Dataset Information

Phase I Study of Everolimus in Combination with Gemcitabine and Split-Dose Cisplatin in Advanced Urothelial Carcinoma.

ABSTRACT:

Background

Cisplatin-based combination chemotherapy is standard first-line treatment for patients with advanced urothelial carcinoma (UC). Molecular profiling studies reveal that the PI3K/AKT/mTOR pathway is altered in a significant percentage of UCs.

Objective

We conducted a phase I trial to evaluate the feasibility of combining the mTOR inhibitor everolimus with gemcitabine and split-dose cisplatin (GC) in advanced UC in the first-line setting.

Methods

Patients received gemcitabine 800 mg/m² and cisplatin 35 mg/m² on days 1 and 8 of 21-day cycles for a total of 6 cycles in combination with everolimus at increasing dose levels (DL1:5 mg QOD, DL2:5 mg daily, DL3:10 mg daily) following a standard 3+3 design. Responses were assessed every 2 cycles. Patients with at least stable disease (SD) continued everolimus until progression. Goals were to establish dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) for the combination.

Results

12 patients were enrolled, 3 at DL1, 3 at DL2, and an additional 6 at DL1^*(DL1 following de-escalation). 3/3 patients at DL2 had DLTs during cycle 1. 2/8 evaluable patients at DL1/DL1^* had DLTs during cycle 1. DLTs were primarily hematologic. Further toxicities, also primarily hematologic, were observed during later treatment cycles, leading to 8 chemotherapy dose reductions overall. Partial responses were observed in 4/10 evaluable patients, and SD in 5/10. Median overall survival was 10.8 months (95% CI 6.9, not reached).

Conclusions

The maximum tolerated dose was reached at the lowest dose level, 5 mg QOD, for everolimus in combination with gemcitabine and split-dose cisplatin in advanced UC. The regimen was limited by hematologic toxicity.

SUBMITTER: Abida W

PROVIDER: S-EPMC4927849 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Phase I Study of Everolimus in Combination with Gemcitabine and Split-Dose Cisplatin in Advanced Urothelial Carcinoma.

Abida Wassim W Milowsky Matthew I MI Ostrovnaya Irina I Gerst Scott R SR Rosenberg Jonathan E JE Voss Martin H MH Apolo Andrea B AB Regazzi Ashley M AM McCoy Asia S AS Boyd Mariel E ME Bajorin Dean F DF

Bladder cancer (Amsterdam, Netherlands) 20160107 1

<h4>Background</h4>Cisplatin-based combination chemotherapy is standard first-line treatment for patients with advanced urothelial carcinoma (UC). Molecular profiling studies reveal that the PI3K/AKT/mTOR pathway is altered in a significant percentage of UCs.<h4>Objective</h4>We conducted a phase I trial to evaluate the feasibility of combining the mTOR inhibitor everolimus with gemcitabine and split-dose cisplatin (GC) in advanced UC in the first-line setting.<h4>Methods</h4>Patients received g ...[more]

PMID: 27376132

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Project description:BACKGROUND:Copanlisib is a pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant PI3K-?/? activity that has demonstrated clinical activity and manageable safety when administered as monotherapy in a phase II study. Combination therapy may overcome compensatory signalling that could occur with PI3K pathway inhibition, resulting in enhanced inhibitory activity, and preclinical studies of copanlisib with gemcitabine have demonstrated potent anti-tumour activity in vivo. METHODS:A phase I, open-label, dose-escalation study to evaluate the safety, tolerability and recommended phase II dose (RP2D) of copanlisib with gemcitabine or with cisplatin plus gemcitabine (CisGem) in patients with advanced malignancies, including an expansion cohort in patients with biliary tract cancer (BTC) at the RP2D of copanlisib plus CisGem. Copanlisib and gemcitabine were administered on days 1, 8 and 15 of a 28-day cycle; maximum tolerated dose (MTD) and RP2D of copanlisib were determined. Copanlisib plus CisGem was administered on days 1 and 8 of a 21-day cycle; pharmacokinetics and biomarkers were assessed. RESULTS:Fifty patients received treatment as follows: dose-escalation cohorts, n=16; copanlisib plus CisGem cohort, n=14; and BTC expansion cohort, n=20. Copanlisib 0.8?mg?kg-1 plus gemcitabine was the MTD and RP2D for both combinations. Common treatment-emergent adverse events included nausea (86%), hyperglycaemia (80%) and decreased platelet count (80%). Copanlisib exposure displayed a dose-proportional increase. No differences were observed upon co-administration of CisGem. Response rates were as follows: copanlisib plus gemcitabine, 6.3% (one partial response in a patient with peritoneal carcinoma); copanlisib plus CisGem, 12% (one complete response and three partial responses all in patients with BTC (response rate 17.4% in patients with BTC)). Mutations were detected in PIK3CA (1 out of 43), KRAS (10 out of 43) and BRAF (2 out of 22), with phosphate and tensin homologue protein loss in 41% (12 out of 29). CONCLUSIONS:Copanlisib plus CisGem demonstrated a manageable safety profile, favourable pharmacokinetics, and potentially promising clinical response.

