We hypothesized that the combination of olaparib and lurbinectedin maximizes DNA damage, thus inc... more We hypothesized that the combination of olaparib and lurbinectedin maximizes DNA damage, thus increasing its efficacy. The POLA phase 1 trial established the recommended phase 2 dose of lurbinectedin as being 1.5 mg (day 1) and that of olaparib as being 250 mg/12 h (days 1–5) for a 21-day cycle. In phase 2, we explore the efficacy of the combination in terms of clinical response and its correlation with mutations in the HRR genes and the genomic instability (GI) parameters. Results: A total of 73 patients with high-grade ovarian (n = 46), endometrial (n = 26), and triple-negative breast cancer (n = 1) were treated with lurbinectedin and olaparib. Most patients (62%) received ≥3 lines of prior therapy. The overall response rate (ORR) and disease control rate (DCR) were 9.6% and 72.6%, respectively. The median progression-free survival (PFS) was 4.54 months (95% CI 3.0–5.2). Twelve (16.4%) patients were considered long-term responders (LTR), with a median PFS of 13.3 months. No clinic...
The poly (ADP-Ribose) polymerase (PARP) inhibitor olaparib has shown antitumor activity in patien... more The poly (ADP-Ribose) polymerase (PARP) inhibitor olaparib has shown antitumor activity in patients with ovarian or breast cancer with or without BRCA1/2 mutations. Lurbinectedin is an ecteinascidin that generates DNA double-strand breaks. We hypothesized that the combination of olaparib and lurbinectedin maximizes the DNA damage increasing the efficacy. A 3 + 3 dose-escalation study examined olaparib tablets with lurbinectedin every 21 days. The purpose of this phase I study is to determine the dose-limiting toxicities (DLTs) of the combination, to investigate the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), efficacy, pharmacokinetics, in addition to genotyping and translational studies. In total, 20 patients with ovarian and endometrial cancers were included. The most common adverse events were asthenia, nausea, vomiting, constipation, abdominal pain, neutropenia, anemia. DLT grade 4 neutropenia was observed in two patients in dose level (DL) 5, DL4 was defi...
10079 Background: Genes involved in cell cycle checkpoints and chromosome stability seem to be re... more 10079 Background: Genes involved in cell cycle checkpoints and chromosome stability seem to be relevant in distant metastases appearance in STS. CUL4A is an E3 ubiquitin ligase that has been related to both p16 activation and maintenance of genomic stability. Expression of CUL4A has been scarcely described in some tumors with divergent outcome and there are no publications regarding its expression in STS patients. We previously showed that protein underexpression of CUL4A in metastatic STS was related to poor survival. Methods: The expression level of CUL4A was determined by quantitative qPCR and was retrospectively performed in a subset of 39 high-risk (grade 3, deep tumours and > than 5 cm) localized STS of limbs or trunk wall patients for which histological material and clinical data were available. Patients of this series were enrolled prospectively into a randomized clinical trial conducted by the Italian and Spanish sarcoma groups (ISG-GEIS 0101) comparing 3 vs 5 cycles of ...
5502 Background: Topotecan was evaluated in a novel combination regimen in comparison to standard... more 5502 Background: Topotecan was evaluated in a novel combination regimen in comparison to standard therapy in front-line EOC. Methods: Women with newly diagnosed advanced EOC stages IIB-IV, ECOG performance status (PS) 0-1, age < 75, were randomized to either Arm 1: cycles 1 - 4: cisplatin 50 mg/m2 d1 plus topotecan 0.75 mg/m2 d1-5 IV; cycles 5 - 8: paclitaxel 175 mg/m2over 3 hrs d1 followed by carboplatin AUC5 day 1 or Arm 2: paclitaxel plus carboplatin as in Arm 1 for 8 cycles. The primary endpoint was progression free survival (PFS) and secondary endpoints included objective response, overall survival (OS), adverse event (AE) and Quality of Life (QoL). The sample size required 800 pts and 631 events to detect an improvement in PFS from 16 to 20 months (power 80%, 2-sided alpha 0.05). Results with 3.6 years median follow-up (MFU) were reported previously: there was no significant difference in PFS (Hoskins P, JNCI 2010). Final results including OS after MFU of 8.2 years are repo...
