Abstract 4463
Background
Irinotecan is widely used, but also known for its severe toxicities neutropenia and diarrhea. Based on preclinical data, combined caloric and protein restriction (CCPR) might improve treatment tolerability without impairing antitumor effect. Therefore, we studied the influence of CCPR on irinotecan pharmacokinetics and toxicity.
Methods
In this cross-over trial, patients with liver metastases of solid tumors were included and randomized to treatment with irinotecan preceded by 5 days of CCPR (∼30% caloric and ∼70% protein restriction) during the 1st cycle and a 2nd cycle preceded by a normal diet (ND) or vice versa. During both cycles, 24-hours blood sampling was performed and 24-26 hours after infusion biopsies of both healthy liver (HL) and liver metastasis (LM) were taken. Primary endpoint was the relative difference in geometric means for the active metabolite SN-38 concentration in HL, as analyzed by a linear mixed model. Secondary endpoints included irinotecan and SN-38 concentrations in LM, plasma area under the curve (AUC0-24h), and toxicity.
Results
Interpatient variability (n = 19) in tissue irinotecan and SN-38 concentrations was high, showing no significant differences in irinotecan (+16.8%, 95% CI: -9.7-51.1%, P = 0.227) and SN-38 (+9.8%, 95% CI: -16.4-44.2%, P = 0.48) concentrations between CCPR and ND in HL, as well as in LM (irinotecan: -38.8%, 90% CI: -59.3:-7.9%, P = 0.05 and SN-38: -13.8%, 90% CI:-40.7-25.4%, P = 0.50). CCPR increased irinotecan plasma AUC0-24h with 7.1% (95% CI: 0.3-14.5%, P = 0.04) compared to ND, while the SN-38 plasma AUC0-24h increased with 50.3% (95% CI: 34.6-67.9%, P < 0.001). CCPR was well tolerated with low incidence of grade ≥3 therapy related toxicity. Grade ≥3 toxicity was not increased during CCPR vs ND (P = 0.69). No difference was seen in neutropenia grade ≥3 (47% vs 32% P = 0.38), diarrhea grade ≥3 (5% vs 21% P = 0.25), febrile neutropenia (5% vs 16% P = 0.50) and hospitalization (11% vs 21% P = 0.634) during CCPR vs ND.
Conclusions
CCPR resulted in a dramatically increased plasma SN-38 exposure, while toxicity did not change. CCPR did not result in altered irinotecan and SN-38 exposure in HL and LM. CCPR might therefore potentially improve the therapeutic window in patients treated with irinotecan.
Clinical trial identification
Netherlands Trial Register NL5624 (NTR5731) release date: 2016-03-04.
Editorial acknowledgement
Legal entity responsible for the study
A.H.J. Mathijssen.
Funding
Has not received any funding.
Disclosure
S.L. Koolen: Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Pfizer; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Cristal Therapeutics; Travel / Accommodation / Expenses: Ipsen. R.H.J. Mathijssen: Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Boehringer; Research grant / Funding (institution): Cristal Therapeutics; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pamgene; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi; Honoraria (institution): Servier; Honoraria (institution): Novartis; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Astellas. All other authors have declared no conflicts of interest.
Resources from the same session
2262 - Real world experience of Nivolumab therapy in Metastatic Renal Cancer patients: a 3 year multi-centre review
Presenter: Joanna Hack
Session: Poster Display session 3
Resources:
Abstract
4441 - “A pilot study of tremelimumab (treme) with or without cryoablation (cryo) in patients (pts) in metastatic renal cell carcinoma (mRCC).”
Presenter: Matthew Campbell
Session: Poster Display session 3
Resources:
Abstract
2613 - Lenvatinib (Len) alone or in combination with Everolimus (Eve) in heavily pretreated patients (pts) with metastatic renal cell carcinoma (mRCC) after immune checkpoint inhibitors (ICI) and VEGFR-targeted therapies: A single-institution experience
Presenter: Andrew Wiele
Session: Poster Display session 3
Resources:
Abstract
3249 - Weight loss is an underestimated adverse event with cabozantinib in patients with metastastic renal cell carcinoma (mRCC).
Presenter: Emeline Colomba
Session: Poster Display session 3
Resources:
Abstract
2405 - Impact of corticosteroids on nivolumab activity in metastatic clear cell renal cell carcinoma.
Presenter: Felix Lefort
Session: Poster Display session 3
Resources:
Abstract
4020 - Skeletal muscle loss as an adverse event during Cabozantinib treatment in patients with metastatic renal cell carcinoma
Presenter: Carolina Alves Costa Silva
Session: Poster Display session 3
Resources:
Abstract
2407 - Long term relative survival (RS) in patients with primary metastatic kidney cancer (primary mRCC): an analysis of 2,167 patients from the Austrian National Cancer Registry (ANCR).
Presenter: Monika Hackl
Session: Poster Display session 3
Resources:
Abstract
2470 - Advanced renal cell carcinoma: first results from the prospective research platform CARAT for patients with mRCC in Germany
Presenter: Peter Goebell
Session: Poster Display session 3
Resources:
Abstract
1533 - Are immune checkpoint inhibitors a valid option for papillary Renal Cell Carcinoma? Transcriptomic characterization of the immune infiltrate
Presenter: Manon De Vries-brilland
Session: Poster Display session 3
Resources:
Abstract
3367 - Treatment-Free Survival, With and Without Toxicity, as a Novel Outcome Applied to Immuno-Oncology Agents in Advanced Renal Cell Carcinoma
Presenter: Meredith Regan
Session: Poster Display session 3
Resources:
Abstract