On June 3, 2015 Celator Pharmaceuticals reported that enrollment is complete in a Phase 2 pharmacokinetic and pharmacodynamics (PK/PD) study evaluating the effects of CPX-351 (cytarabine:daunorubicin) Liposome Injection on cardiac repolarization in adult patients with acute hematologic malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and myelodysplastic syndrome (MDS) (Press release, Celator Pharmaceuticals, JUN 3, 2015, View Source [SID:1234505218]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

The open-label, single-arm, Phase 2 study is a thorough PK/PD assessment designed to: (1) measure the effects of CPX-351 on cardiac repolarization following the first induction cycle of CPX-351, and (2) correlate changes in cardiac repolarization with plasma pharmacokinetic data for cytarabine and daunorubicin and their metabolites. The study began enrolling patients in August 2014. Each patient received a first induction of CPX-351 on days 1, 3 and 5 and, if necessary, a second induction for patients with reduced leukemia/MDS burden not yet achieving a disease-free state. Responding patients were eligible for up to four consolidation courses. Analysis of treatment impact on cardiac electrophysiology, as measured by the QTc interval, and PK assessments were performed following the first induction course.

The study enrolled patients with newly diagnosed de novo and high-risk (secondary) AML, relapsed/refractory AML and relapsed ALL. Fifteen of the 26 patients enrolled are evaluable for response at this time. Six of the 15 patients responded to CPX-351 (defined as CR-complete response or CRi-complete response with incomplete hematologic recovery) including 2 of 3 patients (67%) with high-risk (secondary) AML, the study population of the ongoing Phase 3 trial. Responses were also seen in patients with de novo AML, relapsed AML, and relapsed ALL.

"We are happy to report that this study confirms the broad activity of CPX-351 in multiple populations of acute leukemia patients," said Tara Lin, M.D., Assistant Professor of Medicine at The University of Kansas Cancer Center, the lead investigator of this study, "and will report cardiac repolarization and pharmacokinetic data necessary for the registration of CPX-351 later this year."

The Phase 2 study was conducted to support the U.S. Food and Drug Administration (FDA) requirements of a New Drug Application (NDA) for CPX-351. Our Phase 3 study comparing CPX-351 to the current standard of care, known as 7+3, is being conducted in patients with high-risk (secondary) AML. The Phase 3 study completed enrollment in November 2014. Initial data from a secondary endpoint, induction response rate, is expected by the end of June 2015. The primary endpoint data, of overall survival, is expected in the first quarter of 2016.

"We continue to work expeditiously to bring CPX-351 before the FDA as a potential new treatment option for patients with acute hematologic malignancies," said Scott Jackson, Chief Executive Officer of Celator Pharmaceuticals. "Clinical pharmacology studies are required by the FDA for new drugs in development, so we are pleased to have completed enrollment in this Phase 2 study to support a NDA submission for CPX-351. We expect to report top-line results from this study by the end of the year."

On June 3, 2015 Varian Medical Systems reported that it has been selected to equip and service the new multi-room HollandPTC in Delft with the Varian ProBeam proton therapy system. The company will book the equipment part of the order in its fiscal 2015 third quarter (Press release, Varian Medical Systems, JUN 3, 2015, View Source [SID:1234505220]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

HollandPTC is a key part of Medical Delta, the medical-technological collaboration of the universities and university medical centers of Leiden, Delft and Rotterdam. When completed, the center will feature two proton therapy treatment rooms with full rotational gantries as well as facilities for fixed-beam eye treatments and research. Equipment installation is expected to take place in mid-2016, with patient treatments expected to begin in the second half of 2017.

"We are pleased to be selected to supply our ProBeam system for this prestigious project," said Moataz Karmalawy, managing director of Varian’s particle therapy business. "As well as offering pencil-beam scanning, the most advanced form of proton therapy, HollandPTC will be a key research site feeding into a national program to study the efficacy of protons."

Varian’s ProBeam system with Dynamic Peak Scanning is uniquely capable of high-speed intensity modulated proton therapy (IMPT) which is the most precise form of proton therapy available.

Proton therapy makes it possible to treat certain types of cancer more precisely and with potentially fewer side effects than is possible with conventional radiation therapy. With proton therapy, the risk of damage to healthy tissues and potential side effects is reduced because the beam is designed to stop and deposit dose within the tumor site rather than passing all the way through the patient. Proton therapy can be used for many of the most common types of cancer.

Varian’s ProBeam technology is being used to treat patients at the Scripps Proton Therapy Center in San Diego, the Rinecker Proton Therapy Center in Munich, and at the Paul Scherrer Institute in Switzerland. Varian also has contracts for system installations at eight other sites around the world.

On June 3, 2015 Varian Medical Systems reported Varian Medical Systems is expanding in the Middle East with the creation of a strategic operating entity in Saudi Arabia. Varian Medical Systems Arabia, the result of a joint venture with El Seif Development Group, was officially launched today at a ceremony attended by local dignitaries and Varian’s chief executive officer Dow Wilson (Press release, InfiMed, JUN 3, 2015, View Source [SID:1234505221]).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"This move represents the next step in our commitment both to cancer patients and the medical community in Saudi Arabia," said Dow Wilson. "Radiotherapy plays a vital and cost effective role in treating cancer and we are committed to making more advanced treatment systems available to more patients across the region."

Varian Medical Systems Arabia will be home to 35 sales, service and administrative employees supporting Varian’s three business segments: Oncology Systems, Imaging Components and Particle Therapy. Varian has also established a spare parts depot in Riyadh.

"We look forward to supporting the ministry of health in Saudi Arabia as well as with the other healthcare service providers in the military sector, independent organizations and private hospitals," said Mazyad Al Utaibi, managing director of VMS Arabia. "Our expertise, experience, strengths and capabilities ensure we are well placed to continue offering our partners the latest technology and local service to fight cancer and help save lives."

Varian is the leading provider of radiotherapy systems to Saudi hospitals. The first Varian linear accelerator was installed in Saudi Arabia over 30 years ago and the company now has 22 systems operating across the country. Varian was also selected to equip the Middle East’s first proton therapy center, which is under construction at King Fahad Medical City in Riyadh.

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.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

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

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

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.