10500 Background: Nucleotide excision and homologous recombination DNA repair pathways are the mo... more 10500 Background: Nucleotide excision and homologous recombination DNA repair pathways are the most recognized antitumor mechanism of action of trabectedin in STS. Additionally, our group has shown...
Cervical cancer is the fourth most common cancer in women with 85% of the mortality burden occurr... more Cervical cancer is the fourth most common cancer in women with 85% of the mortality burden occurring in less-developed regions of the world. The Cervix Cancer Research Network (CCRN) was founded by the Gynecologic Cancer InterGroup (GCIG) with a mission to improve outcomes in cervix cancer by increasing access to high-quality clinical trials worldwide, with particular attention to less-developed, underrepresented sites. The CCRN held its second international educational symposium in Mexico City with ninety participants from fifteen Latin America countries in January 2017. The purpose of this symposium was to advance knowledge in cervix cancer therapy, promote recruitment to CCRN clinical trials, and to identify relevant future CCRN clinical trial concepts that could improve global care standards for women with cervical cancer.
European journal of cancer (Oxford, England : 1990), 2018
Patients with extremity and trunk wall soft tissue sarcoma (STS) with high malignancy grade and s... more Patients with extremity and trunk wall soft tissue sarcoma (STS) with high malignancy grade and size >5 cm are at high-risk of death. This risk varies depending also on other patient and tumour features, including histologic subtype. This study investigated whether a prognostic nomogram can improve risk assessment of these patients. Data from high-risk STS patients enrolled in a randomised controlled trial investigating different perioperative chemotherapy regimens were analysed. Ten-year probability of overall survival (OS) and incidence of distant metastasis (DM) were computed using the prognostic nomogram Sarculator (pr-OS and inc-DM, respectively). Tumour response according to RECIST and Choi criteria was also investigated. Variation in pr-OS and inc-DM were observed and patients stratified in three prognostic groups. The 10-year OS in the low, intermediate, and high pr-OS categories were 0·42 (95%CI 0·32-0·52), 0·63 (95%CI 0·53-0·72), and 0·78 (95%CI 0·68-0·85), respectively...
9033 Background: Results from a previous phase I trial (ASCO 2003, abst.3317) demonstrated MTD fo... more 9033 Background: Results from a previous phase I trial (ASCO 2003, abst.3317) demonstrated MTD for GMC 800 mg/m2 by 10 mg/m2/min perfusion associated to DXR 60 mg/m2 Methods: April'02 to December'03 36 patients were included in a phase II trial of first-line treatment in advanced STS with DX at 60 mg/m2 (d 1), followed by GMC 800 mgr/m2 administered in 80 minutes (d 1,8) every 3 weeks. Results: 36 patients ECOG 0–2, metastatic/unresectable STS entered the trial. Results from 23 patients: male/ female 13/10; ECOG 0 = 5 pts, 1 = 15 pts, 2 = 3 pts. Median age 56 (23–76)y. Histology: Lipos. 6, MFH 4, Leiomio 2, other 11. Primary tumor: extremities 8, retroperitoneal 7, uterine 2, truncal 2, other 4. A median of 6 (1–9) and a total of 93 cycles (cy) were administered. Toxicity by patient (23): neutropenia grade(G)IV 7 (30%), GIII 9 (39%); anemia GIII 4 (17%), GII 7 (30%); thrombocytopenia GIV 2 (8%), GIII 3 (13%), GII 4 (17%) pts. Neutropenic fever in 5 (21%) pts. Grade III/IV mucositis in 14 (60%) pts. Toxici...
