Pharmacodynamics of isavuconazole in experimental invasive pulmonary aspergillosis: implications for clinical breakpoints.

Isavuconazole, a novel triazole antifungal agent, has broad-spectrum activity against Aspergillus spp. and other pathogenic fungi. The isavuconazole exposure-response relationship in experimental invasive pulmonary aspergillosis using galactomannan index (GMI) suppression as a marker of disease clearance was explored.
The impact of exposure on GMI suppression in persistently neutropenic rabbits treated with isavuconazonium sulphate (isavuconazole-equivalent dosages of 20, 40 or 60 mg/kg every 24 h, after a 90 mg/kg loading dose) for 12 days was linked using mathematical modelling. Bridging to humans using population pharmacokinetic (PK) data from a clinical trial in invasive aspergillosis was performed using Monte Carlo simulations.
Mean plasma isavuconazole AUC/MIC (EC50) of 79.65 (95% CI 32.2, 127.1) produced a half-maximal effect in GMI suppression. The inhibitory sigmoid Emax curve dropped sharply after an AUC/MIC of ≥30 and was near maximum (EC80) at ∼130. Bridging the experimental PK/pharmacodynamic (PD) target to human population PK data was then used to return to the rabbit model to determine a clinically relevant PD endpoint. The clinical dosing regimen used in the trial would result in a mean GMI of 4.3 ± 1.8, which is a 50% reduction from the starting GMI in the experiment.
The clinical trial results showing the non-inferiority of isavuconazole to voriconazole for all-cause mortality further support the PK-PD endpoint, thereby demonstrating the usefulness of the rabbit model and endpoint for isavuconazole and implications on interpretive breakpoints. Importantly, the analysis supports this model as an important tool for development of antifungal agents.
© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected].

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Medivation Announces Presentation of Phase I Talazoparib Combination Data in Several Advanced Cancers

On April 17, 2016 Medivation, Inc. (NASDAQ: MDVN) reported that Phase I data from its investigational agent talazoparib, a highly-potent PARP inhibitor, was presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans by the study’s lead investigator Zev A. Wainberg, M.D., Associate Professor of Medicine at the University of California Los Angeles (UCLA) and Co-Director of the UCLA GI Oncology Program, during a Clinical Trials Mini-Symposium (Press release, Medivation, APR 17, 2016, View Source [SID:1234510958]). The primary objective of the study was to determine the maximum tolerated dose (MTD) of talazoparib in combination with either low-dose temozolomide or low-dose irinotecan in heavily pretreated patients with advanced malignancies.

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The data from the 40 patient trial demonstrated that combination treatment with talazoparib and low-dose chemotherapy resulted in stable disease or an objective response in 23 of 40 heavily pretreated patients with a variety of advanced cancers (clinical benefit rate of 58%). Most notably, objective responses were seen in four of seven (57%) heavily pre-treated non-BRCA-mutated ovarian cancer patients when talazoparib was used in combination with either low-dose temozolomide or low-dose irinotecan. Six of seven individuals (86%) with non-BRCA ovarian cancer had clinical benefit (four partial responses and two stable disease) and had a reduction in CA 125 levels by 50% or greater.

Importantly, the overall study demonstrated responses to combination talazoparib/low-dose chemotherapy in patients with multiple tumor types in which specific deleterious mutations in certain DNA repair genes extended beyond BRCA deficiency, including one patient who did not meet the criteria of having homologous recombination deficiency (HRD). These effects may be mediated through PARP inhibition, as well as enhanced PARP trapping, which interferes with the tumor cell’s ability to replicate DNA by locking PARP molecules onto the DNA strand.

"In non-clinical studies, talazoparib has been shown to have high potency specifically against PARP 1 and 2, and antitumor effects in various solid tumors. With these new results, we now have evidence in humans that suggests talazoparib in combination with low-dose chemotherapy is active in tumors with defects in DNA repair beyond BRCA deficiency, and possibly in patients without evidence of HRD. We feel these data are consistent with talazoparib’s potent PARP trapping ability, which we believe makes talazoparib a unique and exciting product candidate with the potential to be used in combination with DNA damaging therapies across a wide variety of tumor types," said David Hung M.D., Founder, President and Chief Executive Officer of Medivation. "With more than half of the ovarian cancer patients demonstrating an objective response, particularly in a heavily pre-treated patient population with advanced disease, these findings are encouraging and support further evaluation of the safety and efficacy of talazoparib."