Project description:BackgroundEpidermal growth factor receptor overexpression is associated with poor outcomes in urothelial carcinoma (UC). Cetuximab (CTX) exhibited an antitumor effect in in vivo UC models. The efficacy of gemcitabine/cisplatin (GC) with or without CTX in patients with advanced UC was evaluated.MethodsPatients with advanced UC, measurable disease, and adequate organ function were randomized 1:2 to cisplatin (70 mg/m(2) ) on day 1 plus gemcitabine (1000 mg/m(2) ) on days 1, 8, and 15 (arm A) or GC plus CTX (500 mg/m(2) ) on days 1 and 15 (arm B). The primary endpoint was the overall response rate. The secondary endpoints were the response duration, safety, progression-free survival, overall survival, determination of whether or not CTX sensitized nonresponders to GC, and exploratory biomarker analysis. The accrual targets were 27 and 54 patients for the 2 arms, respectively. The overall response rate was reported by arm with binomial confidence intervals (CIs). Kaplan-Meier methods were used for time-to-event endpoints.ResultsEighty-eight eligible patients were randomized; 87 were toxicity-evaluable, and 85 were response-evaluable. The overall response rates were 57.1% for arm A (95% CI = 37%-76%) and 61.4% for arm B (95% CI = 48%-74%). The median progression-free survival times were 8.5 months for arm A (95% CI = 5.7-10.4 months) and 7.6 months for arm B (95% CI = 6.1-8.7 months). The median overall survival times were 17.4 months for arm A (95% CI = 12.8 months to unreached) and 14.3 months for arm B (95% CI = 11.6-22.2 months). The most common grade 3/grade 4 adverse events in both arms were myelosuppression and nausea. Thromboembolism, acneiform rash, fatigue, pain, hypersensitivity reactions, elevated transaminases, hyponatremia, and hypomagnesemia were more common in arm B; 3 grade 5 adverse events occurred in arm B. The presence of primary disease significantly correlated with thromboembolism. An increased soluble E-cadherin level after cycle 2 correlated with a higher risk of death.ConclusionsGC plus CTX was feasible but was associated with more adverse events and no improvements in outcomes.

Project description:BackgroundTreatment options have been historically limited for cisplatin-ineligible patients with advanced urothelial carcinoma (UC). Given the need for alternatives to platinum-based chemotherapy, including non-chemotherapy regimens for patients with both impaired renal function and borderline functional status, in 2010 (prior to the immune checkpoint blockade era in metastatic UC), we initiated a phase II trial to test the activity of everolimus or everolimus plus paclitaxel in the cisplatin-ineligible setting.MethodsThis was an open-label phase II trial conducted within the US-based Hoosier Cancer Research Network (ClinicalTrials.gov number: NCT01215136). Patients who were cisplatin-ineligible with previously untreated advanced UC were enrolled. Patients with both impaired renal function and poor performance status were enrolled into cohort 1; patients with either were enrolled into cohort 2. Patients received everolimus 10 mg daily alone (cohort 1) or with paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle (cohort 2). The primary outcome was clinical benefit at 4 months. Secondary outcomes were adverse events, progression-free survival (PFS), and 1-year overall survival (OS). Exploratory endpoints included genomic correlates of outcomes. The trial was not designed for comparison between cohorts.ResultsA total of 36 patients were enrolled from 2010 to 2018 (cohort 1, N = 7; cohort 2, N = 29); the trial was terminated due to slow accrual. Clinical benefit at 4 months was attained by 0 (0%, 95% confidence interval [CI] 0-41.0%) patients in cohort 1 and 11 patients (37.9%, 95% CI 20.7-57.7%) in cohort 2. Median PFS was 2.33 (95% CI 1.81-Inf) months in cohort 1 and 5.85 (95% CI 2.99-8.61) months in cohort 2. Treatment was discontinued due to adverse events for 2 patients (29%) in cohort 1 and 11 patients (38%) in cohort 2. Molecular alterations in microtubule associated genes may be associated with treatment benefit but this requires further testing.ConclusionEverolimus plus paclitaxel demonstrates clinical activity in cisplatin-ineligible patients with metastatic UC, although the specific contribution of everolimus cannot be delineated. Patients with both impaired renal function and borderline functional status may be difficult to enroll to prospective trials. (ClinicalTrials.gov Identifier NCT01215136).

