On June 3, 2015 AVEO Oncology reported that, following pre-submission advisory meetings to discuss the potential submission of a Marketing Authorization Application (MAA) for tivozanib in Europe for the treatment of renal cell carcinoma (RCC), it has received written confirmation of support from the Rapporteur and co-Rapporteur for the filing of such an application (Press release, AVEO, JUN 3, 2015, View Source;p=RssLanding&cat=news&id=2056290 [SID:1234505227]). The Rapporteur (from Portugal) and Co-Rapporteur (from the United Kingdom) are the two appointed members of the Committee for Medicinal Products for Human Use (CHMP) who would lead the evaluation of the MAA, if submitted.

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The application would be based on the Company’s existing dataset, which includes results from the Phase 3 TIVO-1 study of tivozanib in the first-line treatment of RCC in which tivozanib demonstrated a significant improvement over sorafenib in the study’s primary endpoint of progression free survival. At the advisory meetings, AVEO provided data demonstrating that the discordance in overall survival (OS), the secondary endpoint of the study, was very likely attributable to the crossover design of the study. The final meeting minutes reflect that the Rapporteurs "did not see a ‘blocking issue’ with the OS trend" and that AVEO "clearly presented a credible story for the Rapporteurs to assess but one which would need to be supported with very careful reasoning." AVEO was also reminded that the Rapporteurs "cannot advise on [the] final outcome of the review."

"We are pleased that both the Rapporteur and Co-Rapporteur were supportive of an MAA filing for tivozanib in RCC using TIVO-1 as the pivotal study," said Michael Bailey, president and chief executive officer of AVEO. "We believe tivozanib may provide an important addition to the clinical armamentarium in the treatment of this disease. Based on our assessment of the economic and infrastructure requirements associated with filing an MAA and subsequently launching tivozanib in Europe, we are evaluating partnership opportunities to take tivozanib forward in this important market as we continue to prepare for a filing."

On June 3, 2015 4SC AG (Frankfurt, Prime Standard: VSC), a discovery and development company of targeted small molecule drugs for cancer and autoimmune diseases, reported that it published clinical data on safety, pharmacokinetics and efficacy for the 4SC-205 cancer compound at the annual meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in Chicago (Press release, 4SC, JUN 3, 2015, View Source [SID:1234506550]). The data has been obtained from the clinical Phase I AEGIS trial examining 4SC-205 in various dosing schemes in 59 patients with advanced solid tumours. 4SC-205 inhibits specifically the human kinesin spindle protein Eg5 (Kif 11), which has been shown to play a crucial role in mitosis (cell division) and, therefore, in tumour growth. To 4SC’s knowledge, 4SC-205 is the only orally available Eg5 inhibitor in clinical development worldwide. The ASCO (Free ASCO Whitepaper) poster can be downloaded from the 4SC website at View Source

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Since the Eg5 target molecule is present in the cell only during mitosis, and since mitoses in humans – in contrast to preclinical models – are very rare events of limited duration (approx. 30 minutes per mitosis), it is necessary to ensure continuous exposure of 4SC-205. This means that potentially efficacious and tolerable levels of the compound must be permanently available in patients in order to become effective immediately as soon as mitosis occurs.

Conducted at two study centres in Germany, the first-in-man, open-label AEGIS dose escalation and dose-schedule finding study investigated the oral administration of 4SC-205 in patients with advanced solid tumours. Initially, the compound was tested in a conventional, intermittent dosing scheme (consisting of higher single doses and longer breaks between treatments). Given its oral availability and its mechanism of action as a potential inhibitor of mitosis (cell division), 4SC-205 was subsequently examined in a daily (continuous) dosing scheme consisting of smaller single daily doses without breaks between treatments. The objective of the study was to evaluate safety, tolerability and pharmacokinetics, and to determine a recommended Phase II dose. The trial ended when treatment of the last patient was completed in the first quarter of 2015.

The data in detail: Good profiles of safety and tolerability, linear pharmacokinetic parameters, 20 mg daily dose of 4SC-205 recommended as Phase II dose

– A comprehensive safety and tolerability profile of 4SC-205 was established. Specifically, no peripheral neuropathies were observed. This side effect is typically observed in connection with conventional chemotherapeutic agents such as taxanes. This means that the approach of a targeted, anti-mitotic therapy, during which these side effects should not occur, was confirmed.

– The main side effects were neutropenia in the intermittent dosing scheme. At a daily dose of 20 mg the neutropenia development was well manageable.

