Zepsyre ASCO18 - 2 de Junio . PM01183 ( Lurbinectedin ) Combinado con el Fármaco de ROCHE Xeloda ( Capecitabine ) . Resultados de Fase I en Pacientes con Cáncer De Mama Metastásico .

Anti-Tumor Activity of PM1183 (Lurbinectedin) in Combination with Capecitabine in Metastatic Breast Cancer Patients :

 Results from a Phase I Trial.

Presented Saturday, June 2, 2018

Authors:

Ahmad Awada, Philippe Georges Aftimos, Emiliano Calvo, Valentina Boni, Victor Moreno, Bernard Doger, Xarles Erik Luepke, Katrin Zaragoza, Mariano Siguero, Carmen Maria Kahatt, Arturo Soto-Matos, Tamara Sauri, Josep Tabernero; Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; START Madrid, Madrid, Spain; START Madrid CIOCC, Hospital HM... View More
Abstract Disclosures

Background:

PM1183 (lurbinectedin, Zepsyre) is a new anticancer drug that blocks transcription, induces DNA double-strand breaks, and modulates the tumor microenvironment. Single-agent PM1183 has antitumor activity in various solid tumors, including metastatic breast cancer (MBC), and pre-clinical synergism/additivity with fluoropyrimidines. A phase I trial determined the recommended dose (RD) for the oral fluoropyrimidine capecitabine (XEL) as 1650mg/m2 BID Day (D) 1 to D14 plus PM1183 2.2 mg/m2 D1, every 3 weeks. Here we present results of the MBC patients (pts) treated in this trial.

Methods:

MBC pts with adequate organ function and < 3 prior chemotherapy lines for advanced disease were treated with PM1183+XEL until disease progression, or unacceptable toxicity. Stable asymptomatic brain metastases were allowed.

Results:

A total of 28 female MBC pts were treated between April 2013 and September 2016; 15 at RD. At cut-off, 5 pts (3 at RD) were still on treatment. Baseline characteristics and efficacy data are shown in Table 1. At RD, hematological toxicities consisted of neutropenia [40% grade (G) 3; 7% G4] and anemia (13% G3). No febrile neutropenia was observed. Non-hematological toxicities were generally mild to moderate, including nausea, fatigue, palmar-plantar erythrodysesthesia syndrome, diarrhea, and decreased appetite. All AEs were reversible and manageable with dose reductions, omissions and/or delays. Main dose-limiting toxicities (DLTs) at maximum tolerated dose were hematological.

Conclusions:

The PM1183+XEL combination showed encouraging clinical activity in MB. Further development is warranted in this indication.

Resumen :

*.- La Combinación PM1183 + XELODA ha Mostrado una Actividad Clínica Alentadora en Cáncer de Mama Metastásico .

*.- El Desarrollo Adicional está Garantizado en esta Indicación .

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Zepsyre ASCO18 - 2 de Junio . Resultados Finales de la Fase II para el Tratamiento de Sarcoma de EWING .

Efficacy and Safety of Lurbinectedin (PM1183) in Ewing Sarcoma : Final Results from a Phase 2 Study.

Time : Saturday June 2 .

Author(s):

 Vivek Subbiah, Kamalesh Kumar Sankhala, Ravin Ratan, Enrique Sanz Garcia, Valentina Boni, Thierry Gil, Victor Manuel Villalobos, Sant P Chawla, Pilar Lardelli, Mariano Siguero, Carmen Maria Kahatt, Arturo Soto-Matos, Stefano Ferrari; The University of Texas MD Anderson Cancer Center, Houston, TX; Sarcoma Oncology Center, Santa Monica, CA; Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; Hospital Vall D’Hebron, Barcelona, ES; START Madrid CIOCC Hospital Universitario Sanchinarro, Madrid, Spain; Institut Jules Bordet, Brussels, Belgium; University of Colorado, Denver, CO; PharmaMar, Madrid, Spain; Istituto Ortopedico Rizzoli, Bologna, Italy

Abstract Disclosures
Abstract:

Background: Patients (pts) with relapsed Ewing sarcoma (ES) have a poor outcome. New therapeutic agents are needed. L is a new anticancer drug that blocks transcription and induces DNA double-strand breaks, leading to apoptosis. Moreover, in sarcomas associated with translocations, such as ES, in which the translocation produces a fusion protein that acts as a deregulated transcription factor, L might interfere with the binding of this protein to specific DNA promoters and thus with the synthesis of downstream proteins.