LBA5002^ Background: In three phase III trials in OC (2 front line, 1 PT-sensitive recurrent), BE... more LBA5002^ Background: In three phase III trials in OC (2 front line, 1 PT-sensitive recurrent), BEV + CT → BEV significantly improved progression-free survival (PFS) vs CT alone. AURELIA is the first randomized trial of BEV in PT-resistant OC. Methods: Eligible patients (pts) had OC (measurable by RECIST 1.0 or assessable) that had progressed ≤6 mo after ≥4 cycles of PT-based therapy. Pts with refractory OC, history of bowel obstruction, or >2 prior anticancer regimens were ineligible. After CT selection by the investigator (pegylated liposomal doxorubicin [PLD], topotecan [TOP], or weekly paclitaxel [PAC]), pts were randomized to CT either alone or with BEV (10 mg/kg q2w or 15 mg/kg q3w depending on CT) until progression (PD), unacceptable toxicity, or withdrawal of consent. Pts in the CT-alone arm could cross over to BEV monotherapy at PD. The primary endpoint was PFS by RECIST. Secondary endpoints included objective response rate (ORR), overall survival, safety, and quality of ...
Perivascular epithelioid cell tumors (PEComas) are infrequent neoplasms with peculiar myomelanocy... more Perivascular epithelioid cell tumors (PEComas) are infrequent neoplasms with peculiar myomelanocytic differentiation. The aggressive abdominopelvic variant is rare, with only a small number of published cases. We present an additional case of this unusual variant, which showed an aggressive histologic and clinical behavior with multiple liver metastases and resistance to several therapies. We also discuss the histological and immunohistochemical profiles as well as the differential diagnosis.
Trebananib, a peptibody that blocks binding of angiopoietin-1 and -2 to Tie2, significantly prolo... more Trebananib, a peptibody that blocks binding of angiopoietin-1 and -2 to Tie2, significantly prolonged progression-free survival (PFS) in patients with recurrent epithelial ovarian cancer in the phase 3 TRINOVA-1 study. We report overall survival (OS) in the intent-to-treat population and clinically relevant subgroups and time to second disease progression (PFS-2). Women with recurrent disease (platinum-free interval<12months) were randomized to receive intravenous paclitaxel 80mg/m(2) (3weeks on/1week off) plus intravenous trebananib 15mg/kg or placebo, weekly. OS in the intent-to-treat population was a key secondary endpoint. Exploratory analysis of PFS-2 was conducted according to guidance by the European Medicines Agency. Median OS was not significantly improved with trebananib compared with placebo (19.3 versus 18.3months; HR, 0.95; 95% CI, 0.81-1.11; P=0.52) in the intent-to-treat population (n=919). In subgroup analysis, trebananib improved median OS compared with placebo (...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jul 16, 2016
Doxorubicin and trabectedin are considered active drugs in soft tissue sarcoma (STS). The combina... more Doxorubicin and trabectedin are considered active drugs in soft tissue sarcoma (STS). The combination of both drugs was hypothesized to be advantageous and safe on the basis of preclinical evidence and a previous phase I trial, respectively. The aim of this study was to compare the clinical outcome of trabectedin plus doxorubicin with doxorubicin as first-line treatment of advanced STS patients. In this open-label randomized phase II trial, the main end point was progression-free survival (PFS). Trabectedin 1.1 mg/m(2) in a 3-hour infusion plus doxorubicin 60 mg/m(2) as the experimental arm and doxorubicin 75 mg/m(2) as the control arm were administered for up to six cycles. Translational research was planned to correlate the expression of apoptotic and DNA repair genes with clinical outcome. In 115 randomly assigned patients, the median PFS was 5.5 months in the control arm and 5.7 months in the experimental arm (hazard ratio, 1.16; 95% CI, 0.79 to 1.71; P = .45) in the intent-to-t...
