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

Our plain-English summary of 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, by D.R. Camidge, N. Blais, D.J. Jonker, et al (Cancer Chemotherapy and Pharmacology, 2013).

The study

• Authors: D.R. Camidge, N. Blais, D.J. Jonker, D. Soulières, R.C. Doebele, A. Ruiz-Garcia, A. Thall, K. Zhang, S.A. Laurie, R.C. Chao, L.Q. Chow
• Journal: Cancer Chemotherapy and Pharmacology
• Published: 2013;71(2):307-19
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Purpose: To determine the maximum tolerated dose (MTD), safety and tolerability of sunitinib plus pemetrexed and cisplatin for advanced solid malignancies.

Methods: Using a 3 + 3 dose-escalation design, patients received oral sunitinib (37.5 or 50 mg) qd on a continuous daily dosing (CDD) schedule or Schedule 2/1 (2 weeks on, 1 week off treatment) plus pemetrexed (400 or 500 mg/m(2) IV) and cisplatin (75 mg/m(2) IV) q3w up to 6 cycles.

Results: Sunitinib 37.5 mg/pemetrexed 400 mg/m(2)/cisplatin 75 mg/m(2) CDD (n = 5) was not tolerated. Lower doses on this schedule were not explored. The Schedule 2/1 MTD (n = 15) was sunitinib 37.5 mg/pemetrexed 500 mg/m(2)/cisplatin 75 mg/m(2), based on one dose-limiting toxicity (myocardial infarction) out of six patients. The MTD was further studied in an expansion cohort of 10 non-small cell lung cancer (NSCLC) patients and one mesothelioma patient. There were no clinically significant drug-drug interactions. Cumulative myelosuppression was problematic: the median relative dose intensity (% actual/intended) across all cycles was 61 % for sunitinib, 78 % for pemetrexed, and 74 % for cisplatin. Four of eight NSCLC patients in the dose-escalation and expansion cohorts at the Schedule 2/1 MTD who were evaluable for efficacy had stable disease ≥ 8 weeks, and the one patient with mesothelioma had a partial response.

Conclusions: In patients with advanced solid malignancies, sunitinib was not tolerated at 37.5 mg CDD with standard pemetrexed and cisplatin doses. Dose reductions were often needed due to cumulative myelosuppression following cycle 1. The MTD showed modest antitumor activity.

In plain English

This phase I trial in the US and Canada tested sunitinib with the chemotherapy drugs pemetrexed and cisplatin in 31 patients with advanced solid cancers. These included an added group of 10 non-small cell lung cancer patients and one epithelioid mesothelioma patient. The article does not discuss asbestos. Daily sunitinib 37.5 mg with pemetrexed 400 mg/m2 and cisplatin was not well tolerated in five patients, mainly because of low white cell counts. One had a fatal intestinal perforation judged related to sunitinib. On a two-weeks-on, one-week-off schedule, the maximum tolerated dose was sunitinib 37.5 mg, pemetrexed 500 mg/m2 and cisplatin 75 mg/m2. One of six patients at this dose had a heart attack. In the added group, the median relative dose intensity (actual versus intended) across all cycles was 61% for sunitinib, 78% for pemetrexed and 74% for cisplatin. The mesothelioma patient in that group had a partial tumor response. Four of eight evaluable lung cancer patients at that dose had stable disease lasting 8 weeks or longer. The authors noted that doses often needed reduction in later cycles. They said sunitinib's role in the mesothelioma response was unclear.

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 and pharmacokinetic trial, with an expansion cohort at the maximum tolerated dose
• Who was studied: 31 patients with advanced solid malignancies in the US and Canada: 5 on the continuous daily dosing schedule, 15 in Schedule 2/1 dose escalation (including 4 with NSCLC and 1 with mesothelioma, histology not specified), and an expansion cohort of 11 (10 NSCLC, 1 epithelioid mesothelioma)
• Exposure: Drug treatment, not an asbestos exposure: oral sunitinib 37.5 or 50 mg once daily, given either continuously (CDD) or 2 weeks on and 1 week off (Schedule 2/1), plus pemetrexed 400 to 500 mg/m2 IV and cisplatin 75 mg/m2 IV every 3 weeks, for up to six 3-week cycles
• Main results:
  • On the continuous daily schedule (sunitinib 37.5 mg/day, pemetrexed 400 mg/m2, cisplatin 75 mg/m2; 5 patients), the combination was not well tolerated because of neutropenia at the end of cycle 1
  • In the continuous daily dosing group, one serious adverse event, a fatal (grade 5) intestinal perforation, was considered related to sunitinib
  • On Schedule 2/1, sunitinib 50 mg/day with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 was declared not tolerated (grade 4 neutropenia in the first patient, cumulative neutropenia in the second)
  • The Schedule 2/1 maximum tolerated dose was sunitinib 37.5 mg/day, pemetrexed 500 mg/m2 and cisplatin 75 mg/m2. In the six-patient cohort at this dose, one patient (pancreatic cancer, history of hypertension and diabetes) had a myocardial infarction considered possibly related to sunitinib
  • In the expansion cohort, the median relative dose intensity (actual compared with intended dose intensity) across all cycles was 61% for sunitinib, 78% for pemetrexed and 74% for cisplatin
  • Blood abnormalities that emerged during treatment in the expansion cohort included grade 4 neutropenia (n = 5) and grade 4 febrile neutropenia (n = 2)
  • Pharmacokinetics: sunitinib blood levels with pemetrexed and cisplatin were judged equivalent to sunitinib alone (compared with historical controls), and sunitinib did not appear to affect pemetrexed or cisplatin levels
  • Of 24 patients with measurable disease treated on Schedule 2/1, none had a complete response. Two (8.3%) had partial responses, and nine (37.5%) had stable disease lasting 8 weeks or more
  • One of the two partial responses was in the patient with malignant epithelioid mesothelioma in the MTD expansion cohort
  • Of eight NSCLC patients treated at the Schedule 2/1 MTD who could be evaluated, four (50%) had stable disease lasting 8 weeks or more as their best response, and three (38%) had progressive disease
• The authors' conclusion: The authors concluded that in patients with advanced solid malignancies, sunitinib 37.5 mg/day on Schedule 2/1 with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 was the maximum tolerated dose. They added that it often required dose reductions in later cycles because of cumulative myelotoxicity.
• Limitations the authors state:
  • Small sample size; it was unclear whether better tolerability in the expansion cohort reflected differences in prior treatment
  • The study was exploratory, and no confirmatory statistical testing was planned
  • No further mesothelioma patients were enrolled because the disease was rare at the participating sites
  • Pemetrexed and cisplatin are standard mesothelioma treatment, so how much sunitinib contributed to the mesothelioma partial response is unclear
  • Sunitinib blood levels were compared with historical controls, because sunitinib alone was not measured in this study

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), Cisplatin, Non-Small Cell Lung Cancer, Mesothelioma.

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