Author(s): Mariano Provencio Pulla, Josep Tabernero, Victor Moreno, Jose Manuel Trigo Perez, Rafael Lopez, Rebecca Kristeleit, Ahmad Awada, Alexandra Leary, Jerome Alexandre, Jean-Pierre Delord, Stefano Ferrari, Armando Santoro, Emilio Bajetta, Vivek Subbiah, Steven Weitman, Victor Manuel Villalobos, Eric Raymond, Anna Sundlov, Pilar Lardelli, Sant P. Chawla; Hospital Puerta de Hierro, Madrid, Spain; Vall d’Hebron University Hospital, Barcelona, Spain; Fundación Jiménez Díaz, Madrid, Spain; Hospital Universitario Virgen de la Victoria, Malaga, Spain; Hospital Clinico Universitario de Santiago de Compostela, Santiago De Compostela, Spain; University College London Hospitals, London, United Kingdom; Jules Bordet Institute, Bruxelles, Belgium; Institut de Cancérologie Gustave Roussy, Villejuif, France; Medical Oncology, Paris Descartes University, Cochin - Port Royal Hospital, AP-HP, Paris, France; Institut Claudius Regaud, Department of Medicine, Toulouse, France; Istituto Ortopedico Rizzoli, Bologna, Italy; Istituto Clinico Humanitas, Rozzano Milano, MI, Italy; Istituto di Oncologia, Policlinico di Monza, Monza, Italy; Department of Investigational Cancer Therapeutics (Phase 1 Program), The University of Texas MD Anderson Cancer Center, Houston, TX; Cancer Therapy & Research Center's, San Antonio, TX; University of Colorado Cancer Center, Aurora, CO; CHUV, Lausanne, Switzerland; University Hospital of Skåne, Malmö, Sweden; PharmaMar, Madrid, Spain; Sarcoma Oncology Center, Santa Monica, CA
Abstract Disclosures
Abstract:
Background: PM01183 (lurbinectedin) is a new anticancer drug that binds to the DNA minor groove and blocks trans-activated transcription, inducing formation of double-strand DNA breaks leading to cell apoptosis. COMPARE analysis revealed that lurbinectedin’s mechanism of action differs from the other 98 chemotherapy agents tested Advanced small cell lung cancer (SLCL), neuroendocrine tumors (NET), head and neck (H&N), biliary tract and endometrial carcinoma, BRCA1/2-associated metastatic breast cancer, carcinoma of unknown primary site, germinal cell tumors and Ewing family of tumors represent unmet medical needs.
Cytotoxic chemotherapy remains a major component of their therapeutic armamentarium but new anticancer agents are needed to broaden clinical benefit.
PM01183 has already shown clinical activity in BRCA1/2 breast cancer, SCLC, endometrial carcinoma, NET, H&N and in tumors with high proliferation index.
This exploratory phase 2 trial has been designed to confirm the PM01183 anticancer activity, as a single agent, in several difficult-to-treat tumors.
Methods: Primary objective: antitumor activity of PM01183 in terms of response rate by RECIST v.1.1, in the aforementioned indications.
Secondary objectives: duration of response, clinical benefit, progression-free survival and 1-year overall survival in each tumor type. Pharmacokinetics, pharmacogenomic analyses of potential prognostic/predictive factors. Safety profile. Patients with each tumor type will be enrolled in nine cohorts. Up to 25 evaluable patients are planned to be recruited in each of them.
To consider PM01183 active in the tumors analyzed, at least two confirmed responses in the 25 patients of each cohort are expected. If no responses are observed in the first 15 evaluable patients of each cohort, the accrual of this cohort will be stopped. If one confirmed response is observed in the first 15 evaluable patients, recruitment of this cohort will continue to 25 patients. Patients will receive PM01183 i.v. as a 1 hour infusion, every three weeks at a dose of 4 mg/m2. In patients with ECOG PS = 2 or > 70-years-old, dose will be 3 mg/m2.
Twenty six centers in 8 countries participate in this trial.
Author(s): Robert L. Coleman, Bradley J. Monk, Roland Elmar Knoblauch, Trilok V. Parekh, Spyros Triantos, Raymond Scott Maul, Youn Choi Park, Thomas J Herzog; The University of Texas MD Anderson Cancer Center, Houston, TX; Division of Gynecologic Oncology, University of Arizona Cancer Center, Phoenix, AZ; Janssen Research & Development, LLC, Raritan, NJ; Division of Gynecologic Oncology, The University of Cincinnati Cancer Institute, Cincinnati, OH
Abstract Disclosures
Abstract:
Background:
Ovarian cancer (OVC) is the eighth most common cancer among women globally, with approximately 60%–70% of cases being diagnosed at an advanced stage (III or IV). Five-year survival rate for advanced stages is under 40%. In a previous pivotal trial, patients with OVC who relapsed after first-line platinum-based chemotherapy (PCT) demonstrated superior progression free survival when treated with the T+PLD combination vs. PLD monotherapy (7.3 vs. 5.8 months; HR = 0.79; p = 0.019). In a subgroup analysis by platinum free interval, T+PLD showed an improved overall survival (OS) for patients with Platinum Free Interval of 6–12 months (HR = 0.64) (J Clin Oncol. 2010 28:3107-14.).
