Presentado Sabado dia 5 Mayo :
A phase II trial of trabectedin (T) in patients (pts) with HER2-positive and BRCA1/2 germ-line-mutated metastatic breast cancer (MBC).
ABSTRACT Nº 1038 .
Author(s): K. L. Tedesco, J. L. Blum, A. Goncalves, J. Lubinski, N. Ben-Baruch, C. R. Osborne, P. Lardelli, J. C. Tercero, F. A. Holmes, S. Delaloge; US Oncology, New York Oncology Hematology, Albany, NY; Baylor-Charles A. Sammons Cancer Center, Texas Oncology PA, and US Oncology, Dallas, TX; Institut Paoli Calmettes, Marseille, France; International Hereditary Cancer Center, Szczecin, Poland; Kaplan Medical Center, Rehovot, Israel; PharmaMar, Colmenar Viejo, Madrid, Spain; US Oncology Research, Houston, TX; Institut Gustave Roussy, Villejuif, France
Abstract:
Background: Single agent T has shown activity in soft tissue sarcoma (STS), ovarian, and breast carcinoma. The European Commission has approved T for STS treatment in adults after failure of standard therapy and for platinum sensitive relapsed ovarian cancer. In 3 phase II studies T showed antitumor activity in pts with pretreated MBC. Preclinical and clinical data suggested T may display specific activity among certain nucleotide excision repair (NER) intact or homologous recombination repair (HRR) deficient MBC, and prompted this phase II trial. Methods: T was given at 1.3 mg/m2 as a 3-hour iv infusion 3qwks to pts with pretreated progressive MBC: Group A: ER/PR/HER2- negative; Group B: HER2 overexpressed (3+), and Group C: BRCA1/2 mutation carriers. Endpoints were objective response rate by RECIST, duration of response, progression free survival (PFS), safety, and pharmacogenomics (PGx).
Results: Group A was closed due to low response rate; results have already been presented. A total of 55 pts have been enrolled in groups B (31) and C (24) (median [med] age: 53, ECOG 0/1: 25/30); med number of prior chemotherapy lines: 3 (1-8). Med number of T cycles administered: 3 (1-12+) for both groups. Per external review, of 29 evaluable HER2 3+ pts, 3 confirmed partial responses (PR) were observed. From 21 BRCA1/2 mutation carrier pts, there were 3 confirmed PR. 17 (58.6%) and 8 (38.1%) pts in groups B and C achieved stable disease (SD). Two HER2 3+ pts had SD longer than 6 months. Med PFS was 3.9 months in each arm. The most frequent grade 3-4 laboratory disorders were neutropenia (38%) and (57%), and ALT elevations (57%) and (45%) for groups B and C, respectively. Fatigue, nausea, and vomiting were the most common AEs (51%, 39% and 20% for both groups B and C) of mild to moderate severity in the vast majority of pts. Tissue samples from HER2 3+ pts and BRCA mutation carriers were collected for RNA expression analysis (XPG + ERCC1 + BRCA1). Analyses are ongoing.
Conclusions: T showed anti-MBC activity in BRCA1/2 mutation carriers and HER2 3+ pts with a manageable safety profile. Complete efficacy data from groups B and C and PGx results will be discussed to help selecting the MBC patients who are at highest chance for response.
Presentado Sabado 5 de Mayo :
Tolerability of long-term use of trabectedin (Tr) in combination with pegylated liposomal doxorubicin (PLD) in patients (pts) with relapsed ovarian cancer (ROC).
ABSTRACT 5121.
Author(s): I. Romero, N. Colombo, S. B. Kaye, J. Arranz, A. Roszak, D. M. Provencher, P. Santabarbara, E. Bayever, E. Almorin, F. Muggia; Instituto Valenciano de Oncologia, Valencia, Spain; University of Milan-Bicocca, Milan, Italy; The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom; Hospital General Universitario Gregorio Marañon, Madrid, Spain; Wielkopolsice Centrum Oncology, Poznan, Poland; CHUM-Hôpital Notre-Dame, Montreal, QC, Canada; PharmaMar, Colmenar Viejo, Madrid, Spain; Johnson & Johnson Pharmaceutical Research and Development, Raritan, NJ; New York University Medical Center, New York, NY
Abstract:
Background: OVA-301 was an open-label, multicenter, randomized phase III study comparing Tr+ PLD to PLD alone in 672 pts with ROC. The combination significantly improved PFS and RR, with a trend toward longer OS and manageable noncumulative toxicity (Monk, Ann Oncol 2008, Abs. LBA4). Protracted tolerability of Tr 1.1 mg/m2 and PLD 30 mg/m2, 3h-q3weeks vs. PLD 50 mg/m2 1.5h- q4weeks in pts receiving ≥6 cycles was analyzed. Methods: Safety evaluated in 320 (of 663 treated) pts receiving ≥ 6 cycles by adverse events (AEs), laboratory data and physical findings (NCI CTC Version 3.0).
