Aplidin ( Pharma Mar ) combinado con Dacarbazine ( Bayer ) en el Tratamiento del Melanoma se Complementan y consiguen una Respuesta Completa . ASCO

Aplidin por sí sola o con dacarbazine como tratamiento de primera línea para el Melanoma Avanzado Inoperable (AUM)


Plitidepsin (APL) alone or with dacarbazine (DTIC) as first-line treatment for advanced unresectable melanoma (AUM).

Sub-category: Melanoma

Category: Melanoma/Skin Cancers

Meeting: 2010 ASCO Annual Meeting

Citation: J Clin Oncol 28:7s, 2010 (suppl; abstr 8537)

Abstract No: 8537

Author(s): E. R. Plummer, P. Lorigan, L. Hayward, J. Jassem, L. Demidov, V. Moiseyenko, V. Soriano, E. Chmielowska, R. Prados, S. Szyldergemajn; Northern Centre For Cancer Care, Newcastle upon Tyne, United Kingdom; The Christie NHS Foundation Trust, Manchester, United Kingdom; Western General Hospital, Edinburgh, United Kingdom; Medical University of Gdansk, Gdansk, Poland; Russian Cancer Research Center, Moscow, Russia; N. N. Petrov Research Institute of Oncology, St. Petersburg, Russia; Instituto Valenciano de Oncologia, Valencia, Spain; Centrum Onkologii Prof. F. Lukaszczyka, Bydgoszcz, Poland; PharmaMar, Colmenar Viejo, Madrid, Spain

Abstract:

Background: In patients (pts) with AUM, DTIC alone is associated with response rates (RR) 8%-15%. Aplidin, a novel cytotoxic, gave a RR of 6% as second line therapy in AUM. APL+DTIC have shown additive cytotoxicity in preclinical models. In the prior dose-finding stage of this study, 16% of 19 evaluable pts had a partial response (PR). Recommended dose (RD) was APL 2.4 mg/m2/d 1, 8 and 15 + DTIC 800 mg/m2/d1 q4w (Plummer, J Clin Oncol 27:15s, 2009; abstr 9059). Methods: A randomized 2 stage phase II study aim to determine the activity of Arm A (APL3.2 mg/m2/d 1, 8 and 15 q4w) or Arm B (APL+DTIC) at their established RD was performed. If at least 2 responses were observed per arm after 17 evaluable pts, 13 more pt would be included in the second stage. Results: 20 pts were randomized to Arm A and 38 pt (2 not treated) to Arm B (ITT population). Of these, 17 and 29 pts, respectively were evaluable for efficacy (PP population). Baseline characteristics were: 52% males; median (med) age, 53 y (range: 21-78); med ECOG, 1 (0-2); and med LDH 1.2 upper limit normal (0.4-8.2). All pts had metastases, with a med of 2 sites involved (1-6). Arm A was discontinued as no responses were seen; Arm B continued to stage 2. In arm B, relative dose intensity was 67% and 99% for APL and DTIC, respectively. Most frequent reason for missing doses was grade (G) 2/3 ALT/AST increase. Common mild toxicities included nausea, vomiting, hypersensitivity (G3/4 reactions in 9%), myalgia, diarrhea, and constipation. G1/2 anemia occurred in 61% of pts, and G3/4 neutropenia or thrombocytopenia in 6 and 8% of pts respectively, with no febrile neutropenia. Antitumor activity included 1 (3%) complete response, 6 (21%) PR and 8 (28%) stabilizations (SD); disease control rate (CR+PR+SD) was 52% (PP) and 42% (ITT). As of Dec 2009, with a med follow-up of 4 months, PFS is 3 months (95%CI: 2-5) and 96% of pts are alive at 1 year (95% CI: 89-100%). Pharmacogenomic analyses are ongoing. Conclusions: Weekly APL alone showed no activity in AUM, while combined with DTIC showed encouraging activity. Toxicity was manageable and non-life threatening, but it led to frequent APL dose omissions. A biweekly schedule should undergo clinical evaluation.

Yondelis , Analisis del Tratamiento en Sarcomas con 1400 Pacientes muy Pretratados . ASCO 2010 .

Trabectedin (Tr) as single agent for advanced soft tissue sarcomas (STS) failing standard of care: Interim analysis of 1,400 patients (pts) in an expanded access program study.