– The oral compound demonstrated very good linear pharmacokinetic parameters, which is an ideal prerequisite for daily dosage.

– A pharmacodynamic biomarker is regulated in a dose-dependent manner, even at a low daily dose.

– The daily dose of 20 mg is recommended as the dose for further Phase II development of the compound. This dose was safe and well-tolerated by patients and furthermore demonstrated initial signs of clinical efficacy.

– An additional, positive result of the daily dose of 20 mg of 4SC-205 was the median time on treatment of 162 days, thus being four times longer than the time on treatment seen in the intermittent treatment regime (42 days). Moreover, 67% of patients in the 20 mg daily cohort showed disease stabilisation for more than 100 days.

Enno Spillner, CEO of 4SC AG, commented: "We are pleased with the successful completion of the AEGIS trial. 4SC-205 very specifically inhibits an interesting therapeutic target in anti-cancer treatment, the Eg5 protein, which plays an important role in cell mitosis and tumour growth. Since 4SC-205 is orally available, we were able to evaluate this compound as the first of its kind in a clinically promising continuous dosing scheme. In this process we identified a safe and potentially effective dose for possible future Phase II trials. We are currently reviewing scenarios of further clinical development and will intensify discussions with clinical experts and potential academic and industry partners."

Details of ASCO (Free ASCO Whitepaper) poster presentation

View Source
Abstract No. 2528
Poster Title: Overcoming the proliferation rate paradox: Clinical evaluation of a continuous dosing scheme of the novel oral Eg5 inhibitor 4SC-205.
Time/Location: 30 May 2015, 8:00-11:30am, CDT, McCormick Place: S Hall A, Board #244
Poster Session: Developmental Therapeutics – Clinical Pharmacology and Experimental Therapeutics
Sub-Category: Cell Cycle and Checkpoints
Authors: Klaus B. Mross, Dirk Scharr, Heike Richly, Sebastian Bauer, Babett Krauss, Rolf Krauss, Bernhard Hauns, Tanja Prenzel, Hella Kohlhof, Roland Baumgartner, Max E. Scheulen;
Klinik für Tumorbiologie, Freiburg, Germany; Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Germany; University Clinic Essen, Germany; 4SC AG, Planegg-Martinsried, Germany; Innere Universitaetsklinik und Poliklinik, Essen, Germany

About 4SC-205

4SC-205 is a specific small molecule inhibitor of the human kinesin spindle protein Eg5 which is of crucial importance for cell division (mitosis). Eg5 interacts with microtubules, a component of the cellular mitosis machinery, and mediates the segregation of the two spindle poles resulting in the correct distribution of the chromosomes to the daughter cells. Inhibition of Eg5 leads to cell cycle arrest in mitosis und subsequent programmed cell death (apoptosis). Mitosis is the fundamental process leading to cell division and tissue growth. The mitotic spindle apparatus has been for decades a primary target for the development of anti-mitotic agents such as the taxanes and vinca alkaloids which are broadly used in cancer therapies as single chemotherapeutic agents or in combination. In preclinical tests 4SC-205 has proven to be a particularly effective inhibitor of tumour cell proliferation of various cancer origins, both in vitro and in vivo.

On June 2, 2015 Bristol-Myers Squibb reported that results from an interim analysis of its Phase III, randomized, open-label ELOQUENT-2 trial were published in the June 2 online edition of the New England Journal of Medicine (Press release, Bristol-Myers Squibb, JUN 2, 2015, View Source [SID:1234505207]). The trial (n=646) evaluated elotuzumab, an investigational immunostimulatory antibody, in combination with lenalidomide and dexamethasone (ELd) versus lenalidomide and dexamethasone alone (Ld) for the treatment of relapsed or refractory multiple myeloma. The study met its co-primary endpoints demonstrating superior progression-free survival (PFS) and overall response rate (ORR).

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The ELd arm demonstrated a 30% reduction in the risk of disease progression or death compared to the Ld arm (HR 0.70, 95% CI, [0.57, 0.85]; p = 0.0004). The PFS rates in the ELd arm versus the Ld arm were 68% versus 57% at 1 year and 41% versus 27% at 2 years, respectively. A significant ORR also was observed with 79% (74% to 83%) in the ELd arm compared to 66% (60% to 71%) in the Ld arm (odds ratio, 1.9; 1.4 to 2.8; p=0.0002). The safety profile was consistent with previously-reported studies and there were minimal incremental adverse events (AEs) with the addition of elotuzumab to lenalidomide and dexamethasone.