We hypothesized that the combination of olaparib and lurbinectedin maximizes DNA damage, thus inc... more We hypothesized that the combination of olaparib and lurbinectedin maximizes DNA damage, thus increasing its efficacy. The POLA phase 1 trial established the recommended phase 2 dose of lurbinectedin as being 1.5 mg (day 1) and that of olaparib as being 250 mg/12 h (days 1–5) for a 21-day cycle. In phase 2, we explore the efficacy of the combination in terms of clinical response and its correlation with mutations in the HRR genes and the genomic instability (GI) parameters. Results: A total of 73 patients with high-grade ovarian (n = 46), endometrial (n = 26), and triple-negative breast cancer (n = 1) were treated with lurbinectedin and olaparib. Most patients (62%) received ≥3 lines of prior therapy. The overall response rate (ORR) and disease control rate (DCR) were 9.6% and 72.6%, respectively. The median progression-free survival (PFS) was 4.54 months (95% CI 3.0–5.2). Twelve (16.4%) patients were considered long-term responders (LTR), with a median PFS of 13.3 months. No clinic...
The poly (ADP-Ribose) polymerase (PARP) inhibitor olaparib has shown antitumor activity in patien... more The poly (ADP-Ribose) polymerase (PARP) inhibitor olaparib has shown antitumor activity in patients with ovarian or breast cancer with or without BRCA1/2 mutations. Lurbinectedin is an ecteinascidin that generates DNA double-strand breaks. We hypothesized that the combination of olaparib and lurbinectedin maximizes the DNA damage increasing the efficacy. A 3 + 3 dose-escalation study examined olaparib tablets with lurbinectedin every 21 days. The purpose of this phase I study is to determine the dose-limiting toxicities (DLTs) of the combination, to investigate the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), efficacy, pharmacokinetics, in addition to genotyping and translational studies. In total, 20 patients with ovarian and endometrial cancers were included. The most common adverse events were asthenia, nausea, vomiting, constipation, abdominal pain, neutropenia, anemia. DLT grade 4 neutropenia was observed in two patients in dose level (DL) 5, DL4 was defi...
10079 Background: Genes involved in cell cycle checkpoints and chromosome stability seem to be re... more 10079 Background: Genes involved in cell cycle checkpoints and chromosome stability seem to be relevant in distant metastases appearance in STS. CUL4A is an E3 ubiquitin ligase that has been related to both p16 activation and maintenance of genomic stability. Expression of CUL4A has been scarcely described in some tumors with divergent outcome and there are no publications regarding its expression in STS patients. We previously showed that protein underexpression of CUL4A in metastatic STS was related to poor survival. Methods: The expression level of CUL4A was determined by quantitative qPCR and was retrospectively performed in a subset of 39 high-risk (grade 3, deep tumours and > than 5 cm) localized STS of limbs or trunk wall patients for which histological material and clinical data were available. Patients of this series were enrolled prospectively into a randomized clinical trial conducted by the Italian and Spanish sarcoma groups (ISG-GEIS 0101) comparing 3 vs 5 cycles of ...
5502 Background: Topotecan was evaluated in a novel combination regimen in comparison to standard... more 5502 Background: Topotecan was evaluated in a novel combination regimen in comparison to standard therapy in front-line EOC. Methods: Women with newly diagnosed advanced EOC stages IIB-IV, ECOG performance status (PS) 0-1, age < 75, were randomized to either Arm 1: cycles 1 - 4: cisplatin 50 mg/m2 d1 plus topotecan 0.75 mg/m2 d1-5 IV; cycles 5 - 8: paclitaxel 175 mg/m2over 3 hrs d1 followed by carboplatin AUC5 day 1 or Arm 2: paclitaxel plus carboplatin as in Arm 1 for 8 cycles. The primary endpoint was progression free survival (PFS) and secondary endpoints included objective response, overall survival (OS), adverse event (AE) and Quality of Life (QoL). The sample size required 800 pts and 631 events to detect an improvement in PFS from 16 to 20 months (power 80%, 2-sided alpha 0.05). Results with 3.6 years median follow-up (MFU) were reported previously: there was no significant difference in PFS (Hoskins P, JNCI 2010). Final results including OS after MFU of 8.2 years are repo...
