Abstract PO2-19-05: Randomized Phase II trial evaluating three anti-diarrhoeal prophylaxis strategies in patients with HER2+/HR+ early breast cancer treated with extended adjuvant neratinib (DIANER GEICAM/2018-06)
Authors: Gil-Gil Miguel , Martín Miguel , Carrasco Eva , Galve Elena , Martínez-Jáñez Noelia , González-Santiago Santiago , Adamo Barbara , Valero María , Martínez Clara , Guerrero Angel , Novoa Silvia Antolin , Ruíz - Borrego Manuel , Blancas Isabel , Andrés Raquel , Alonso-Romero José L , Vethencourt ANDREA , Chacón J. Ignacio , Chavarría Natalia , Espinosa Enrique , Hernando Blanca , Adrover Encarnación , Rojo Federico , Casas Maribel , McCulloch Leanne , Vedovato Jean-Claude 
Published: May 2024

Background: Neratinib (NER), and irreversible pan-HER tyrosine kinase inhibitor, is approved for the extended adjuvant treatment of HER2+/HR+ early breast cancer (EBC) patients within 1 year of trastuzumab (T)-based therapy completion. The ExteNET trial showed that the extended adjuvant NER compared with placebo modifies the risk of recurrence by an absolute rate of 2.5% at 5 years in HR+/HER2+ patients (Martin et al., 2017). However, without prespecified prophylaxis, diarrhoea was the most common reason for NER discontinuation in the first three cycles in said study.

The CONTROL trial evaluated effectiveness of different anti-diarrhoeal strategies showing a reduction of severe diarrhoea and early discontinuation when indirectly compared to ExteNET (Chan et al., 2022). DIANER (NCT05252988) evaluates the 3 best reported anti-diarrhoeal strategies from CONTROL in patients receiving NER as per European approved label.

Trial design and patients: DIANER is an international, multicenter, controlled, randomized, phase II study. Patients with HER2+/HR+ EBC (stage IB-IIIC) who completed prior neo/adjuvant T-based therapy within 2 weeks and 1 year will be included and randomized 1:1:1 to 3 treatment arms. Arm A: NER (240 mg/day[d] x 1 year) + loperamide (12 mg/d x 14 d → 8 mg/d till end of cycle 2 → as needed [PRN]), Arm B: NER dose escalation (120 mg/d x 7 d → 160 mg/d till d 14 → 240 mg/d x 13 cycles) + loperamide PRN, and Arm C: NER (like Arm A) + loperamide (12 mg/d x 14 d → 8 mg/d till end of cycle 1 → PRN) + colesevelam (3,750 mg/d x 28 d). Patients are stratified by menopausal status and prior anti-HER2 therapy (T versus T + pertuzumab).

Specific aims: Primary objective is incidence of NER discontinuations due to diarrhoea in the first 3 cycles. Secondary objectives are: incidence of NER discontinuations; AEs and hospitalizations; duration, severity, and treatments for diarrhoea; NER exposure; and health-related quality of life (HRQoL) using FACT B and EQ5D-5L. Exploratory objectives include HRQoL using STIDAT; minimal residual disease and molecular alterations.

Statistical methods: A maximum of 315 pts (105 per arm) will be needed using a Simon’s optimal two-stage design with the hypotheses of a desirable early discontinuation rate of 5% (H1) versus an undesirable early discontinuation rate of 13% (H0). In the first stage, arms with ≥ 4 pts discontinuing due to diarrhoea in the first 3 cycles, will be closed for enrolment.

The 2-sided 90% confidence intervals using the method described by Koyama et al. (Koyama and Chen 2008) will be provided for the primary endpoint at the end of the 2nd stage of the Simon 2-stage design.

Present accrual and target accrual: DIANER will take place in 81 sites in 5 European countries. As of Jul 10/2023 the study is open in 52 sites in Spain with 80 randomized patients.

Contact information for people with a specific interest in the trial:

Evelia Cortazar (Geicam PM): ecortazar@geicam.org

Citation Format: Miguel Gil-Gil, Miguel Martín, Eva Carrasco, Elena Galve, Noelia Martínez-Jáñez, Santiago González-Santiago, Barbara Adamo, María Valero, Clara Martínez, Angel Guerrero, Silvia Antolin Novoa, Manuel Ruíz - Borrego, Isabel Blancas, Raquel Andrés, José L Alonso-Romero, ANDREA Vethencourt, J. Ignacio Chacón, Natalia Chavarría, Enrique Espinosa, Blanca Hernando, Encarnación Adrover, Federico Rojo, Maribel Casas, Leanne McCulloch, Jean-Claude Vedovato. Randomized Phase II trial evaluating three anti-diarrhoeal prophylaxis strategies in patients with HER2+/HR+ early breast cancer treated with extended adjuvant neratinib (DIANER GEICAM/2018-06) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-05.