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A phase I/II pharmacokinetic and pharmacogenomic study of calcitriol in combination with cisplatin and docetaxel in advanced non-small-cell lung cancer.

ABSTRACT: Preclinical studies demonstrated antiproliferative synergy of 1,25-D3 (calcitriol) with cisplatin. The goals of this phase I/II study were to determine the recommended phase II dose (RP2D) of 1,25-D3 with cisplatin and docetaxel and its efficacy in metastatic non-small-cell lung cancer.Patients were ?18 years, PS 0-1 with normal organ function. In the phase I portion, patients received escalating doses of 1,25-D3 intravenously every 21 days prior to docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) using standard 3 + 3 design, targeting dose-limiting toxicity (DLT) rate <33 %. Dose levels of 1,25-D3 were 30, 45, 60, and 80 mcg/m(2). A two-stage design was employed for phase II portion. We correlated CYP24A1 tagSNPs with clinical outcome and 1,25-D3 pharmacokinetics (PK).34 patients were enrolled. At 80 mcg/m(2), 2/4 patients had DLTs of grade 4 neutropenia. Hypercalcemia was not observed. The RP2D of 1,25-D3 was 60 mcg/m(2). Among 20 evaluable phase II patients, there were 2 confirmed, 4 unconfirmed partial responses (PR), and 9 stable disease (SD). Median time to progression was 5.8 months (95 % CI 3.4, 6.5), and median overall survival 8.7 months (95 % CI 7.6, 39.4). CYP24A1 SNP rs3787554 (C > T) correlated with disease progression (P = 0.03) and CYP24A1 SNP rs2762939 (C > G) trended toward PR/SD (P = 0.08). There was no association between 1,25-D3 PK and CYP24A1 SNPs.The RP2D of 1,25-D3 with docetaxel and cisplatin was 60 mcg/m(2) every 21 days. Pre-specified endpoint of 50 % confirmed RR was not met in the phase II study. Functional SNPs in CYP24A1 may inform future studies individualizing 1,25-D3.

SUBMITTER: Ramnath N

PROVIDER: S-EPMC3637851 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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A phase I/II pharmacokinetic and pharmacogenomic study of calcitriol in combination with cisplatin and docetaxel in advanced non-small-cell lung cancer.

Ramnath N N Daignault-Newton S S Dy G K GK Muindi J R JR Adjei A A Elingrod V L VL Kalemkerian G P GP Cease K B KB Stella P J PJ Brenner D E DE Troeschel S S Johnson C S CS Trump D L DL

Cancer chemotherapy and pharmacology 20130223 5

<h4>Background</h4>Preclinical studies demonstrated antiproliferative synergy of 1,25-D3 (calcitriol) with cisplatin. The goals of this phase I/II study were to determine the recommended phase II dose (RP2D) of 1,25-D3 with cisplatin and docetaxel and its efficacy in metastatic non-small-cell lung cancer.<h4>Methods</h4>Patients were ≥18 years, PS 0-1 with normal organ function. In the phase I portion, patients received escalating doses of 1,25-D3 intravenously every 21 days prior to docetaxel 7 ...[more]

PMID: 23435876

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Project description:Recent studies have suggested the superiority of concomitant over sequential administration of chemotherapy and radiotherapy. Docetaxel and cisplatin have demonstrated efficacy in advanced non-small-cell lung cancer (NSCLC). This study evaluated the safety, toxicity, and antitumour activity of docetaxel/cisplatin with concurrent thoracic radiotherapy for patients with locally advanced NSCLC. Patients with locally advanced NSCLC (stage IIIA or IIIB), good performance status, age <or=75 years, and adequate organ function were eligible. Both docetaxel and cisplatin were given on days 1, 8, 29, and 36. Doses of docetaxel/cisplatin (mg m(-2)) in the phase I study portion were escalated as follows: 20/30, 25/30, 30/30, 30/35, 30/40, 35/40, 40/40, and 45/40. Beginning on day 1 of chemotherapy, thoracic radiotherapy was given at a total dose of 60 Gy with 2 Gy per fraction over 6 weeks. In the phase I portion, the maximum tolerated doses (MTD) among 33 patients were docetaxel 45 mg m(-2) and cisplatin 40 mg m(-2). The major dose-limiting toxicity (DLT) was radiation oesophagitis. The recommended doses (RDs) for the phase II study were docetaxel 40 mg m(-2) and cisplatin 40 mg m(-2). A total of 42 patients were entered in the phase II portion. Common toxicities were leukopenia, granulocytopenia, anaemia, and radiation oesophagitis, with frequencies of grade >or=3 toxicities of 71, 60, 24, and 19%, respectively. Toxicity was significant, but manageable according to the dose and schedule modifications. Dose intensities of docetaxel and cisplatin were 86 and 87%, respectively. Radiotherapy was completed without a delay in 67% of 42 patients. The overall response rate was 79% (95% confidence interval (CI), 66-91%). The median survival time was 23.4+ months with an overall survival rate of 76% at 1 year and 54% at 2 years. In conclusion, chemotherapy with cisplatin plus docetaxel given on days 1, 8, 29, and 36 and concurrent thoracic radiotherapy is efficacious and tolerated in patients with locally advanced NSCLC and should be evaluated in a phase III study.