 Methods:

 A multicenter phase 2 trial to assess efficacy and safety of L in several types of advanced solid tumors (basket trial), including ES, is ongoing. In the ES cohort, 15 adult pts who had received no more than two prior chemotherapy regimens for advanced disease were recruited. If one confirmed response was observed, recruitment was to be increased to at least 25 evaluable patients. The study treatment was lurbinectedin 3.2 mg/m2 in a 1-hour infusion every 3 weeks.

 Results: 

28 evaluable pts were enrolled. Median age was 33 years (range, 18-74) and 16 (57%) were males. 26 (93%) had an ECOG of 0/1. ES was extraosseous in 15 pts; 7 pts had ≥3 disease sites and 27 had received ≥2 lines of prior chemotherapy. 28 pts received a median of 4 cycles of L (range, 1-12) and a median total dose of 11.9 mg/m2 (range, 3.2-38.4). 

Efficacy: 

4 pts (14.3%) had a partial response and 12 (42.8%) had disease stabilization, 6 of them for  4 months. Median duration of the response was 2.9 months (range, 2.9-5.5) and median progression-free survival was 2.8 months (CI 95% 1.4-4.2). 

Safety: 

Most common adverse events were related to myelosuppression: 53.6% neutropenia grade (G) 3/4, 14.3% febrile neutropenia, and 18% thrombocytopenia G 3/4; 6 pts had dose delay due to neutropenia G 2-4 or thrombocytopenia G1, and 6 pts had dose reduced because of neutropenia G2-4. G-CSF was given to 12 pts. There were no withdrawals or deaths due to toxicity. 

Conclusions: 

L as a single agent has shown activity in pretreated pts with advanced ES, with acceptable safety profile and tolerability. Myelotoxicity was well controlled with dose adjustments and G-CSF. Further and larger studies of L alone or in combination regimens are warranted for pts with advanced ES.

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Yondelis ASCO18 - 2 de Junio . Trabectedin más RadioTerapia . Resultados de Fase I-II en el que han Colaborado el GEIS de España , el ISG de Italia y el FSG de Francia .

Multi-institutional European phase I/II trial of trabectedin plus radiotherapy in metastaticsoft tissue sarcoma (STS) patients. A Collaborative Spanish (GEIS), Italian (ISG) and French (FSG) Sarcoma Groups study.

Presented Saturday, June 2, 2018 .

Authors:

Javier Martin Broto, Antonio Lopez-Pousa, Nadia Hindi, Josefina Cruz, Javier Peinado, Carlo Morosi, Josep Isern, Maria Carmen Dolado, Rosa Maria Alvarez Alvarez, Ana Alvarez, Giovanni Grignani, Marco Gatti, Pablo Luna Fra, Ignacio Alastuey, Jean-Yves Blay, Marie-Pierre Sunyach, Inmaculada Rincon, Alessandro Gronchi, Jesus Romero; Virgen del Rocio University Hospital, Institute of Biomedicine... View More

Abstract Disclosures
Background:

Patients (pts) with advanced STS who require tumor shrinkage beyond first line, have very limited options since the approved drugs exhibit less than 10% of RECIST response. Trabectedin (T) had shown preclinical synergy with radiotherapy (RT). Low-dose RT concurrent with T was conducted in a phase I/II trial as a proof-of-concept of synergy. We present here data from the phase I (pulmonary metastatic cohort)

Methods:

Pts received T along with RT (30 Gy) in 10 fractions (3Gy/fr). Dose Levels for T were: -1 (1.1 mg/m2), 1 (1.3 mg/m2) and 2 (1.5 mg/m2). Dose level 1 was expanded for a better cardiotoxicity assessment. Dose-limiting toxicity (DLT) were defined as grade ≥3 events excluding G3/4 neutropenia lasting < 5 days, G3 transaminitis if not led to T delay and G3-4 nausea/vomiting due to inadequate prophylaxis. Primary endpoint was response rate according to RECIST Results: From 04/2015 to 06/2017, 18 pts were enrolled. Histologies were: synovial sarcoma in 10 (56%) pts, UPS in 3 (17%), myxoid liposarcoma, dedifferentiated liposarcoma, G3 NOS sarcoma, leiomyosarcoma and MPNST in 1 pts each. Median previous lines 1 (0-3). Twelve pts received T at dose level 1 and 6 pts at level 2. Overall, G 3/4 AEs were: neutropenia (8), ALT elevation (2), GGT elevation (2), anemia (2), febrile neutropenia and pneumonitis (1 each). There were two DLTs: Transient G4 ALT elevation in level 1 and G4 neutropenia ( > 5 days) in level 2. Based on central radiological review and 17 evaluable pts, 2 pts achieved CR (12%), 3 PR (18%), 6 SD (35%), 6 PD (35%). On local review, we found 2 CR (12%), 5 PR (29%), 4 SD (24%), 6 PD (35%). On the irradiated lesions, 4 CR (24%), 8 PR (47%), 4 SD (24%) and 1 PD (5%) were found. With a median FU of 18 m, median PFS was 2.83 (2.3-3.3). Thirteen pts (72%) have died, with a median OS of 8.77 m (3.6-13.9) and 12-month OS rate of 48% .

Conclusions:

T concurrent with RT was feasible in pts with pulmonary metastatic STS regardless of histologic subtype. T at 1.5 mg/m2 is the recommended dose for phase II part. We confirmed the synergy of T+RT, with 71% of the irradiated lesions showing long-lasting dimensional responses. Clinical trial information: NCT02275286 .

Resumen : 

*.- Yondelis más RadioTerapia fue Factible en Pacientes con Sarcoma Metastásico Pulmonar Independientemente del Subtipo Histológico.

*.- Yondelis a 1.5 mg / m2 es la Dosis Recomendada para el Ensayo de la fase II.

*.- Confirmamos la Sinergia de Yondelis + RadioTerapia, con el 71% de las Lesiones Irradiadas que Muestran Respuestas Dimensionales de Larga Duración.

Yondelis ASCO18 - 2 de Junio . Ensayo en Combinación Triple de Fase I-II con Inmunoterapia para el Tratamiento de Sarcomas en Pacientes de Primera Linea

Phase 1/2 Study of Safety/Efficacy using Trabectedin, Ipilimumab and Nivolumab Triple Therapy as First Line Treatment of Advanced Soft Tissue Sarcoma.

Presented Saturday, June 2, 2018

Authors:

Erlinda Maria Gordon, Victoria S. Chua-Alcala, Katherine Kim, Shiva Sreenath Andrali, Marie Del Rosario, William W. Tseng, Seth Pollack, Sant P. Chawla, Sarcoma Oncology Research Center; Sarcoma Oncology Center, Santa Monica, CA; Sarcoma Oncology Research Center, Santa Monica, CA; The University of Texas MD Anderson Cancer Center, Houston, TX; Fred Hutchinson Cancer Research Center, Seattle, WA

Abstract Disclosures
Background:

Sarcoma cells are most immunogenic at the onset of cancer when the immune system can recognize and destroy them (Schreiber 2011). Hence, immune checkpoint inhibitors would be most effective when given as first line therapy. Objectives: Primary: To investigate the maximum tolerated dose of trabectedin, an alkylating agent, when given sequentially with ipilimumab, a CTLA4 inhibitor, and nivolumab, a PD-1 inhibitor, in advanced STS. Secondary: To investigate the objective response rate (ORR), progression free survival (PFS) and overall survival (OS). Exploratory: To correlate PFS with PD-L1 and other biomarker expression in patients’ tumors.

Methods:

Forty patients + -18 years of age with advanced STS will be enrolled. This is an open label, dose-seeking phase ½ study using a defined dose of ipilimumab (1 mg/kg i.v. q 12 weeks), nivolumab (3 mg/kg i.v. q 2 weeks), and escalating doses of trabectedin (1.0, 1.3, 1.5 mg/m2 i.v. q 3 weeks). I. Dose Escalation Phase 1 (previously treated patients): The study will employ the standard “cohort of three” design. The maximum tolerated dose is defined as the highest safely tolerated dose, where not more than one patient experienced DLT, with the next higher dose level having at least two patients who experienced DLT. II.