Results: Baseline characteristics were balanced: median age 56 years (26-87); ECOG 0: 68%; median platinum-free interval: 9.2 months; prior taxanes: 78%; papillary/serous histology: 72%.
Conclusions: This novel nonplatinum, nontaxane combination is an efficacious regimen in pts with ROC with reasonable long-term tolerability in pts that received ≥ 6 cycles. Hematological toxicity and transaminase elevations were more common in the combination arm, yet transient, and not cumulative; and less frequent than at <6 cycles. HFS, mucosal inflammation, and stomatitis were more common with PLD. Discontinuation rates due to AEs were low. Updated data will be presented.
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Pts with ≥ 6 cycles Tr + PLD
(173 pts/1,580 cycles) PLD
(147 pts/1,224 cycles)
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Median cycles (range) 8 (6-21) 7 (6-22)
G3-4 hematologic AEs (per cycle) (%)
Neutropenia1/anemia/thrombocytopenia/
febrile neutropenia 40/4/5/1 17/1/1/<1
G3-4 transaminase elevations (per cycle) (%)2,3
AST/ALT 11/2 -/-
Any grade AEs (per cycle) (%)
Hand-foot syndrome(HFS)/mucosal inflammation/
stomatitis/hypersensitivity4 7/3/5/0.3 22/10/11/0.4
Supportive therapies (per cycle) (%)
G- CSF/antianemics 26/14 7/5
Reason for discontinuation (per pts)5
Drug-related AE (mainly neutropenia and
hand-foot syndrome) (%) 9 6
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1 Neutropenia more common at cycle <6 for both arms. 2 No hepatic failures. 3 In contrast to cycle <6: ALT, 95%; AST, 92%. 4 Only occurred in cycle 1-2. 5 Disease progression is most common reason for both arms.
One drug-related death with Tr+PLD: acute myeloid leukemia.
Presentado Sabado 5 de Mayo :
ABSTRTACT 5060 .
Author(s): J. del Campo, T. Ciuleanu, C. Sessa, A. M. Westermann, A. Roszak, S. Chan, T. Hogberg, P. Zintl, Y. C. Park, C. N. Krasner; Vall d'Hebron Hospital, Barcelona, Spain; Institutul Oncologic I. Chiricuta, Cluj-Napoca, Romania; Oncology Institute of Southern Switzerland, Ospedale Regionale Bellinzona e Valli, Bellinzona, Switzerland; Center Department of Medical Oncology, Amsterdam Zuidoost, Netherlands; Wielkopolsice Centrum Oncology, Poznan, Poland; Nottingham University Hospital, Nottingham, United Kingdom; Nordic Society of Gynaecological Oncology, Lund, Sweden; PharmaMar, Colmenar Viejo, Madrid, Spain; Johnson & Johnson Pharmaceutical Research and Development, New Jersey, NJ; Massachusetts General Hospital Gillette Center for Women's Cancer, Boston, MA
Abstract:
Background: A pooled analysis of efficacy with Tr as second/third line in 295 ROC pts demonstrated a median time to progression (TTP) of 4.6 months (mo) (McMeekin, ASCO 2007). Pts sensitive to platinum with a PFI > 6 m (PS), reached a TTP of 6.0 mo, and an overall response rate (ORR) of 36.4% (45.5% in pts with ≥ 2 prior lines). This subanalysis is focused in ROC pts with partially platinum sensitive (PPS) disease, i.e. relapsing between 6-12 m after the end of last prior platinum regimen (PFI:6-12 mo).
Methods: Of the 295 pts, 103 were PPS). Three Tr schedules were studied: weekly (0.58 mg/m2 3-h x3 q4w), and two every 3 weeks (1.3 mg/m2 3-h and 1.5 mg/m2 24-h), that were administered to 41%, 34% and 25% patients, respectively. Efficacy and safety in these patients are reported.