"Despite advances in treatment, multiple myeloma remains a largely incurable disease," said lead author Sagar Lonial, M.D., chief medical officer of the Winship Cancer Institute of Emory University School of Medicine. "These ELOQUENT-2 data are significant because they show that adding elotuzumab to the standard treatment yielded an impressive reduction in the risk of disease progression, which was maintained over time, demonstrating the benefit of an immune-based approach in multiple myeloma."

Results from the ELOQUENT-2 trial will be presented at the 2015 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago during an Oral Abstract Session on Tuesday, June 2 from 9:45 – 9:57 a.m. CDT [Abstract # 8508].

Also presented in a poster session at ASCO (Free ASCO Whitepaper) on Sunday, May 31 were results from the Phase II study that evaluated elotuzumab in combination with bortezomib and dexamethasone (EBd, n=77) versus bortezomib and dexamethasone (Bd, n=75) alone in patients with relapsed or refractory multiple myeloma [Abstract #8573]. Consistent with data from ELOQUENT-2, results from the Phase II study demonstrated a 28% reduction in the risk for disease progression or death in the EBd arm compared to Bd alone (HR 0.72, 70% CI, 0.59, 0.88). One-year PFS rates were 39% (95% CI 28%, 50%) for EBd versus 33% (95% CI 22%, 44%) for Bd. One-year survival rates were 85% (95% CI 75%, 92%) in the EBd arm versus 74% (95% CI 62%, 83%) in the Bd arm. Grade 3-4 AEs were reported in 68% of patients in the EBd group and 60% in the Bd group, including infections (19% vs. 15%), thrombocytopenia (9% vs. 17%), and peripheral neuropathy (8% vs. 9%).

"These trials, which evaluated elotuzumab in combination with either an IMiD or a proteasome inhibitor, demonstrated that elotuzumab, an immunostimulatory antibody, has the potential to be a new modality for the treatment of multiple myeloma," said Michael Giordano, senior vice president, Head of Development, Oncology, Bristol-Myers Squibb. "Bristol-Myers Squibb continues to make great progress toward delivering on our commitment to expand the role of immunotherapy into hematologic malignancies, such as multiple myeloma. We look forward to continued follow-up of the ELOQUENT-2 trial as we know improvement in long-term outcomes, including survival, is critical for patients."

About ELOQUENT-2

ELOQUENT-2 (CA204-004) is an open-label, multicenter Phase III study evaluating elotuzumab in combination with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with relapsed or refractory multiple myeloma. The trial enrolled 646 patients who had received one to three prior therapies and who were not lenalidomide-refractory. Patients were randomized 1:1 to receive either elotuzumab 10 mg/kg in combination with lenalidomide and dexamethasone (ELd) or lenalidomide and dexamethasone alone (Ld) in 28-day cycles to disease progression or unacceptable toxicity. The co-primary endpoints were progression-free survival, as defined by hazard ratio, and objective response rate. Median follow-up for this interim analysis was 24.5 months with 35% of ELd patients (n=113) and 21% of Ld patients (n=66) remaining on therapy. Key secondary endpoints included overall survival and pain severity/interference with daily life. Exploratory objectives included tumor response, duration of response, health-related quality of life, and safety.

Along with a 30% reduction in the risk of disease progression, which was sustained at two years, the median PFS in the ELd group was 19.4 months (95% CI, 16.6 to 22.2) versus 14.9 months (95% CI, 12.1 to 17.2) in the Ld group. The PFS benefit observed was consistent across all pre-specified subgroups. Patients in the ELd arm were exposed to treatment with lenalidomide 30% (or median of approximately five months) longer than patients in the Ld arm. Discontinuation was mainly due to disease progression (42% ELd, 47% Ld). The rate of discontinuation due to adverse events did not differ between arms. Grade 3-4 hematologic adverse events in the ELd and Ld arms, respectively, included lymphopenia (77% vs. 49%), neutropenia (34% vs. 44%), anemia (19% vs. 21%) and thrombocytopenia (19% vs. 20%), and the exposure-adjusted infection rate was the same in both arms. Infusion reactions occurred in 10% of patients with ELd; these were mostly Grade 1-2, and were manageable and resulted in discontinuation in only 1% of patients. A similar proportion of patients in each study group (2%) died due to an adverse event. As of this analysis, there were a total of 210 deaths in the study with 94 [30%] in the ELd group versus 116 [37%] in the Ld group. This represents a total of 49% of the 427 deaths required for the final analysis. Follow-up of longer-term outcomes, including overall survival, is ongoing.