Sub-category: Soft Tissue

Category: Sarcoma

Meeting: 2010 ASCO Annual Meeting

Citation: J Clin Oncol 28:7s, 2010 (suppl; abstr 10027)

Abstract No: 10027

Author(s): B. L. Samuels, W. D. Tap, S. Patel, M. von Mehren, J. T. Hamm, P. E. Kaiser, S. Schuetze, J. Li, E. Bayever, G. D. Demetri; Kootenai Cancer Center, Post Falls, ID; University of California, Los Angeles Medical Hematology Oncology, Santa Monica, CA; University of Texas M. D. Anderson Cancer Center, Houston, TX; Fox Chase Cancer Center, Philadelphia, PA; Norton Health Care, Louisville, KY; Oncology Specialists, Niles, IL; University of Michigan, Ann Arbor, MI; Johnson & Johnson Pharmaceutical Research and Development, LLC, Raritan, NJ; Johnson & Johnson Pharmaceutical Research and Development, Raritan, NJ; Ludwig Center, Dana-Farber Cancer Institute/Harvard Cancer Center and Sarcoma Center, Boston, MA

Abstract:

Background: Between 2005 and 2009, 1404 pts with advanced STS were enrolled in an Expanded Access Program (EAP) of Tr in the United States, Canada and Israel, and were treated with Tr 1.5mg/m2/ via 24h continuous IV infusion q21d. The purpose of this analysis was to assess activity and tolerability of Tr in pts treated in this EAP. Methods: A total of 25 centers participated, enrolling pts with incurable STS following failure of currently available therapies. Inclusion criteria were similar to Study ET743-STS-201 (J Clin Oncol, 2009 Sep 1;27(25):4188- 96). No restrictions were placed on the number of lines of prior therapy. Data cutoff for this analysis was September 28, 2009. Results: In this analysis of 1404 Tr-treated pts; 93% were enrolled in the US. Median age was 54 years (range16-87), 59% female; major histological subgroups were leiomyosarcoma (35%) and liposarcoma (15%). The majority of pts had prior treatment with an anthracycline and ifosfamide. Median number of Tr cycles administered was 3 (range 1-55); ≥6 cycles were given to 419 pts (30%). Median dose intensity of Tr was 1.3 mg/m2/cycle (0.20-1.77), 0.433 mg/m2/week (0.07; 0.59), relative dose intensity 87% (13-118). There were 429 (31%) dose reductions due to AE and 378 (27%) cycle delays. The most common AEs were neutropenia and transaminase elevations, however these were manageable and without serious clinical consequences. The primary reported causes of treatment termination (1191 pts) were disease progression (859 pts, 61%), adverse events (105, 7%), subject choice (99, 7%), and death (61, 4%) {fatal outcomes reported in association with adverse events 30; drug related, progressive disease 27, or other 4}. Reported best outcomes in 504 evaluable pts were CR 1 (<1%), PR 36 (7%), SD 166 (33%), PD 229 (45%). Conclusions: This EAP for heavily pretreated pts with STS represents one of the largest therapeutic experiences. Tr activity is consistent with prior trials, with a clinical benefit (objective responses + SD) of 41% with an expected toxicity profile. These results demonstrate the potential clinical utility of Tr in STS following failure of conventional therapies.

Yondelis en Pacientes con Sarcoma Sinovial . ASCO 2010 .

Trabectedin (T) in advanced, pretreated synovial sarcomas (SS): A retrospective analysis of 39 patients (pts) from three European institutions.

Sub-category: Soft Tissue

Category: Sarcoma

Meeting: 2010 ASCO Annual Meeting

Citation: J Clin Oncol 28:7s, 2010 (suppl; abstr 10030)

Abstract No: 10030

Author(s): P. Dileo, R. Sanfilippo, F. Grosso, E. Fumagalli, J. Blay, J. Domont, A. Le Cesne, J. C. Tercero, P. G. Casali; Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; ASO Alessandria, Alessandria, Italy; Université Claude Bernard Lyon I, Lyon, France; Institut Gustave Roussy, Villejuif, France; PharmaMar, Colmenar Viejo, Madrid, Spain; Istituto Nazionale dei Tumori, Milano, Italy

Abstract:

Background: T is effective in advanced soft tissue sarcomas, with special regard to liposarcoma and leiomyosarcoma. Mechanisms of action may be multifold: induction of DNA damage, involving specific and peculiar DNA repair pathways, and transcriptional interference. The latter mechanism may be more significant in myxoid liposarcomas. Other translocation-related sarcomas may be sensitive to T. SS is a translocation-related sarcoma. We report on a series of 39 pts with advanced SS who were treated with T in three European sarcoma centres within compassionate-use programs. Methods: The datasets of Istituto Nazionale Tumori, Milano, Italy; Centre Leon Berard, Lyon, and Institut Gustave Roussy, Villejuif, France, were retrospectively reviewed from 2000 to 2009. Overall, 21/39 pts were female, and age ranged from 18 to 67 years. Sites of primary lesions were extremities = 23, mediastinum = 6, trunk = 5, pelvis = 4, head and neck = 1. At the time of treatment, all pts presented with metastatic disease, and were pre-treated with a median of 3 chemotherapy lines (range: 2-7). Results: 186 courses were delivered (median: 3). All pts were evaluable for response. Seven pts had a PR, for an overall response rate (RR) of 18%. In addition, 2 MR, and 11 SD were observed. Progression-free survival at 6 months (PFR-6) was 23%. Median PFS was 29, 21, and 18 weeks, respectively, in pts who experienced PR, MR and SD. Conclusions: In this series of adult pts with advanced pre-treated SS, T induced a RR of 18% and a PFR-6 of 23%. This suggests that SS constitute a sarcoma subgroup with distinct sensitivity to T.

Yondelis : Una Decada de Experiancia . ASCO 2010 .

Yondelis es Activo en el Tratamiento de LeioMyoSarcoams Uterinos en Pacientes Pretratados . ASCO 2010 .

Trabectedin (Tr) in the treatment of advanced uterine leiomyosarcomas (U-LMS): Results of a pooled analysis of five single-agent phase II studies using the recommended dose.

Tuesday 8 June 2010 .
Abstract No: 10028


Author(s): I. R. Judson, J. Blay, S. P. Chawla, J. A. Radford, A. Le Cesne, J. Verweij, M. von Mehren, J. Pontes, E. Bayever, G. D. Demetri; Cancer Research UK Centre for Cancer Therapeutics, London, United Kingdom; Université Claude Bernard Lyon I, Lyon, France; Sarcoma Oncology Center, Santa Monica, CA; University of Manchester and Christie NHS Foundation Trust, Manchester, United Kingdom; Institut Gustave Roussy, Villejuif, France; Department of Medical Oncology, Erasmus University Medical Center Daniel den Hoed Cancer Center, Rotterdam, Netherlands; Fox Chase Cancer Center, Philadelphia, PA; PharmaMar, Colmenar Viejo, Madrid, Spain; Johnson & Johnson Pharmaceutical Research and Development, Raritan, NJ; Ludwig Center, Dana-Farber Cancer Institute/Harvard Cancer Center and Sarcoma Center, Boston, MA

Abstract:

Background: Trabectedin is approved in Europe and 19 other countries around the world for second-line treatment of advanced soft tissue sarcomas (STS), with activity documented in several phase II studies. Uterine sarcoma represent 1% of all gynecological malignancies and 30% of all uterine sarcoma are U-LMS. A pooled analysis of activity and tolerability of Tr in U-LMS patients (pts) from five phase II trials is presented. Methods: Retrospective analysis was done on data from 5 different trials, with a total of 62 generally pretreated pts with advanced U-LMS (prior anthracycline-based chemotherapy: 91.9%; prior surgery: 98.4%; prior radiotherapy: 48.4%), exposed to a median of two prior chemotherapy lines (range 0-6), received iv Tr 1.5 mg/m2 24-h q3wk. Efficacy endpoints were response rate (RR) by investigator assessment (IA), progression-free survival (PFS) and overall survival (OS). Safety was also analyzed. Results: Median age 53 (range:34-75) years; median No. cycles 3 (1-38); median relative dose intensity 90%. Eleven pts achieved PR (17.7%) and 20 pts SD (32.3%; 13% ≥6 months), PD 43.5% and NE 6.5%. Median PFS was 2.5 months (95% CI:1.7-4.2); 30.7% (CI 95% 19-43) pts were progression free at 6 months. Median OS was 12.1 months, with 52% (CI 95% 39-64) and 20% (CI 95% 10-30) of pts alive at 12 and 24 months, respectively. Worst per patient grade 3-4 AEs included neutropenia (41.9%), thrombocytopenia (9.7%), anemia (9.7 %), fatigue (8.1%) and febrile neutropenia (1.6%). G-CSF was used in 17.7% of pts. Transient G3-4 ALT and AST elevations occurred in 43.5% and 30.6 % without symptoms/signs of hepatic failure. Alopecia (4.8%) and peripheral neuropathy (1.6%) were uncommon. Conclusions: Tr has activity and is reasonably safe for pts with advanced U-LMS. Nearly one-third of pts were progression-free for 6 months or more, and over half (52%) of these pretreated pts were alive at one year. RR, PFS and OS compare favorably to published outcomes with other single agents (e.g., doxorubicin). These results warrant further prospective studies in first-line U-LMS combining Tr with other active drugs.