Project description:ImportancePreclinical studies suggest that inhibition of single-stranded DNA repair by ataxia telangiectasia and Rad3 (ATR) may enhance the cytotoxicity of cisplatin, gemcitabine, and other chemotherapeutic agents. Cisplatin with gemcitabine remains the standard up-front therapy for treatment in patients with metastatic urothelial cancer.ObjectiveTo determine whether the use of the selective ATR inhibitor, berzosertib, could augment the activity of cisplatin with gemcitabine.Design, setting, and participantsIn a phase 2 randomized clinical trial, 87 patients across 23 centers in the National Cancer Institute Experimental Therapeutics Clinical Trials Network were randomized to receive either cisplatin with gemcitabine alone (control arm) or cisplatin with gemcitabine plus berzosertib (experimental arm). Key eligibility criteria included confirmed metastatic urothelial cancer, no prior cytotoxic therapy for metastatic disease, 12 months or more since perioperative therapy, and eligibility for cisplatin receipt based on standard criteria. The study was conducted from January 27, 2017, to December 15, 2020.InterventionsIn the control arm, cisplatin, 70 mg/m2, was given on day 1 and gemcitabine, 1000 mg/m2, was given on days 1 and 8 of a 21-day cycle. In the experimental arm, cisplatin, 60 mg/m2, was given on day 1; gemcitabine, 875 mg/m2, on days 1 and 8; and berzosertib, 90 mg/m2, on days 2 and 9 of a 21-day cycle.Main outcomes and measuresThe primary end point of the study was progression-free survival. The analysis was on all patients who started therapy.ResultsOf the total of 87 patients randomized, 41 patients received cisplatin with gemcitabine alone and 46 received cisplatin with gemcitabine plus berzosertib. Median age was 67 (range, 32-84) years, and 68 patients (78%) were men. Median progression-free survival was 8.0 months for both arms (Bajorin risk-adjusted hazard ratio, 1.22; 95% CI, 0.72-2.08). Median overall survival was shorter with cisplatin with gemcitabine plus berzosertib compared with cisplatin with gemcitabine alone (14.4 vs 19.8 months; Bajorin risk-adjusted hazard ratio, 1.42; 95% CI, 0.76-2.68). Higher rates of grade 3 vs grade 4 thrombocytopenia (59% vs 39%) and neutropenia (37% vs 27%) were observed with cisplatin with gemcitabine and berzosertib compared with cisplatin with gemcitabine alone; consequently, more dose reductions were needed in the experimental arm. Patients in the experimental arm received a median cisplatin dose of 250 mg/m2, which was significantly lower than the median dose of 370 mg/m2 in the control arm (P < .001).Conclusions and relevanceThe addition of berzosertib to cisplatin with gemcitabine did not prolong progression-free survival relative to cisplatin with gemcitabine alone in patients with metastatic urothelial cancer, and a trend toward inferior survival was observed with this combination. Berzosertib plus cisplatin with gemcitabine was associated with significantly higher hematologic toxicities despite attenuated dosing of cisplatin with gemcitabine.Trial registrationClinicalTrials.gov Identifier: NCT02567409.

Project description:PurposePatients with metastatic urothelial carcinoma are often ineligible for cisplatin-based treatments. A National Cancer Institute Cancer Therapy Evaluation Program-sponsored trial assessed the tolerability and efficacy of a gemcitabine-eribulin combination in this population.MethodsPatients with treatment-naïve advanced or recurrent metastatic urothelial carcinoma of the bladder, ureter, or urethra not amenable to curative surgery and not candidates for cisplatin-based therapy were eligible. Cisplatin ineligibility was defined as creatinine clearance less than 60 mL/min (but ≥ 30 mL/min), grade 2 neuropathy, or grade 2 hearing loss. Treatment was gemcitabine 1,000 mg/m2 intravenously followed by eribulin 1.4 mg/m2, both on days 1 and 8, repeated in 21-day cycles until progression or unacceptable toxicity. A Simon two-stage phase II trial design was used to distinguish between Response Evaluation Criteria in Solid Tumors, version 1.1 objective response rates of 20% versus 50%.ResultsBetween June 2015 and March 2017, 24 eligible patients with a median age of 73 years (range, 62 to 88 years) underwent therapy. Performance status of 0, 1, or 2 was seen in 11, 11, and two patients, respectively. Sites of disease included: lymph nodes, 16; lungs, nine; liver, seven; bladder, five; bones, two. Median number of cycles received was four (range, one to 16). Of 24 patients, 12 were confirmed responders; the observed objective response rate was 50% (95% CI, 29% to 71%). Median overall survival was 11.9 months (95% CI, 5.6 to 20.4 months), and median progression-free survival was 5.3 months (95% CI, 4.5 to 6.7 months). The most common treatment-related any-grade toxicities were fatigue (83% of patients), neutropenia (79%), anemia (63%), alopecia (50%), elevated AST (50%), and constipation, nausea, and thrombocytopenia (42% each).ConclusionGemcitabine-eribulin treatment response and survival for cisplatin-ineligible patients compare favorably to other regimens. Additional research is needed.

Dataset Information

Phase I Study of Everolimus in Combination with Gemcitabine and Split-Dose Cisplatin in Advanced Urothelial Carcinoma.

Background

Objective

Methods

Results

Conclusions

Publications

Phase I Study of Everolimus in Combination with Gemcitabine and Split-Dose Cisplatin in Advanced Urothelial Carcinoma.

Similar Datasets

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