About Elotuzumab

Elotuzumab is an investigational immunostimulatory antibody targeted against Signaling Lymphocyte Activation Molecule (SLAMF7), a cell-surface glycoprotein that is highly and uniformly expressed on myeloma cells and Natural Killer (NK) cells, but is not detected on normal solid tissues or on hematopoietic stem cells. Elotuzumab is being investigated to determine whether the compound may selectively target myeloma cells. It is believed that elotuzumab works through a dual mechanism of action: binding to SLAMF7 on NK cells, directly activating them and binding to SLAMF7 on myeloma cells, flagging them for NK cell recognition and destruction.

In May 2014, the U.S. Food and Drug Administration (FDA) granted elotuzumab Breakthrough Therapy Designation for use in combination with one of the chemotherapy treatments for multiple myeloma (lenalidomide, used in combination with dexamethasone) in patients who have received one or more prior treatments. Elotuzumab is an investigational compound and its safety and efficacy have not been evaluated by the FDA or any other health authority.

Bristol-Myers Squibb and AbbVie are co-developing elotuzumab, with Bristol-Myers Squibb solely responsible for commercial activities.

On June 2, 2015 Synta Pharmaceuticals reported updates to its clinical program for Ganetespib, a next-generation inhibitor of the chaperone protein Hsp90 (Press release, Synta Pharmaceuticals, JUN 2, 2015, View Source;p=RssLanding&cat=news&id=2055568 [SID:1234505212]). Ganetespib is currently being studied in several large, randomized studies, including the Phase 3 GALAXY-2 trial in non-small cell lung cancer, as well as a number of other investigator-sponsored studies in various malignancies, including acute myeloid leukemia, breast cancer and ovarian cancer.

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The Company announced today that the first patient has been enrolled in the Phase 2 portion of the GANNET53 study, a randomized, pan-European study evaluating the combination of ganetespib and paclitaxel vs. paclitaxel alone in over 200 patients with metastatic, predominantly p53 mutant, platinum-resistant ovarian cancer. Enrollment in the Phase 2 portion follows the successful completion of Phase 1, the results of which were recently presented at the 2015 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago. The Phase 1 data demonstrated that the combination of ganetespib 150 mg/m² with paclitaxel 80 mg/m² once weekly for 3 out of 4 weeks was generally well tolerated, with no dose limiting toxicities, and was therefore chosen for the randomized phase 2 trial. GANNET53 is sponsored by Innsbruck Medical University in Austria and funded by the European Commission.

"The Phase 1 portion of GANNET53 has established the feasibility and tolerability of combining ganetespib and paclitaxel, and we eagerly look forward to the enrollment of, and results from the randomized Phase 2 portion of this trial." said Professor Nicole Concin of the Innsbruck Medical University in Austria and the GANNET53 trial Principal Investigator. "We are very excited about a recent scientific insight into the relationship of p53 gain-of-function mutations which are the molecular hallmark of aggressive, high-grade serous ovarian carcinoma, and Hsp90 inhibition leading to tumor cell death in vitro and significant tumor control and prolonged survival in a novel p53 mutant mouse model. This unique mechanism of action and encouraging preclinical data support our choice of the ganetespib combination in an effort to optimize treatment for women with platinum-resistant ovarian cancer."

The Company also announced today that results from the Phase 2 GALAXY-1 trial, a global, randomized, multi-center study designed to identify the patients with advanced non-small cell lung cancer (NSCLC) most likely to benefit from second-line treatment with ganetespib in combination with docetaxel versus docetaxel alone, have been published in the journal Annals of Oncology. As previously announced, a pre-specified stratification factor analysis demonstrated that patients diagnosed with advanced non-small cell lung adenocarcinoma more than six months prior to study entry derived the most benefit from combination treatment, leading to the selection of this population for the ongoing Phase 3 GALAXY-2 trial. Based on current projections and statistical assumptions, the first interim overall survival (OS) analysis of GALAXY-2 is on track to occur in the second half of 2015, and the second interim and final OS analyses will be conducted in 2016. The GALAXY-1 publication is available online here.

"We are pleased to see the GALAXY-1 findings published in the Annals of Oncology and look forward to understanding how outcomes from this trial translate to the ongoing, pivotal Phase 3 GALAXY-2 trial," said Dr. Suresh Ramalingam, M.D., Professor, Hematology & Medical Oncology, and Director, Division of Medical Oncology, of the Winship Cancer Institute of Emory University, and a principal investigator of the GALAXY program. "Ganetespib’s unique mechanism of action has the potential to play an important role in the evolving treatment landscape in lung cancer. I look forward to the outcome of GALAXY-2."

