A randomized phase 2 study of sapanisertib in combination with paclitaxel versus paclitaxel alone in women with advanced, recurrent, or persistent endometrial cancer

Endometrial cancer; Metastatic; RecurrentCàncer d'endometri; Metastàtic; RecurrentCáncer endometrial; Metastásico; RecurrenteObjective This phase 2 study investigated sapanisertib (selective dual inhibitor of mTORC1/2) alone, or in combination with paclitaxel or TAK-117 (a selective small molecule inhibitor of PI3K), versus paclitaxel alone in advanced, recurrent, or persistent endometrial cancer. Methods Patients with histologic diagnosis of endometrial cancer (1–2 prior regimens) were randomized to 28-day cycles on four treatment arms: 1) weekly paclitaxel 80 mg/m2 (days 1, 8, and 15); 2) weekly paclitaxel 80 mg/m2 + oral sapanisertib 4 mg on days 2–4, 9–11, 16–18, and 23–25; 3) weekly sapanisertib 30 mg, or 4) sapanisertib 4 mg + TAK-117 200 mg on days 1–3, 8–10, 15–17, and 22–24. Results Of 241 patients randomized, 234 received treatment (paclitaxel, n = 87 [3 ongoing]; paclitaxel+sapanisertib, n = 86 [3 ongoing]; sapanisertib, n = 41; sapanisertib+TAK-117, n = 20). The sapanisertib and sapanisertib+TAK-117 arms were closed to enrollment after futility analyses. After a median follow-up of 14.4 (paclitaxel) versus 17.2 (paclitaxel+sapanisertib) months, median progression-free survival (PFS; primary endpoint) was 3.7 versus 5.6 months (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.58–1.15; p = 0.139); in patients with endometrioid histology (n = 116), median PFS was 3.3 versus 5.7 months (HR 0.66; 95% CI 0.43–1.03). Grade ≥ 3 treatment-emergent adverse event rates were 54.0% with paclitaxel versus 89.5% paclitaxel+sapanisertib. Conclusions Our findings support inclusion of chemotherapy combinations with investigational agents for advanced or metastatic disease. The primary endpoint was not met and toxicity was manageable. Trial registration: ClinicalTrials.gov number, NCT02725268Takeda Development Center Americas, Inc., Lexington, MA, USA. This work was supported by funding from Takeda Development Center Americas, Inc. The study was designed by the authors in conjunction with the sponsors. Data were gathered and analyzed by the investigator and the sponsor; all the authors had access to the data. The authors received medical writing support for drafting the manuscript, which was funded by Takeda Pharmaceuticals USA, Inc. Manuscript drafts were reviewed by all authors and the sponsor and all the authors made the decision to submit the manuscript for publication

Maintenance treatment with rucaparib for recurrent ovarian carcinoma in ARIEL3, a randomized phase 3 trial: The effects of best response to last platinum-based regimen and disease at baseline on efficacy and safety

Assaigs clínics; Oncologia ginecològica; Càncer de les donesEnsayos clínicos; Oncología ginecológica; Cáncer de las mujeresClinical trials; Gynecological oncology; Women's cancerBackground The efficacy and safety of rucaparib maintenance treatment in ARIEL3 were evaluated in subgroups based on best response to most recent platinum-based chemotherapy and baseline disease. Methods Patients were randomized 2:1 to receive either oral rucaparib at a dosage of 600 mg twice daily or placebo. Investigator-assessed PFS was assessed in prespecified, nested cohorts: BRCA-mutated, homologous recombination deficient (HRD; BRCA mutated or wild-type BRCA/high loss of heterozygosity), and the intent-to-treat (ITT) population. Results Median PFS for patients in the ITT population with a complete response to most recent platinum-based chemotherapy was 11.1 months in the rucaparib arm (126 patients) versus 5.6 months in the placebo arm (64 patients) (HR, 0.33 [95% CI, 0.23–0.48]), and in patients with a partial response (249 vs. 125), it was 9.0 versus 5.3 months (HR, 0.38 [0.30–0.49]). In subgroups of the ITT population based on baseline disease, median PFS was 8.2 versus 5.3 months (HR, 0.40 [0.28–0.57]) in patients with measurable disease (141 rucaparib vs. 66 placebo), 10.4 versus 4.5 months (HR, 0.31 [0.20–0.48]) in those with nonmeasurable but evaluable disease (104 vs. 56), and 14.1 versus 7.3 months (HR, 0.35 [0.24–0.51]) in those with no residual disease (130 vs. 67). Across subgroups, significantly longer median PFS was observed with rucaparib versus placebo in the BRCA-mutated and HRD cohorts. Objective responses were reported in patients with measurable disease and in patients with nonmeasurable but evaluable baseline disease. Safety was consistent across subgroups. Conclusion Rucaparib maintenance treatment provided clinically meaningful efficacy benefits across subgroups based on response to last platinum-based chemotherapy or baseline disease.A.O. has served on advisory boards for Clovis Oncology, AstraZeneca, Deciphera, Genmab/Seattle Genetics, GlaxoSmithKline/Tesaro, ImmunoGen, Merck/Merck Sharp & Dohme, Mersana Therapeutics, PharmaMar, and Roche; has received support for travel or accommodation from Clovis Oncology, AstraZeneca, PharmaMar, and Roche; and reports institutional research grant support from Clovis Oncology, AbbVie Deutschland, Ability Pharmaceuticals, Advaxis, Aeterna Zentaris, Amgen, Aprea Therapeutics, Eisai, ImmunoGen, Merck/Merck Sharp & Dohme, Millennium Pharmaceuticals, PharmaMar, Roche, and Tesaro