Given this demonstrated efficacy, we are conducting a global phase III registration trial to investigate the OS of T+PLD vs. PLD in patients with platinum sensitive epithelial OVC, peritoneal or fallopian tube cancer, in the third-line setting. Methods: In this open-label, active-controlled trial, approximately 670 women who have received 2 prior lines of PCT will be enrolled at approximately 135 sites in 9 countries.
Key inclusion criteria: all women must be platinum sensitive (defined as no evidence of disease progression for ≥ 6 months after the last dose of first-line PCT), and demonstrated a partial or complete response to second line PCT. Key exclusion criteria: OVC with mucinous histology and > 2 prior lines of chemotherapy.
Patients will be stratified by Platinum Free Interval, ECOG performance status, BRCA 1 or 2 mutation status, and prior PLD therapy. Stratified patients will be randomized (1:1) to receive PLD (30 mg/m2, 1.5 h, i.v.) followed by T (1.1 mg/m2, 3 h, i.v.) every 3 weeks or PLD alone (50 mg/m2, 1.5 h, i.v.) every 4 weeks. Primary endpoint is OS.
Secondary endpoints include progression free survival, overall response rate (ORR), safety, and pharmacokinetics of T. Planned study duration is 64 months. An interim OS analysis is planned after 308 events.
Final OS analysis will be done after ≥ 514 events have been observed. As of 19 January 2015, 145 patients have been randomized (ClinicalTrials.gov #: NCT01846611).
Author(s): Masashi Takano, Hiroko Kouta, Kazuya Kudoh, Tsunekazu Kita, Ryoko Kikuchi, Morikazu Miyamoto, Tomoyuki Yoshikawa, Tomoko Goto, Kenichi Furuya, Yutaka Tamada, Arata Suga, Yoshihiro Kikuchi; National Defense Medical College, Tokorozawa, Japan; Tama-Hokubu Medical Center, Higashimurayama, Japan; Nara Prefectural Nara Hospital, Nara, Japan; Kyoundo Hospital, Chiyoda, Japan; Tachikawa Hospital, Tachikawa, Japan; Koshigaya City Hospital, Koshigaya, Japan; Ohki Memorial Kikuchi Cancer Center for Women, Tokorozawa, Japan
Abstract Disclosures
Abstract:
Background: Recurrent clear cell carcinoma (RCCC) of the ovary showed exceedingly chemo-resistant phenotype, especially in the case with recurrent or refractory to previous therapy. A phase II trial to evaluate the effect of combination therapy with temsirolimus and trabectedin for patients with RCCC was performed.
Methods: Eligible patients were as follows: (a) ECOG PS = 0~2 (b) histologically confirmed ovarian clear cell adenocarcinoma (c) diagnosed as platinum-resistant ovarian cancer (d) written informed consent.
Patients with RCCC were treated with weekly regimen using two drugs: 15mg/m2 of temsirolimus and 0.15mg/m2 of trabectedin (3 weeks, one week rest).
Treatment was continued until development of progressive disease (PD) or unmanageable adverse effects. There was no significant difference of serum level of VEGF according to the response evaluation. Biomarker analyses including serum VEGF and BNP were also conducted.
Results: A total of 21 patients were analyzed in the present study.
There were no cases that discontinued the therapy due to toxicities. Median age was 59 years (range: 30-69), and median number of previous chemotherapy was 3 (range: 1-6). All cases were assessable by RECIST and CTCAE.
One patient (5%) had a complete response (CR), and two cases (10%) achieved a partial response (PR), and 6 patients (29%) had a stable disease (SD) beyond three months, resulting in clinical benefit rate (CBR; CR+PR+SD > 3month) of 43%.
Median response duration in CBR case was 3.5 months (range: 3-40+). There were no cases that developed toxicities more than grade2. There was no significant difference of serum level of VEGF according to the response evaluation.
Conclusions: Combination therapy with temsirolimus and trabectedin was a candidate for salvage therapy for patients with RCCC. These results warrant further study in such clinical settings with biomarker analyses.