10500 Background: Nucleotide excision and homologous recombination DNA repair pathways are the mo... more 10500 Background: Nucleotide excision and homologous recombination DNA repair pathways are the most recognized antitumor mechanism of action of trabectedin in STS. Additionally, our group has shown...
Cervical cancer is the fourth most common cancer in women with 85% of the mortality burden occurr... more Cervical cancer is the fourth most common cancer in women with 85% of the mortality burden occurring in less-developed regions of the world. The Cervix Cancer Research Network (CCRN) was founded by the Gynecologic Cancer InterGroup (GCIG) with a mission to improve outcomes in cervix cancer by increasing access to high-quality clinical trials worldwide, with particular attention to less-developed, underrepresented sites. The CCRN held its second international educational symposium in Mexico City with ninety participants from fifteen Latin America countries in January 2017. The purpose of this symposium was to advance knowledge in cervix cancer therapy, promote recruitment to CCRN clinical trials, and to identify relevant future CCRN clinical trial concepts that could improve global care standards for women with cervical cancer.
European journal of cancer (Oxford, England : 1990), 2018
Patients with extremity and trunk wall soft tissue sarcoma (STS) with high malignancy grade and s... more Patients with extremity and trunk wall soft tissue sarcoma (STS) with high malignancy grade and size >5 cm are at high-risk of death. This risk varies depending also on other patient and tumour features, including histologic subtype. This study investigated whether a prognostic nomogram can improve risk assessment of these patients. Data from high-risk STS patients enrolled in a randomised controlled trial investigating different perioperative chemotherapy regimens were analysed. Ten-year probability of overall survival (OS) and incidence of distant metastasis (DM) were computed using the prognostic nomogram Sarculator (pr-OS and inc-DM, respectively). Tumour response according to RECIST and Choi criteria was also investigated. Variation in pr-OS and inc-DM were observed and patients stratified in three prognostic groups. The 10-year OS in the low, intermediate, and high pr-OS categories were 0·42 (95%CI 0·32-0·52), 0·63 (95%CI 0·53-0·72), and 0·78 (95%CI 0·68-0·85), respectively...
9033 Background: Results from a previous phase I trial (ASCO 2003, abst.3317) demonstrated MTD fo... more 9033 Background: Results from a previous phase I trial (ASCO 2003, abst.3317) demonstrated MTD for GMC 800 mg/m2 by 10 mg/m2/min perfusion associated to DXR 60 mg/m2 Methods: April'02 to December'03 36 patients were included in a phase II trial of first-line treatment in advanced STS with DX at 60 mg/m2 (d 1), followed by GMC 800 mgr/m2 administered in 80 minutes (d 1,8) every 3 weeks. Results: 36 patients ECOG 0–2, metastatic/unresectable STS entered the trial. Results from 23 patients: male/ female 13/10; ECOG 0 = 5 pts, 1 = 15 pts, 2 = 3 pts. Median age 56 (23–76)y. Histology: Lipos. 6, MFH 4, Leiomio 2, other 11. Primary tumor: extremities 8, retroperitoneal 7, uterine 2, truncal 2, other 4. A median of 6 (1–9) and a total of 93 cycles (cy) were administered. Toxicity by patient (23): neutropenia grade(G)IV 7 (30%), GIII 9 (39%); anemia GIII 4 (17%), GII 7 (30%); thrombocytopenia GIV 2 (8%), GIII 3 (13%), GII 4 (17%) pts. Neutropenic fever in 5 (21%) pts. Grade III/IV mucositis in 14 (60%) pts. Toxici...