Phase III, randomized trial of mirvetuximab soravtansine versus chemotherapy in patients with platinum-resistant ovarian cancer: primary analysis of FORWARD I

Chemotherapy; Mirvetuximab soravtansine; Ovarian cancerQuimioterapia; Mirvetuximab soravtansina; Cáncer de ovariosQuimioteràpia; Mirvetuximab soravtansina; Càncer d'ovarisBackground Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate comprising a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. The randomized, open-label, phase III study FORWARD I compared MIRV and investigator's choice chemotherapy in patients with platinum-resistant epithelial ovarian cancer (EOC). Patients and methods Eligible patients with 1-3 prior lines of therapy and whose tumors were positive for FRα expression were randomly assigned, in a 2 : 1 ratio, to receive MIRV (6 mg/kg, adjusted ideal body weight) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary endpoint was progression-free survival [PFS, Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, blinded independent central review] in the intention-to-treat (ITT) population and in the prespecified FRα high population. Results A total of 366 patients were randomized; 243 received MIRV and 109 received chemotherapy. The primary endpoint, PFS, did not reach statistical significance in either the ITT [hazard ratio (HR), 0.98, P = 0.897] or the FRα high population (HR, 0.69, P = 0.049). Superior outcomes for MIRV over chemotherapy were observed in all secondary endpoints in the FRα high population including improved objective response rate (24% versus 10%), CA-125 responses (53% versus 25%), and patient-reported outcomes (27% versus 13%). Fewer treatment-related grade 3 or higher adverse events (25.1% versus 44.0%), and fewer events leading to dose reduction (19.8% versus 30.3%) and treatment discontinuation (4.5% versus 8.3%) were seen with MIRV compared with chemotherapy. Conclusions In patients with platinum-resistant EOC, MIRV did not result in a significant improvement in PFS compared with chemotherapy. Secondary endpoints consistently favored MIRV, particularly in patients with high FRα expression. MIRV showed a differentiated and more manageable safety profile than chemotherapy.This work was supported by ImmunoGen, Inc (no grant number)

Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2)

Càncer d'ovaris; Biomarcadors tumoralsCáncer de ovarios; Biomarcadores tumoralesOvarian cancer; Tumour biomarkersARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity

Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: integrated analysis of data from Study 10 and ARIEL2

