ApoA-I autoantibodies are elicited in individuals without autoimmune disease.

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JNJ-63709178, a bispecific antibody that targets CD3 and CD123, was created under a collaboration between Genmab and Janssen using Genmab’s DuoBody technology (Company Pipeline, Genmab, APR 26, 2016, View Source [SID:1234511406]). JNJ-63709178 is being investigated in a Phase I clinical study to treat relapsed or refractory acute myeloid leukemia and is the second bispecific antibody created with the DuoBody technology to be added to Genmab’s pipeline.

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To assess sirukumab, an anti-interleukin-6 monoclonal antibody, for treatment of active lupus nephritis (LN).
Patients with Class III or IV LN (renal biopsy within 14 months of randomization), persistent proteinuria (≥0.5 g/d) despite immunosuppression, and stable renin-angiotensin system blockade were randomized (5:1) to receive intravenous sirukumab 10 mg/kg (n=21) or placebo (n=4) every 4 weeks through week 24. The primary endpoint was percent reduction of proteinuria (measured as the protein/creatinine ratio in a 12-hour urine collection) from baseline to week 24.
Twenty-five patients were enrolled; 19 (76.0%) completed treatment through week 24, and 6 (24.0%) discontinued the study agent early, 5 due to adverse events. At week 24, the median percent change in proteinuria from baseline in sirukumab-treated patients was 0.0% (95% CI: -61.8, 39.6). In contrast, the 4 placebo patients showed a median percent increase in proteinuria of 43.3% at week 24. Of note, a subset of 5 sirukumab-treated patients had ≥50% improvement in their protein/creatinine ratio through week 28. In the sirukumab group, 47.6% of patients had ≥1 serious adverse event; most were infection-related. No deaths or malignancies occurred. No serious adverse events were observed in the four placebo-treated patients.
This proof-of-concept study did not demonstrate the anticipated efficacy or an acceptable safety profile following sirukumab treatment in this population of patients with active LN receiving concomitant immunosuppressive treatment. This article is protected by copyright. All rights reserved.
© 2016, American College of Rheumatology.

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