Results: Baseline characteristics: median age 58 years (35-80), ECOG PS 0/1: 72%/27%; papillary/serous histology 76%; histology grade 1-2/3: 28%/58%; liver involvement 35%. Treatment with Tr induced 4% complete responses (CR), 26% partial responses (PR), and 40% stable disease (SD); median response duration (RD:PR+CR) 5.2 mo.(95%CI: 3.9-5.8). Median TTP was 5.3 mo (95%CI: 3.8-6.2); 44% pts were progression free at 6 mo (95%CI: 34%-54%). In pts with liver metastases CR+PR was 36% with median TTP 5.3 mo (95%CI: 3.7-6.5). The most common adverse events were neutropenia and transaminase elevations, which were manageable and without serious clinical consequences.
Conclusions: Tr monotherapy is active in patients with ROC, including patients with PPS disease (PFI 6-12 mo), with a 30% ORR plus 40% SD, with a median TTP of 5.3 mo. Activity was retained in pts with liver metastasis, with 36% ORR and identical TTP. These single-agent results support the findings of the randomized phase III trial OVA-301 where trabectedin + PLD demonstrated superior clinical benefit over PLD alone in the overall population with particularly pronounced efficacy in the PPS cohort.
P.D. : Esta Presentación podría NO estar a Cargo de Pharma Mar .
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A phase II study of the Gynecologic Oncology Group (GOG).
Abstrac 5046 .
Author(s): B. J. Monk, M. Sill, J. L. Walker, P. Hanjani, R. P. Edwards, J. Rotmensch, K. De Geest, A. J. Bonebrake; University of California, Irvine Medical Center, Orange, CA; Gynecologic Oncology Group Statistical and Data Center, Buffalo, NY; University of Oklahoma Health Sciences Center, Oklahoma City, OK; Abington Memorial Hospital, Abington, PA; Magee-Women's Hospital of the University of Pittsburgh Medical Center, Pittsburgh, PA; Rush-Presbyterian St. Luke's Medical Center, Chicago, IL; University of Iowa Hospitals and Clinics, Iowa City, IA; Cancer Research for the Ozarks-Cox Health, Springfield, MO
Background: To estimate the activity of docetaxel 60 mg/m2 IV over 1 hr followed by trabectedin 1.1 mg/m2 over 3 hrs with filgrastim, pegfilgrastim, or sargramostim every 3 weeks (one cycle) until disease progression or adverse effects prohibit further therapy.
Methods: Patients with recurrent and measurable disease, acceptable organ function, and PS ≤ 2 were eligible. The number of prior cytotoxic regimens was limited to 3 (including no more than 1 non-platinum, non-taxane regimen). Patients receiving only 1 prior cytotoxic regimen (platinum-based regimen for management of primary disease) must have had a platinum-free interval of < 12 mo. A two-stage design was utilized with a target sample size of 35 subjects per stage. Another GOG study within the same protocol queue involving a single agent taxane yielded 8 responses (16%) among 49 subjects (90% CI 8.6-28.5%) and served as a historical control for direct comparison. The current study was designed to determine if the current regimen increased the probability of response by 20% with 90% power while limiting the probability of declaring regimens with similar activity as the historical control as being interesting to 10%. The minimum number of responses to declare the regimen interesting was 21
Results: 71 patients were enrolled with 70 being eligible and evaluable at this time (prior regimens:1 = 29%, 2 = 51%, 3 = 20%). The median number of cycles was 6 (396 total cycles). The number of patients responding was 21 (30%; 90% CI 21-40%). The odds ratio for responding was 2.2 (90% 1-sided CI 1.09-Infinity). The median progression-free survival and overall survival was 4.4 mo and 12.5 mo, respectively. The median response duration was 8.4 mo. Numbers of subjects with grade 3/4 toxicity included: neutropenia 6/14; constitutional 8/0; GI (excluding nausea/vomiting) 10/0; metabolic 9/1; pain 6/0. There were no treatment related deaths nor cases of liver failure.
Conclusions: This combination is well tolerated and appears more active than single agent taxane therapy in those with recurrent ovarian and peritoneal cancer after failing multiple lines of chemotherapy. Further study is warranted.
Presentado Sabado dia 5 Mayo :