Objective: An integrated analysis was undertaken to characterize the antitumor activity and safety profile of the oral poly(ADP-ribose) polymerase inhibitor rucaparib in patients with relapsed high-grade ovarian carcinoma (HGOC). Methods: Eligible patients from Study 10 (NCT01482715) and ARIEL2 (NCT01891344) who received a starting dose of oral rucaparib 600 mg twice daily (BID) with or without food were included in these analyses. The integrated efficacy population included patients with HGOC and a deleterious germline or somatic BRCA1 or BRCA2 (BRCA1/2) mutation who received at least two prior chemotherapies and were sensitive, resistant, or refractory to platinum-based chemotherapy. The primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included duration of response (DOR) and progression-free survival (PFS). The integrated safety population included patients with HGOC who received at least one dose of rucaparib 600 mg BID, irrespective of BRCA1/2 mutation status and prior treatments. Results: In the efficacy population (n = 106), ORR was 53.8% (95% confidence interval [CI], 43.8–63.5); 8.5% and 45.3% of patients achieved complete and partial responses, respectively. Median DOR was 9.2 months (95% CI, 6.6–11.6). In the safety population (n = 377), the most frequent treatment-emergent adverse events (AEs) were nausea, asthenia/fatigue, vomiting, and anemia/hemoglobin decreased. The most common grade ≥ 3 treatment-emergent AE was anemia/hemoglobin decreased. Treatment-emergent AEs led to treatment interruption, dose reduction, and treatment discontinuation in 58.6%, 45.9%, and 9.8% of patients, respectively. No treatment-related deaths occurred. Conclusions: Rucaparib has antitumor activity in advanced BRCA1/2-mutated HGOC and a manageable safety profile

Clinical yield of diagnostic endoscopic retrograde cholangiopancreatography in orthotopic liver transplant recipients With suspected biliary complications

Diagnostic endoscopic retrograde cholangiopancreatography (D‐ERCP) is commonly performed for the evaluation of biliary complications after orthotopic liver transplantation (OLT). This practice is contrary to the national trend of reserving endoscopic retrograde cholangiopancreatography (ERCP) for therapeutic purposes. Our aim was to evaluate the clinical yield and complications of D‐ERCP in OLT recipients. In this retrospective study, 165 OLT recipients who underwent ERCP between January 2006 and December 2010 at the University of Michigan were divided into 2 groups: (1) a therapeutic endoscopic retrograde cholangiopancreatography (T‐ERCP) group (if they met prespecified criteria that suggested a high likelihood of endoscopic intervention) and (2) a D‐ERCP group (if there was clinical suspicion of biliary disease but they did not meet any criteria). The 2 groups were compared with respect to the proportion of subjects undergoing high‐yield ERCP, which was defined as a procedure resulting in a clinically important intervention that modified the disease course. 66.3% of the D‐ERCP procedures were classified as high‐yield, whereas 90.1% of the T‐ERCP procedures were ( P < 0.001). Serious complications were infrequent in both groups. A survey of practitioners caring for OLT recipients suggested that the rate of high‐yield D‐ERCP seen in this study is congruent with what is considered acceptable in clinical practice. In conclusion, although T‐ERCP is more likely to reveal a pathological process requiring an intervention, D‐ERCP appears to be an acceptable clinical strategy for OLT recipients because of the high likelihood of a high‐yield study and the low rate of serious complications. Liver Transpl, 2012. © 2012 AASLD.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95170/1/23535_ftp.pd

Barriers in phase I cancer clinical trials referrals and enrollment: five-year experience at the Princess Margaret Hospital

BACKGROUND: There is a paucity of literature on the referral outcome of patients seen in phase I trial clinics in academic oncology centres. This study aims to provide information on the accrual rate and to identify obstacles in the recruitment process. METHODS: A retrospective chart review was performed for all new patients referred and seen in the phase I clinic at the Princess Margaret Hospital between January 2000 and June 2005. Data on their demographics, medical history, and details of trial participation or non-entry were recorded. RESULTS: A total of 667 new phase I referrals were seen during the stated period. Of these patients, 197 (29.5%) patients were enrolled into a phase I trial, and 64.5% of them started trial within 1 month of the initial visit. About a quarter (165 of 667) of the patients referred were deemed ineligible at their first visit, with the most frequent reasons for ineligibility being poor performance status, unacceptable bloodwork, too many prior treatments and rapid disease progression. The remaining 305 patients (45.7%) were potentially eligible at their initial visit, but never entered a phase I trial. The main reasons for their non-entry were patient refusal, other treatment recommended first, and lack of available trials or trial spots. CONCLUSION: This study provides information on the clinical realities underlying a referral to a phase I clinic and eventual trial enrollment. Better selection of patients, appropriate education of referring physicians, and opening phase I trials with fewer restrictions on some criteria such as prior therapy may enhance their recruitment rates

Secondary somatic mutations restoring RAD51C and RAD51D associated with acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma

High-grade epithelial ovarian carcinomas (OC) containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pre-treatment and post-progression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase 2 study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed OC. In six of 12 pre-treatment biopsies, a truncation mutation in BRCA1, RAD51C or RAD51D was identified. In five of six paired post-progression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51C. In vitro complementation assays and a patient-derived xenograft (PDX), as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations

Exploratory outcome analyses according to stage and/or residual disease in the ICON7 trial of carboplatin and paclitaxel with or without bevacizumab for newly diagnosed ovarian cancer

Objective: In the randomized phase 3 ICON7 trial (ISRCTN91273375), adding bevacizumab to chemotherapy for newly diagnosed ovarian cancer significantly improved progression-free survival (PFS; primary endpoint) but not overall survival (OS; secondary endpoint) in the intent-to-treat (ITT) population. We explored treatment effect according to stage and extent of residual disease. Methods: Patients with stage IIB–IV or high-risk (grade 3/clear-cell) stage I–IIA ovarian cancer were randomized to receive six cycles of carboplatin and paclitaxel either alone or with bevacizumab 7.5 mg/kg every 3 weeks followed by single-agent bevacizumab for 12 further cycles (total duration 12 months). Post hoc exploratory analyses of subgroups defined by stage and extent of residual disease at diagnosis within the stage IIIB–IV population (European indication) was performed. Results: The PFS benefit from bevacizumab was seen consistently in all subgroups explored. The PFS hazard ratio was 0.77 (95% confidence interval [CI], 0.59–0.99) in 411 patients with stage IIIB–IV ovarian cancer with no visible residuum and 0.81 (95% CI, 0.69–0.95) in 749 patients with stage IIIB–IV disease and visible residuum. As in the ITT population, no OS difference was detected in any subgroup except the previously described ‘high-risk’ subgroup. Safety results in analyzed subgroups were consistent with the overall population. Conclusions: Adding bevacizumab to front-line chemotherapy improves PFS irrespective of stage/residual disease. In patients with stage III with \u3e1 cm residuum, stage IV or inoperable disease, this translates into an OS benefit. No OS benefit or detriment was seen in other subgroups explored

Niraparib Maintenance Therapy in Patients With Recurrent Ovarian Cancer After a Partial Response to the Last Platinum-Based Chemotherapy in the ENGOT-OV16/NOVA Trial

PURPOSEIn the ENGOT-OV16/NOVA trial (ClinicalTrials.gov identifier: NCT01847274), maintenance therapy with niraparib, a poly(ADP-ribose) polymerase inhibitor, prolonged progression-free survival in patients with platinum-sensitive, recurrent ovarian cancer who had a response to their last platinum-based chemotherapy. The objective of the study was to assess the clinical benefit and patient-reported outcomes in patients who had a partial response (PR) and complete response (CR) to their last platinum-based therapy.PATIENTS AND METHODSA total of 553 patients were enrolled in the trial. Of 203 patients with a germline BRCA mutation (gBRCAmut), 99 had a PR and 104 had a CR to their last platinum-based therapy; of 350 patients without a confirmed gBRCAmut (non?gBRCAmut), 173 had a PR and 177 had a CR. Post hoc analyses were carried out to evaluate safety and the risk of progression in these patients according to gBRCAmut status and response to their last platinum-based therapy. Ovarian cancer?specific symptoms and quality of life were assessed using the Functional Assessment of Cancer Therapy?Ovarian Symptom Index.RESULTSProgression-free survival was improved in patients treated with niraparib compared with placebo in both the gBRCAmut cohort (PR: hazard ratio [HR], 0.24; 95% CI, 0.131 to 0.441; P < .0001; CR: HR, 0.30; 95% CI, 0.160 to 0.546; P < .0001) and the non?gBRCAmut cohort (PR: HR, 0.35; 95% CI, 0.230 to 0.532; P < .0001; CR: HR, 0.58; 95% CI, 0.383 to 0.868; P = .0082). The incidence of any-grade and grade 3 or greater adverse events was manageable. No meaningful differences were observed between niraparib and placebo in PR and CR subgroups with respect to patient-reported outcomes.CONCLUSIONPatients achieved clinical benefit from maintenance treatment with niraparib regardless of response to the last platinum-based therapy