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2 results on '"Daniel DiPrimeo"'

1. Preclinical and clinical evaluation through serial colonoscopic evaluation of neratinib‐induced diarrhea in HER2‐positive breast cancer—A pilot study

Author

Joanne Bowen, Sofia Braga, Valeria Dal Zotto, John Finnie, Daniel DiPrimeo, Blaire Cooke, Georg F. Bischof, Alvin Wong, and Jack A. Di Palma

Subjects
colonoscopy study, diarrhea, HER2‐positive breast cancer, neratinib, rat model, Physiology, QP1-981
Abstract

Abstract The irreversible pan‐HER tyrosine kinase inhibitor neratinib is approved for patients with HER2‐positive, early‐stage and metastatic breast cancer (BC). Neratinib‐associated diarrhea is the most common reason for early discontinuation. Preclinical studies identified mechanisms of neratinib‐induced diarrhea and rationale for prophylactic and preventive measures. We studied effects of neratinib on rat intestines and conducted a phase 2 study of colon pathogenesis in patients with HER2‐positive BC treated with neratinib (NCT04366713). Colon samples from female albino Wistar rats receiving neratinib or vehicle were examined for histopathological changes. Patients with HER2‐positive BC received neratinib 240 mg once daily for up to 1 year. Colonoscopy biopsies were collected at baseline and at Day 28 to identify changes consistent with rat pathologies. Rat colons were markedly altered in appearance, with similar short circuit currents (Isc) and responses to carbachol and forskolin. Mucosal barrier loss and/or significant increase in secretory propensity in neratinib‐ versus control‐treated animals were not seen. Two of four endpoint‐evaluable patients presented with mild pathological changes, largely comparable with the rat model. Preclinical evidence supports an inflammatory component of neratinib‐induced diarrhea without mucosal barrier function loss. Colonoscopy findings in patients with BC indicate mild or no pathological changes in the colon due to neratinib treatment.

Published
2024
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2. Final findings from the CONTROL trial: Strategies to reduce the incidence and severity of neratinib-associated diarrhea in patients with HER2-positive early-stage breast cancer

Author

Arlene Chan, Manuel Ruiz-Borrego, Gavin Marx, A. Jo Chien, Hope S. Rugo, Adam Brufsky, Michael Thirlwell, Maureen Trudeau, Ron Bose, José A. García-Sáenz, Daniel Egle, Barbara Pistilli, Johanna Wassermann, Kerry A. Cheong, Benjamin Schnappauf, Dieter Semsek, Christian F. Singer, Navid Foruzan, Daniel DiPrimeo, Leanne McCulloch, Sara A. Hurvitz, and Carlos H. Barcenas

Subjects
Diarrhea, Health-related quality of life, Clinical Trials and Supportive Activities, Clinical Sciences, Diarrhea prophylaxis, Neratinib, Tyrosine kinase inhibitor, Breast Neoplasms, Loperamide, Breast cancer, ErbB-2, Clinical Research, Antineoplastic Combined Chemotherapy Protocols, Humans, Oncology & Carcinogenesis, Budesonide, Cancer, Dose escalation, Incidence, Prevention, Early stage, Evaluation of treatments and therapeutic interventions, General Medicine, Health -related quality of life, HER2-positive, Good Health and Well Being, 6.1 Pharmaceuticals, Colestipol, Quality of Life, Public Health and Health Services, Surgery, Female, Receptor
Abstract

BackgroundNeratinib is an irreversible pan-HER tyrosine kinase inhibitor approved for HER2-positive early-stage and metastatic breast cancer. Diarrhea is the most frequent side effect and the most common reason for early discontinuation. The phase II CONTROL trial investigated antidiarrheal prophylaxis or neratinib dose escalation (DE) for prevention of diarrhea. We present complete study results including final data for two DE strategies.MethodsPatients who completed trastuzumab-based adjuvant therapy received neratinib 240mg/day for 1 year. Early cohorts investigated mandatory prophylaxis with loperamide, then additional budesonide or colestipol. Final cohorts assessed neratinib DE over the first 2 (DE1) or 4 weeks (DE2). The primary endpoint was incidence of grade ≥3 diarrhea. Health-related quality of life (HRQoL) was assessed using FACT-B and EQ-5D-5L.Results563 patients were enrolled into six cohorts. All strategies reduced grade ≥3 diarrhea with the lowest incidence in DE1 (DE1 13%; colestipol+loperamide [CL] 21%, DE2 27%; budesonide+loperamide [BL] 28%; loperamide [L] 31%; colestipol+loperamide as needed [CL-PRN] 33%). Diarrhea-related discontinuations occurred early and were lowest in DE1 (DE1 3%; CL 4%; DE2 6%; CL-PRN 8%; BL 11%; L 20%). More patients stayed on neratinib for the prescribed period versus historical controls. Prior pertuzumab use did not affect rates of grade ≥3 diarrhea, diarrhea-related discontinuations, or treatment duration. Early transient reductions in HRQoL scores were observed.ConclusionsThese complete results from CONTROL show improved neratinib tolerability with proactive management at the start of therapy. Two-week neratinib DE with loperamide as needed was particularly effective.ClinicaltrialsGov registration numberNCT02400476.

Published
2023

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