Sunitinib combined with pemetrexed and carboplatin in patients with advanced solid malignancies--results of a phase I dose-escalation study

Our plain-English summary of Sunitinib combined with pemetrexed and carboplatin in patients with advanced solid malignancies--results of a phase I dose-escalation study, by N. Blais, D.R. Camidge, D.J. Jonker, et al (Investigational New Drugs, 2013).

The study

• Authors: N. Blais, D.R. Camidge, D.J. Jonker, D. Soulières, S.A. Laurie, S.G. Diab, A. Ruiz-Garcia, A. Thall, K. Zhang, R.C. Chao, L.Q. Chow
• Journal: Investigational New Drugs
• Published: 2013;31(6):1487-98
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Objectives: The maximum tolerated dose (MTD) and overall safety of sunitinib plus pemetrexed and carboplatin was determined in patients with advanced solid malignancies.

Methods: In this phase I dose-escalation study, patients received oral sunitinib on a continuous daily dosing (CDD) schedule (37.5 mg/day) or Schedule 2/1 (2 weeks on treatment, 1 week off treatment; 37.5 or 50 mg/day). Pemetrexed (400-500 mg/m(2) IV) and carboplatin (AUC = 5 mg·min/ml IV) were administered q3w. At the MTD for the chosen schedule, a cohort of patients with non-small cell lung cancer (NSCLC) or mesothelioma was further evaluated.

Results: Twenty-one patients were enrolled on Schedule 2/1 (expansion cohort included) and 3 patients on the CDD schedule. The MTD on Schedule 2/1 was sunitinib 37.5 mg/day with pemetrexed 500 mg/m(2) and carboplatin AUC = 5 mg·min/ml; MTD on the CDD schedule was not established. Dose-limiting toxicities included grade 3/4 neutropenia, grade 3 thrombocytopenia, and grade 3 hand-foot syndrome. The most common grade 3/4 drug-related non-hematologic adverse events at Schedule 2/1 MTD were fatigue/asthenia and diarrhea (both n = 4). Grade 3/4 hematologic abnormalities included neutropenia (83%) and leukopenia (83%). Pharmacokinetic data revealed no clinically significant drug-drug interactions. Best response at the Schedule 2/1 MTD was stable disease ≥8 weeks in 3/5 evaluable patients (60%).

Conclusions: With this combination, in patients with advanced solid malignancies, sunitinib MTD on Schedule 2/1 was 37.5 mg/day. Sunitinib plus pemetrexed and carboplatin were tolerable at the MTD, although sunitinib dose delays and reductions were often required due to myelosuppression.