Author(s): Feriel Boumedien, Jean-Philippe Adam, Khalid Akkour, Nathalie LeTarte, Diane M. Provencher; Faculty of Medicine, Université de Montreal, Montreal, QC, Canada; Centre hospitalier de l’Université de Montréal (CHUM), Montreal, QC, Canada; Centre hospitalier de l’Université de Montréal, Montréal (Québec),, Montreal, QC, Canada; CHUM, Montreal, QC, Canada; Centre hospitalier de l'Université de Montréal, Montreal, QC, Canada
Abstract Disclosures
Abstract:
Background: Trabectedin is approved in Canada since 2010 in combination with liposomal doxorubicin for platinum-sensitive ROC in patients who are not expected to benefit, are ineligible or not willing to receive retreatment with platinum-based chemotherapy. In 2012, due to a shortage of liposomal doxorubicin, single agent trabectedin was proposed to patients with ROC. The aim of this study was to evaluate the efficacy and tolerability of trabectedin in this context.
Methods: This retrospective IRB approved study included all patients who received trabectedin for ROC between January 1st 2012 and June 30th 2014 at the CHUM.
This study was not funded.The primary outcome was progression free survival (PFS) based on CA-125 and clinical exam. We also evaluated overall survival (OS), response rate and toxicities (CTCAE v4.0). PFS and OS were estimated by Kaplan-Meier method.
Results: A total of 25 evaluable patients with a median age of 59 years received trabectedin 1.3 mg/m2 I.V. in 3 hours every 3 weeks in 3rd or 4th line (36%), 5th or 6th line (36%) and ≥ 7 lines (28%). Among the patients, 60% were platinum-sensitive and 40% platinum-resistant.
The median number of cycles received was 5 (range 1-16 cycles) for a total of 130 cycles.
" Complete Response " (CR), partial response (PR), stable disease (SD) and progression occurred in 16%, 20%, 24% and 40% of patients respectively.
The median PFS was 3.7 months (95% CI 1.9-5.6). In patients with a response (CR, PR, SD), the median PFS was 4.9 vs 0.8 months (p < 0.001). Death occurred in 15 patients (60%).
The median OS was 16.2 months. The Cox model reported that response to treatment is the only variable influencing the PFS and the OS (p < 0.001), but not the platinum status or the number of previous lines received. Grade 3 or 4 toxicities include: neutropenia (8%), febrile neutropenia (4%) and muscle weakness (4%). Dose reduction was required in 4 patients for hepatic and hematologic toxicities. No death was attributable to toxicities.
Conclusions: Our results demonstrate that trabectedin has an interesting efficacy as a single agent in heavily treated ROC patients. At a dose of 1.3 mg/m2 every 3 weeks, trabectedin is well tolerated with few adverse events.
Por LINDSEY TANNER // Associated Press .
Por primera vez, un estudio numeroso demuestra que un fármaco que activa el sistema inmunológico podría mejorar la supervivencia en los pacientes del tipo más común de cáncer pulmonar.
Esta nueva clase de fármacos ha transformado el tratamiento del melanoma, la variante más mortífera del cáncer de piel. Los estudios presentados el viernes en una conferencia indican que estas "terapias inmunológicas" pueden desempeñar un papel más amplio en formas más comunes del cáncer, incluso de pulmón, hígado, colon, cabeza y cuello.
Los médicos también podrían haber hallado un modo de pronosticar qué pacientes responderán mejor a algunos de estos tratamientos más nuevos, según una investigación presentada en la reunión de Chicago. Los fármacos de la terapia inmunológica se proponen ayudar al sistema inmunológico a reconocer y atacar el cáncer.
El estudio sobre cáncer pulmonar puso a prueba Opdivo, de Bristol-Myers Squibb, que bloquea una proteína que impide al sistema inmunológico atacar las células cancerosas. Funcionó mejor que la quimioterapia para los pacientes con una variedad de cáncer pulmonar diagnosticada en más de 120.000 personas en Estados Unidos cada año.
Opdivo, también llamado nivolumab, fue aprobada en marzo para una forma menos común de cáncer pulmonar, y el año pasado para el melanoma. También se aprobaron otras dos inmunoterapias para el melanoma: Keytruda y Yervoy.
"Estos fármacos se encuentran entre los más promisorios en muchos años", afirmó el doctor Richard Schilsky, director médico de la Sociedad Estadounidense de Oncología Clínica, organizadora del encuentro. "Lo que estamos viendo es un mayor alcance para estos fármacos".
Todo éxito en la lucha contra el cáncer pulmonar es bienvenido. Los pacientes suelen ser diagnosticados cuando la enfermedad ya está avanzada. Es el cáncer más mortífero en la nación. Unas 220.000 personas serán diagnosticadas este año y que unas 160.000 morirán, estima la Sociedad Oncológica Estadounidense.
En el nuevo estudio, unos 300 pacientes fueron asignados al azar para recibir infusiones de Opdivo o Docetaxel, un fármaco de quimioterapia, cada dos semanas. La tasa de supervivencia mediana fue de más de 12 meses para los primeros y unos 9 meses para los segundos. La diferencia parecería poco significativa, pero la supervivencia a largo plazo suele ser mínima para estos pacientes.
Los tumores se redujeron en casi el 20% de los pacientes de Opdivo en comparación con un 12% entre los demás.