"We remain highly encouraged by the progress of the ganetespib program across a broad spectrum of malignancies and grateful to our collaborating investigators for their strong, ongoing support for what is today the most advanced, next generation inhibitor of Hsp90," said Chen Schor, President and Chief Executive Officer of Synta. "We look forward to several transformative milestones on the horizon, both for ganetespib and our lead HDC candidate, STA-12-8666."

About Ganetespib

Ganetespib, an investigational drug candidate, is a selective inhibitor of heat shock protein 90 (Hsp90), a molecular chaperone which controls the folding and activation of a number of client proteins that drive tumor development and progression. Many solid and hematologic tumors are dependent on Hsp90 client proteins including proteins involved in "oncogene addiction" (ALK, HER2, mutant BRAF and EGFR, androgen receptor, estrogen receptor, and JAK2); proteins involved in resistance to chemotherapy and radiation therapy (ATR, BCL2, BRCA1/2, CDK1/4, CHK1, survivin, and WEE1); proteins involved in angiogenesis (HIF-1alpha, VEGFR, PDGFR, and VEGF); and proteins involved in metastasis (MET, RAF, AKT, MMPs, HIF-1alpha, and IGF-1R). In preclinical models, inhibition of Hsp90 by ganetespib results in the inactivation, destabilization, and eventual degradation of these cancer-promoting proteins. Ganetespib is being evaluated in trials in lung cancer, breast cancer, and other tumor types. The most common adverse event seen to date has been transient, mild or moderate diarrhea, which has been manageable with standard supportive care. Information on these trials can be found at www.clinicaltrials.gov. Ganetespib has received Fast Track designation from FDA for second-line treatment of non-small cell lung adenocarcinoma in combination with docetaxel.

On June 2, 2015 Aptose Biosciences reported that the U.S. Food and Drug Administration (FDA) has granted the company orphan drug designation for APTO-253 for the treatment of acute myeloid leukemia (AML) (Press release, Aptose Biosciences, JUN 2, 2015, View Source [SID:1234505214]). APTO-253, a first-in-class inducer of the KLF4 gene, is the company’s lead product candidate in a Phase Ib clinical trial in patients with AML, high-risk myelodysplastic syndrome (MDS) and other hematologic malignancies in which KLF4 silencing is reported as operative.

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"AML is a particularly challenging cancer of the blood and bone marrow for which there are currently few treatment options," said William G. Rice, Ph.D., Chairman, President and CEO. "APTO-253, with its unique mechanism of action, has the potential to emerge as an entirely new therapeutic approach for this patient population, and receiving orphan drug designation is a key regulatory milestone along the path."

Epigenetic suppression of the Krüppel-like factor 4 (KLF4) gene has been reported in the scientific literature as a key transforming event in AML. APTO-253 is a first-in-class, targeted inducer of the KLF4 tumor suppressor gene, and has demonstrated a favorable safety profile with no evidence of suppression of the normal bone marrow. Preclinical studies have shown potent single-agent activity to kill AML cells and strong synergy as part of a combination strategy with various marketed and investigational agents. APTO-253 is currently in a Phase 1b clinical study in patients with relapsed or refractory hematologic malignancies.

Orphan drug designation is granted by the FDA to encourage companies to develop therapies for the treatment of diseases that affect fewer than 200,000 individuals in the United States. Orphan drug status provides research and development tax credits, an opportunity to obtain grant funding, exemption from FDA application fees and other benefits. If APTO-253 is approved to treat AML, the orphan drug designation provides Aptose with seven years of marketing exclusivity.

About Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a cancer derived from myeloid progenitor or stem cells that typically mature into red blood cells, white blood cells or platelets. AML initiates in the bone marrow when stem or progenitor cells lose cell cycle control, anti-apoptotic factor or other means to limit rampant proliferations. Leukemic cells have the ability to rapidly spread from the marrow to the bloodstream. Further, these rapidly proliferating cells quickly crowd out normal cells as they infiltrate other organs and tissue systems.

AML is the most common type of acute leukemia among adults, with an annual incidence of more than 18,000 patients, and causing more than 10,000 deaths each year in the U.S. It is a particularly devastating blood cancer, with less than 25 percent of newly diagnosed patients surviving beyond five years.