In plain English

This open-label phase I dose-escalation trial, run in the US and Canada, tested the cancer drug sunitinib combined with the chemotherapy drugs pemetrexed and carboplatin in adults with advanced solid cancers. It did not study asbestos exposure. Of 24 patients, 3 were assigned to daily sunitinib with no scheduled week off and 21 to 'Schedule 2/1' (2 weeks on, 1 week off). The 21 included an expansion group of 5 patients with non-small cell lung cancer and 1 with mesothelioma. On Schedule 2/1 the maximum tolerated dose was sunitinib 37.5 mg/day with pemetrexed 500 mg/m2 and carboplatin AUC=5 mg·min/ml. On the daily schedule no maximum tolerated dose was established. At the Schedule 2/1 dose, 9 of 12 patients had sunitinib dose delays and 6 had dose reductions, and low blood counts were common. Of 21 evaluable patients on Schedule 2/1, 4 had a confirmed partial response. The article did not report the mesothelioma patient's response separately. The authors concluded the combination was tolerable at that dose, although dose delays and reductions were often needed, and that further study was warranted.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: open-label, multicenter phase I dose-escalation trial (standard 3+3 design)
• Who was studied: 24 adults with advanced solid malignancies treated in the US and Canada. 3 were assigned to the continuous daily dosing (CDD) schedule and 21 to Schedule 2/1. The 21 included an expansion cohort of 5 patients with non-small cell lung cancer and 1 with mesothelioma.
• Exposure: Oral sunitinib 37.5 or 50 mg once daily, on either the continuous daily dosing (CDD) schedule or Schedule 2/1 (2 weeks on, 1 week off). It was combined with intravenous pemetrexed 400–500 mg/m2 and carboplatin AUC=5 mg·min/ml every 3 weeks, for up to six 3-week cycles. No asbestos exposure was studied.
• Main results:
  • On Schedule 2/1 the maximum tolerated dose (MTD) was sunitinib 37.5 mg/day plus pemetrexed 500 mg/m2 plus carboplatin AUC=5 mg·min/ml. At this dose there was one dose-limiting toxicity (grade 3 neutropenia). At the higher sunitinib dose of 50 mg/day there were dose-limiting toxicities of grade 3 thrombocytopenia (n=1) and grade 4 neutropenia (n=2).
  • On the CDD schedule, the first dose level produced two dose-limiting toxicities: grade 3 hand–foot syndrome (n=1) and grade 4 neutropenia (n=1). No further dose levels were tested, so no MTD was established for that schedule.
  • All 3 patients on the CDD schedule (100 %) had at least one sunitinib dose delay of 1–3 weeks. 2 of them had their sunitinib dose reduced to 25 mg.
  • At the Schedule 2/1 MTD, 9 of 12 patients (75 %) had at least one sunitinib dose delay, and 6 patients (50 %) had their sunitinib dose reduced to 25 mg.
  • Blood-count abnormalities at the Schedule 2/1 MTD included grade 3/4 neutropenia in 5 patients (83 %) and grade 3 leukopenia in 5 patients (83 %).
  • In the original Schedule 2/1 MTD cohort (n=6), the most common treatment-related non-hematologic adverse events were fatigue/asthenia and diarrhea, each in 4 patients (67 %).
  • There were three deaths across all cohorts. All occurred more than 28 days after the last dose and were considered related to the disease under study.
  • In the 3 patients with full drug-level data, adding sunitinib did not appear to affect the blood levels of pemetrexed or carboplatin.
  • Of 21 evaluable patients on Schedule 2/1, 4 had a confirmed partial response (objective response rate 19.0 %) and 9 (42.9 %) had stable disease for 8 weeks or more.
  • Of 5 evaluable patients with non-small cell lung cancer at the Schedule 2/1 MTD, 3 had stable disease for 8 weeks or more, 1 had progressive disease and 1 could not be evaluated.
  • All 3 evaluable patients on the CDD schedule had stable disease for 8 weeks or more as their best response.
• The authors' conclusion: The authors concluded that sunitinib plus pemetrexed and carboplatin was tolerable at the Schedule 2/1 MTD, although sunitinib dose delays and reductions were often required because of myelosuppression. They also wrote that further exploration of the combination in solid tumors is warranted.
• Limitations the authors state:
  • Because the number of evaluable patients was small and responses occurred in different tumor types, the authors said no definitive conclusion on the response rate was possible.
  • Full drug-level (pharmacokinetic) profiles came only from the last 3 patients in the Schedule 2/1 MTD cohort. Sunitinib levels were compared with historical controls because sunitinib alone was not measured in this study.
  • The MTD was set during the first treatment cycle, but the authors noted that initial tolerability was not uniformly sustained over later cycles.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Sunitinib (Sutent), Pemetrexed (Alimta), Carboplatin, Non-Small Cell Lung Cancer, Mesothelioma, Neutropenia.

Related studies

• Sunitinib combined with pemetrexed and cisplatin: results of a phase I dose-escalation and pharmacokinetic study in patients with advanced solid malignancies, with an expanded cohort in non-small cell lung cancer and mesothelioma — D.R. Camidge, N. Blais, et al. (2013)
• Phase I combination study of the PARP inhibitor veliparib plus carboplatin and gemcitabine in patients with advanced ovarian cancer and other solid malignancies — H.J. Gray, K. Bell-McGuinn, et al. (2018)
• A first-in-human phase I dose-escalation, pharmacokinetic, and pharmacodynamic evaluation of intravenous LY2090314, a glycogen synthase kinase 3 inhibitor, administered in combination with pemetrexed and carboplatin — J.E. Gray, J.R. Infante, et al. (2015)
• Phase I dose-escalation study of milciclib in combination with gemcitabine in patients with refractory solid tumors — S. Aspeslagh, K. Shailubhai, et al. (2017)
• Randomised phase II study of cisplatin-etoposide versus infusional carboplatin in advanced non-small-cell lung cancer and mesothelioma — S.C. White, H. Anderson, et al. (2000)
• Carboplatin plus pemetrexed as first-line treatment of patients with malignant pleural mesothelioma: a phase II study — N. Katirtzoglou, I. Gkiozos, et al. (2010)

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