Talazoparib currently is in Phase III development for patients with locally advanced and/or metastatic breast cancer who harbor a germline BRCA1/2 mutation. It is also being studied in several investigator-sponsored trials across multiple tumor types.

The Phase I investigator-sponsored study evaluated escalating doses of talazoparib ( ≥ 0.5 mg given orally once daily) with either temozolomide ( ≥ 25 mg/m2 given orally on days 1-5; Arm A) or irinotecan ( ≥ 25 mg/m2 given by intravenous infusion every two weeks; Arm B) every 28 days in patients with advanced malignancies. Study participants ranged in age from 21 to 77 years (median: 57 years) and had received one to 15 prior chemotherapy regimens (median: 6). The primary endpoint of the study was the determination of the MTD. Secondary endpoints included pharmacokinetics, tumor response and biomarkers.

A total of 40 patients received escalating doses of talazoparib (0.5-1.0 mg) and either temozolomide or irinotecan (18 patients in Arm A and 22 in Arm B). Results showed the MTD for talazoparib was 1.0 mg. and 37.5 mg/m2 for either temozolomide or irinotecan when combined with 1.0 mg talazoparib. Partial responses were seen in four of seven (57%) germline BRCA wild type ovarian cancer patients who were platinum-resistant. Additional responses were seen in one patient each with Ewing’s Sarcoma, cervical adenocarcinoma, small cell lung cancer, and triple negative breast cancer. An association was observed between response and the presence of deleterious somatic mutations in DNA repair genes (PALB2 and RAD51D) distinct from BRCA mutations.

The most common grade 3/4 adverse events ( ≥ 5%) observed in patients treated with talazoparib plus temozolomide were neutropenia (28%), anemia (33%), and thrombocytopenia (33%). Among those treated with talazoparib plus irinotecan, the most common adverse events were thrombocytopenia (13%), anemia (27%) and neutropenia (31%). No significant pharmacokinetic interactions were observed between talazoparib and either temozolomide or irinotecan.

About Talazoparib
Talazoparib is a potent and specific inhibitor of PARP 1 and 2(i) that is being developed by Medivation for the treatment of selected solid tumors. In pre-clinical studies, talazoparib has shown single-agent anti-tumor activity, as well as synergy in combination with lowered doses of DNA-damaging agents, due to its dual mechanisms of cytotoxicity, PARP trapping, and inhibition of PARP enzyme activity. Trapping of PARP on DNA impairs DNA replication resulting in tumor cell death. Talazoparib currently is in Phase III development for patients with locally advanced and/or metastatic breast cancer who harbor a germline BRCA1/2 mutation.

Targeting the Heterogeneity of Cancer with Individualized Neoepitope Vaccines.

Somatic mutations binding to the patient’s MHC and recognized by autologous T cells (neoepitopes) are ideal cancer vaccine targets. They combine a favorable safety profile due to a lack of expression in healthy tissues with a high likelihood of immunogenicity, as T cells recognizing neoepitopes are not shaped by central immune tolerance. Proteins mutated in cancer (neoantigens) shared by patients have been explored as vaccine targets for many years. Shared ("public") mutations, however, are rare, as the vast majority of cancer mutations in a given tumor are unique for the individual patient. Recently, the novel concept of truly individualized cancer vaccination emerged, which exploits the vast source of patient-specific "private" mutations. Concurrence of scientific advances and technological breakthroughs enables the rapid, cost-efficient, and comprehensive mapping of the "mutanome," which is the entirety of somatic mutations in an individual tumor, and the rational selection of neoepitopes. How to transform tumor mutanome data to actionable knowledge for tailoring individualized vaccines "on demand" has become a novel research field with paradigm-shifting potential. This review gives an overview with particular focus on the clinical development of such vaccines.Clin Cancer Res; 22(8); 1885-96. ©2016 AACR (Free AACR Whitepaper) SEE ALL ARTICLES IN THIS CCR FOCUS SECTION, "OPPORTUNITIES AND CHALLENGES IN CANCER IMMUNOTHERAPY".
©2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper).