 Expansion Phase 2 (previously untreated patients): An additional 22-28 patients will receive trabectedin at the MTD and defined doses of ipilimumab and nivolumab to assess overall safety and potential efficacy in a greater number of patients. Patients may continue treatment until significant disease progression or unacceptable toxicity occurs. 

Statistical Considerations: 

NIH CTCAE v4.03 and RECIST v1.1 will be used. Categorical variables will be summarized by the n and percent in each category. Point estimates for efficacy endpoint incidences will be accompanied by a 2-sided 95% exact binomial CI. Time to event endpoints will be summarized descriptively using the KM method. The analyses of all study objectives will be descriptive and hypothesis generating, for planning Phase 2/3 studies. 

Yondelis ASCO18 - 2 de Junio . Whole Exome Sequencing (WES) of Metastatic Leiomyosarcoma (LMS) and Liposarcoma (LPS) and Correlation of Genomic Aberrations with Clinical Outcomes in the Phase III Randomized Trial of Trabectedin (T) vs. Dacarbazine (D).

Presented Saturday, June 2, 2018

Authors:

Gurpreet Kapoor, Weimin Li, Dong Shen, Roland Elmar Knoblauch, Michael Gormley, George C. Wang, Deborah S. Ricci, Michael P. Smith, Clifford Motley, Sigrid Malbrain, Robert G. Maki, Margaret vonMehren, Shreyaskumar Patel, George D. Demetri; Scientific Operations, LabConnect LLC, Seattle, WA; Janssen Research and Development, LLC, Spring House, PA; Janssen Research & Development, LLC,... View More

Abstract Disclosures
Background:

This phase 3 study (NCT01343277) showed statistically significant improvement in disease control by T vs. D in patients (pts) with metastatic LMS and LPS (Demetri et al., JCO, 2016). WES was done to explore associations between genomic alterations and clinical outcomes in this prospective database.

Methods:

Of 518 pts enrolled on study, archival tumor samples were collected from 456 (88%) pts: 180 uterine LMS (uLMS), 149 non-uterine LMS (non-uLMS), 66 de-differentiated LPS (ddLPS), 46 myxoid LPS (mLPS) and 15 pleomorphic LPS (pLPS). Peripheral blood samples from a subset of 346 patients were also analyzed as matched normal to filter noise from nonpathogenic variants in WES.

Results:

Consistent with sarcoma TCGA data, these LMS and LPS samples had frequent homozygous gene deletions with relatively low mutational load. TP53 & RB1 alterations were frequent in LMS compared to LPS, and showed no association with clinical outcomes. Analyses of 103 DNA damage response (DDR) genes showed frequent ( > 20%) somatic alterations across subtypes, correlating with improved PFS only in uLMS tumors (HR: 0.63, p = 0.03). Genomic alterations in PI3K pathway genes were noted in 30% of mLPS and associated with worse PFS (HR: 3.0, p = 0.045). A trend towards better OS was noted in ddLPS tumors with MDM2 amplification (90%) compared to normal MDM2 copy number. Certain subtype-specific genomic aberrations in immune modulation pathways (uLMS and ddLPS) were associated with worse clinical outcomes, whereas alterations in immune suppressors (non-uLMS) and lipid metabolism (ddLPS) were associated with improved clinical outcomes.

Conclusions:

This detailed genomic analysis of a large cohort of metastatic LMS and LPS pts matched with prospective data on treatment outcomes suggests that aberrations in oncogenic pathways (DDR, PI3K, MDM2-p53) and immune modulation may contribute to response or resistance to treatment with T or D. Further analyses should inform our understanding of sarcomas and may aid clinical decision making for LMS and LPS.

Yondelis ASCO18 - 2 de Junio . Impact of pathological stratification of advanced well differentiated/dedifferentiated (WD/DD) liposarcoma (LPS) on the response to trabectedin (T).

Presented Saturday, June 2, 2018 .