Project description:IntroductionCurrent treatment options for advanced esophagogastric cancer (AEGC) are still unsatisfactory. The aim of this prospective phase Ib/II study was to evaluate the safety and efficacy of a novel regimen, AVDCX, consisting of weekly docetaxel and cisplatin together with capecitabine and bevacizumab, in AEGC.MethodsPatients with AEGC received treatment with different dose levels of AVDCX (cisplatin and docetaxel 25-35 mg/m2, days 1,8, capecitabine 1,600 mg/m2 days 1-14, bevacizumab 7.5 mg/kg, day 1, Q:21 days). The study's primary objectives were to establish the recommended phase II doses of docetaxel and cisplatin in AVDCX (phase Ib part) and to determine the tumor response rate (phase II part).ResultsThe study was closed early, after the accrual of 22 patients, due to accumulating toxicity-related deaths. The median age was 59 years and 77% of patients had gastric or gastroesophageal adenocarcinomas. Grade ≥3 adverse events were documented in 18 patients (82%), usually neutropenia (36%), fatigue (54%) or diarrhea (23%). There were three fatal toxicities (14%): mesenteric thromboembolism, gastric perforation and pancytopenic sepsis. The recommended phase II doses of cisplatin and docetaxel were determined to be 25 mg/m2 and 30 mg/m2, respectively. Twenty-one patients were evaluable for response: 12 (54%) had partial response (PR), 4 (18%) had stable disease (SD) and none had complete response (CR). Hence, the objective response rate (CR+PR) was 54% and the disease control rate (CR+PR+SD) was 72%. For the 17 patients treated at the MTD, the objective response rate was 41% and the disease control rate was 88%. The median overall survival (OS) for these patients was 13.9 months (range, 1.5-52.2 months) and the median progression-free survival was 7.6 months (range, 1.3-26.6 months). The 2-year OS rate reached 23.7%.ConclusionsAVDCX was associated with a high rate of regimen related fatal adverse events and is not appropriate for further development in AEGC patients.Trial registrationClinicalTrials.gov NCT00845884.

Project description:Objective: The objective of this trial is to evaluate and compare the acute toxicity in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) treated with docetaxel plus cisplatin, or docetaxel, or cisplatin concurrently with helical tomotherapy during concurrent chemoradiotherapy (CCRT). Methods: In a prospective, single-center, open-label, randomized phase II study, after 2 cycles of induction chemotherapy with docetaxel plus cisplatin regimen, 125 patients with LA-NPC (stage III and IVA, UICC eighth) diagnosed pathologically from June 2017 to November 2019 were randomized into CCRT with docetaxel plus cisplatin group (25 patients), CCRT with docetaxel group (50 patients), and CCRT with cisplatin group (50 patients). The incidence of grade 3 or 4 acute toxicities and clinical efficacy were analyzed among the 3 groups. Results: Safety evaluation was completed in all the 125 patients, during the CCRT period, 66.4% of patients completed 3 cycles of chemotherapy, 24.0% completed 2 cycles of chemotherapy, and 9.6% completed 1 cycle of chemotherapy according to the research plan. The incidence of grade 3 or 4 acute toxicity in CCRT with docetaxel plus cisplatin (DP), docetaxel (D), and cisplatin (P) groups was 88.0%, 72.0%, and 56.0%, respectively. The incidence of grade 3 or 4 acute toxicities in the DP group was significantly higher than that in the D and P groups (P = .015), no significant difference was detected between the D and P groups (P = .096). The most common toxicities were mucositis (40.0%), leukopenia (29.6%), neutropenia (26.4%), and pharyngo-esophagitis (12.0%); compared to D and P groups, DP group did not significantly improved the 3-year overall survival (96.0% vs 87.0% and 87.6%), progression-free survival (92.0% vs 79.7% and,76.9%), locoregional failure-free survival (96.0% vs 91.8% and 92.7%), and distant failure-free survival (100% vs 90.0% and 89.0%), there were no significant difference in survival data among the 3 groups (all P > .05). Conclusions: Higher survival benefits did not achieve from intensified CCRT with DP, CCRT with P or D obtained similar short-term survival outcomes with similar acceptable toxicities in LA-NPC patients.

Dataset Information

A phase I/II pharmacokinetic and pharmacogenomic study of calcitriol in combination with cisplatin and docetaxel in advanced non-small-cell lung cancer.

Publications

A phase I/II pharmacokinetic and pharmacogenomic study of calcitriol in combination with cisplatin and docetaxel in advanced non-small-cell lung cancer.

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