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Seattle Genetics Highlights Novel Antibody-Drug Conjugate (ADC) Technology Advances at the American Association for Cancer Research (AACR) Annual Meeting

On April 17, 2016 Seattle Genetics, Inc. (NASDAQ: SGEN) reported novel antibody-drug conjugate (ADC) technology advances presented at the 107th Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) being held April 16 through 20, 2016 in New Orleans, LA (Press release, Seattle Genetics, APR 17, 2016, View Source;p=RssLanding&cat=news&id=2157672 [SID:1234510959]). Data in multiple presentations demonstrate the company’s leadership and innovation in the field of ADCs. Presentations will showcase a new auristatin-based drug-linker as well as several novel linkers that expand Seattle Genetics’ proprietary ADC technology platform and may enable application of previously inaccessible cytotoxic payloads.

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"We have a comprehensive scientific understanding of the multiple components necessary to develop antibody-drug conjugates for the potential treatment of hematologic malignancies and solid tumors," said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics. "Our data presentations at the AACR (Free AACR Whitepaper) Annual Meeting illustrate novel linker systems and cell-killing payloads as well as continued progress in understanding the chemical and biological properties of ADCs to inform potential future development. We believe ADCs will continue to play an increasingly important role in cancer treatment."

ADCs are monoclonal antibodies designed to deliver cytotoxic agents selectively to tumor cells. Seattle Genetics has developed proprietary technology employing synthetic cytotoxic agents and stable linker systems that attach these cytotoxic agents to the antibody. Seattle Genetics’ linker systems are designed to be stable in the bloodstream and release the potent cell-killing agent once inside targeted cancer cells. This approach is intended to spare non-targeted cells and thus reduce many of the toxic effects of traditional chemotherapy while enhancing antitumor activity.

Multiple oral and poster presentations are being featured at AACR (Free AACR Whitepaper) that highlight Seattle Genetics’ ADC technology advances. Abstracts can be found at www.aacr.org and include the following:

Three poster presentations on Sunday and Monday, April 17 and 18, 2016 (Abstracts #0351, 1285, 2082) will highlight the role of the tumor microenvironment in ADC clearance, antitumor activity and uptake. Importantly, preclinical data demonstrate the potential for tumor associated macrophages to contribute to antitumor activity through release of MMAE.
The development of novel quaternary ammonium linkers for the stable conjugation and efficient release of tertiary amine-containing payloads will be presented in a poster presentation on Monday, April 18, 2016 (Abstract #2056). Preliminary data demonstrate that this technology enables the evaluation of drug classes previously inaccessible as ADCs, including auristatin E and tubulysin.

The development of a novel methylene-alkoxy-carbamate (MAC) linker that enables direct conjugation of drugs through alcohol functional groups will be presented in an oral presentation at 3:50 p.m. ET on Tuesday, April 19, 2016 (Abstract #4334). This linker has the potential to expand the types of payloads utilized in ADCs.
Data from a novel monomethyl auristatin E (MMAE) linker technology will be highlighted in a poster presentation on Tuesday, April 19, 2016 (Abstract #2956). By incorporating a short polyethylene glycol (PEG) unit, a self-hydrolysing maleimide and a glucuronidase release mechanism, the new MMAE drug-linker demonstrates pronounced activity with an increased therapeutic index in preclinical models.

Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial.

The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting.
This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660.
Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3-33·9). Progression-free survival (median 11·0 months [95% CI 10·6-12·9] with afatinib vs 10·9 months [9·1-11·5] with gefitinib; hazard ratio [HR] 0·73 [95% CI 0·57-0·95], p=0·017) and time-to-treatment failure (median 13·7 months [95% CI 11·9-15·0] with afatinib vs 11·5 months [10·1-13·1] with gefitinib; HR 0·73 [95% CI 0·58-0·92], p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure.
Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population.
Boehringer Ingelheim.
Copyright © 2016 Elsevier Ltd. All rights reserved.

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