Authors:

Roberta Sanfilippo, Elena Fumagalli, Paola Collini, Giovanni Fucà, Salvatore Lorenzo Renne, Marta Barisella, Rossella Bertulli, Salvatore Provenzano, Carlo Morosi, Alessandro Gronchi, Angelo Paolo Dei Tos, Paolo Giovanni Casali; Medical Oncology Unit 2, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Pathology, Fondazione IRCCS... View More


Abstract Disclosures
Background:

Recently, we showed that the FNCLCC grading system can prognosticate the outcome of retroperitoneal LPS. We aimed to explore the impact of pathological stratification using the FNCLCC grading system on the response to Trabectedin (T) of advanced/metastatic WD/DD LPS.

Methods:

We analyzed patients (pts) with advanced WD/DD LPS and treated with T at our Institution for whom formalin-fixed paraffin-embedded (FFPE) tumor samples were available. Histologically, samples were categorized according to the 2013 WHO classification, complemented by Evans’ refinements. The “cellular subvariant” (CS) was diagnosed in the presence of a non-lipogenic area with a mitotic count < 5/10HPF. In cases in which the mitotic count was ≥5/10 HPF, the diagnosis was DDLPS and graded as 2 or 3 according to the FNCLCC grading system. Patients were divided into two subgroups: WDLPS/CS and G2/G3 DDLPS. Response rate (RR) and progression-free survival (PFS) were compared using the Fisher’s exact test and the log-rank test, respectively.

Results:

We included a total of 39 pts with advanced WD/DD LPS treated with T from April 2003 up to present. In 21 pts the sample analyzed was the primitive tumor prior to starting any systemic treatment. In 18 pts we analyzed the sample obtained at the closest date to T initiation. Four patients had a WDLPS, 7 a CS, 21 a G2 DDLPS and 7 a G3 DDLPS. In the subgroup of 11 WDLPS/CS, 5 partial responses, two minor responses and two stable diseases were observed, while in the subgroup of 28 G2/G3 DDLPS we observed one PR and 13 SD. RR was 45% for WDLPS/CS versus 4% for G2/G3 DDLPS (p = 0.0165). Median PFS was 14 months for WDLPS/CS and 3 months for G2/G3 DDLPS (HR 0.28; 95% CI 0.14-0.59; p = 0.0006).

Conclusions:

In this series, sensitivity to T was higher in WDLPS/CS. If what suggested by this limited retrospective case series analysis were confirmed on larger series, WD/CS vs G2/G3 DD histologies could serve as predictive factors for T in advanced WD/DD LPS.

Zepsyre ( PM1183 ) . Development and validation of a liquid chromatography-tandem mass spectrometry assay for the quantification of lurbinectedin in human plasma and urine .

Journal of Pharmaceutical and Biomedical Analysis.
Available online 1 June 2018.

Lvan Andela , H. Rosinga, R. Lubomirov, P. Avilés, S. Fudio, M.M. Tibbena, L. Nan-Offeringa, J.H.M. Schellens , J.H. Beijnena .

Highlights

• A rapid and sensitive LC-MS/MS method developed to quantify lurbinectedin in human plasma and urine.

• The assay has successfully been validated in the 0.1–100 and 1–1,000 ng/mL ranges .

• The assay was successfully applied for quantification of lurbinectedin in plasma and urine in a mass balance study .

Abstract

Lurbinectedin is a novel highly selective inhibitor of RNA polymerase II triggering caspase-dependent apoptosis of cancerous cells.

This article describes the development and validation of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay to quantify lurbinectedin in human plasma and urine. 

Plasma samples were pre-treated with 1 M aqueous ammonia after which they were brought onto supported liquid extraction (SLE) columns. 
Lurbinectedin was eluted from the columns using tert-butyl methyl ether (TBME).

Urine was first diluted in plasma and lurbinectedin was extracted from this matrix by liquid-liquid extraction using TBME. Samples were measured by LC-MS/MS in the positive electron ion spray mode.

The method was linear over 0.1–100 ng/mL and 1–1000 ng/mL in plasma and urine, respectively, with accuracies and precisions within ±15% (20% for LLOQ) and below 15% (20% for LLOQ), respectively.

The method was developed to support a mass balance study in which patients received a dose of 5 mg lurbinectedin.