JPMorgan Intl Equity Index Fund C (OIICX) .

La supresión de blindajes a cotizadas no se está haciendo con el mecanismo idóneo, según un informe .

... El profesor del IE Business School calificó este "problema" como "de gestores y accionistas", y lamentó además que en los blindajes "se trata de elegir entre el secuestro de una compañía por su accionista principal y el secuestro por directivos". "Damos por hecho que, en todo caso, la compañía está secuestrada", añadió.
...

El Fondo del Mar sigue Aportando Fármacos contra el Cáncer . Aplidin inicia la Fase III de Registro en Cáncer de Myeloma Multiple Recurrente .

NUEVO MEDICAMENTO PARA EL CÁNCER de Myeloma Multiple Recurrente inicia la Fase III .

En relación al Farmaco :

The mechanism of action of Aplidin.

Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Arturo Duperier, 4, E-28029 Madrid, Spain.

Plitidepsin (PharmaMar SA) is a cyclodepsipeptide originally isolated from the Mediterranean tunicate Aplidium albicans, and has demonstrated strong anticancer activity against a large variety of cultured human cancer cells and in xenografted mice. Phase I/II clinical trials of plitidepsin yielded promising results of anticancer activity in patients with cancer. Several studies have revealed that plitidepsin induces cell cycle arrest or apoptosis in a cell type- and dose-dependent manner. These effects are related to the induction of early oxidative stress, the activation of Rac1 GTPase and the inhibition of protein phosphatases, which in conjunction cause the sustained activation of JNK and p38 MAPK. This review outlines the current knowledge of plitidepsin activity, with a primary focus on the molecular mechanisms of action of the compound.

Aplidin Inicia la Fase III para Tratar el Myeloma Multiple .

P.D. : Como BioFarmaceutica Oncologica supone un Exito importantisimo y todo un logro en su Apuesta en la I+D Marina . Un Farmaco ya en el Mercado ( Yondelis ) y un Segundo Farmaco ( Aplidin ) ya en Fase III , una Fase III Pivotal que Pharma Mar llevara a cabo en Solitario .

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PharmaMar inicia una Fase III de registro de Aplidin® en pacientes con mieloma múltiple recurrente

Madrid, 8 de junio de 2010:

PharmaMar SA (Grupo Zeltia, ZEL.MC) ha anunciado el inicio de un ensayo clínico de registro con Aplidin® (plitidepsin) en combinación con dexametasona, comparado con dexametasona como agente único, para el tratamiento del mieloma múltiple recurrente.

El ensayo clínico internacional multicéntrico de Fase III pivotal con Aplidin® para mieloma múltiple, llamado ADMYRE, se llevará a cabo en 60 centros de 20 países (incluidos Estados Unidos, Europa, Asia y América del Sur). Involucrará a 300 pacientes, con un periodo establecido de reclutamiento de 24 meses. El objetivo primario del ensayo ADMYRE es supervivencia libre de progresión.

Aplidin® es un agente antitumoral descubierto en el tunicado mediterráneo



Aplidium albicans y obtenido actualmente por síntesis química. Es el segundo compuesto más avanzado en desarrollo clínico de PharmaMar.

NUEVA TÉCNICA CONTRA CÁNCER DE MAMA , En Reino Unido .

"Estamos lejos de desterrar la quimio" .

Un arsenal de 800 fármacos inteligentes acecha al cáncer .