LBA5002^ Background: In three phase III trials in OC (2 front line, 1 PT-sensitive recurrent), BE... more LBA5002^ Background: In three phase III trials in OC (2 front line, 1 PT-sensitive recurrent), BEV + CT → BEV significantly improved progression-free survival (PFS) vs CT alone. AURELIA is the first randomized trial of BEV in PT-resistant OC. Methods: Eligible patients (pts) had OC (measurable by RECIST 1.0 or assessable) that had progressed ≤6 mo after ≥4 cycles of PT-based therapy. Pts with refractory OC, history of bowel obstruction, or >2 prior anticancer regimens were ineligible. After CT selection by the investigator (pegylated liposomal doxorubicin [PLD], topotecan [TOP], or weekly paclitaxel [PAC]), pts were randomized to CT either alone or with BEV (10 mg/kg q2w or 15 mg/kg q3w depending on CT) until progression (PD), unacceptable toxicity, or withdrawal of consent. Pts in the CT-alone arm could cross over to BEV monotherapy at PD. The primary endpoint was PFS by RECIST. Secondary endpoints included objective response rate (ORR), overall survival, safety, and quality of ...
Perivascular epithelioid cell tumors (PEComas) are infrequent neoplasms with peculiar myomelanocy... more Perivascular epithelioid cell tumors (PEComas) are infrequent neoplasms with peculiar myomelanocytic differentiation. The aggressive abdominopelvic variant is rare, with only a small number of published cases. We present an additional case of this unusual variant, which showed an aggressive histologic and clinical behavior with multiple liver metastases and resistance to several therapies. We also discuss the histological and immunohistochemical profiles as well as the differential diagnosis.
Trebananib, a peptibody that blocks binding of angiopoietin-1 and -2 to Tie2, significantly prolo... more Trebananib, a peptibody that blocks binding of angiopoietin-1 and -2 to Tie2, significantly prolonged progression-free survival (PFS) in patients with recurrent epithelial ovarian cancer in the phase 3 TRINOVA-1 study. We report overall survival (OS) in the intent-to-treat population and clinically relevant subgroups and time to second disease progression (PFS-2). Women with recurrent disease (platinum-free interval<12months) were randomized to receive intravenous paclitaxel 80mg/m(2) (3weeks on/1week off) plus intravenous trebananib 15mg/kg or placebo, weekly. OS in the intent-to-treat population was a key secondary endpoint. Exploratory analysis of PFS-2 was conducted according to guidance by the European Medicines Agency. Median OS was not significantly improved with trebananib compared with placebo (19.3 versus 18.3months; HR, 0.95; 95% CI, 0.81-1.11; P=0.52) in the intent-to-treat population (n=919). In subgroup analysis, trebananib improved median OS compared with placebo (...
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jul 16, 2016
Doxorubicin and trabectedin are considered active drugs in soft tissue sarcoma (STS). The combina... more Doxorubicin and trabectedin are considered active drugs in soft tissue sarcoma (STS). The combination of both drugs was hypothesized to be advantageous and safe on the basis of preclinical evidence and a previous phase I trial, respectively. The aim of this study was to compare the clinical outcome of trabectedin plus doxorubicin with doxorubicin as first-line treatment of advanced STS patients. In this open-label randomized phase II trial, the main end point was progression-free survival (PFS). Trabectedin 1.1 mg/m(2) in a 3-hour infusion plus doxorubicin 60 mg/m(2) as the experimental arm and doxorubicin 75 mg/m(2) as the control arm were administered for up to six cycles. Translational research was planned to correlate the expression of apoptotic and DNA repair genes with clinical outcome. In 115 randomly assigned patients, the median PFS was 5.5 months in the control arm and 5.7 months in the experimental arm (hazard ratio, 1.16; 95% CI, 0.79 to 1.71; P = .45) in the intent-to-t...
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