Testing the Addition of Ipatasertib to Usual Chemotherapy and Radiation for Stage III-IVB Head and Neck Cancer

Titre officiel

Phase I/Ib Study of AKT Inhibitor Ipatasertib With Chemoradiation for Locally Advanced Head and Neck Cancer

Sommaire:

Cet essai de phase I/Ib vise à déterminer l’innocuité et la dose optimale de l’ipatasertib en association avec l’approche thérapeutique habituelle utilisant la chimiothérapie en association avec la radiothérapie (« chimioradiothérapie ») chez les patients atteints d’un cancer de la tête et du cou de stade III-IVB. L’ipatasertib appartient à une classe de médicaments appelés inhibiteurs de la protéine kinase B (AKT). Le médicament peut stopper la croissance des cellules tumorales et les éliminer. Le cisplatine, qui est une chimiothérapie utilisée dans le cadre de cet essai, fait partie d’une classe de médicaments connus sous le nom de composés à base de platine. Il agit en éliminant les cellules cancéreuses, ou en stoppant ou en ralentissant leur croissance. La radiothérapie administre une haute énergie afin de tuer les cellules tumorales et de réduire la taille des tumeurs. L’administration d’ipatasertib en association avec la chimioradiothérapie peut être meilleure que la chimioradiothérapie, en monothérapie, pour le traitement des patients atteints d’un cancer avancé de la tête et du cou.

Description de l'essai

Primary Outcome:

• Maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of ipatasertib in combination with definitive chemo-radiation

• Acute and late toxicities
• Duration and completion rate of prescribed radiation and chemotherapy
• Objective response rate
• Pharmacokinetic (PK) profile of ipatasertib in combination with cisplatin
• Pharmacodynamic effects of ipatasertib
• Locoregional control
• Relapse-free survival
• Overall survival

PRIMARY OBJECTIVE:

• To determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of ipatasertib in combination with definitive chemoradiation in locally advanced head and neck squamous cell carcinoma (HNSCC) based on dose-limiting toxicities (DLTs).

SECONDARY OBJECTIVES:

• To assess acute and late toxicities, based on Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
• To assess long-term swallowing function, based on gastric tube dependency at 6 and 12 months that is different from baseline.
• To determine duration and completion rate of prescribed radiation and chemotherapy.
• To determine pharmacokinetic profile of ipatasertib in combination with cisplatin and radiation therapy, based on peak and trough blood levels in patients administered ipatasertib orally.
• To determine pharmacodynamic effects of ipatasertib at the MTD, based on pAKT, pS6 and pPRAS40 as markers of AKT pathway inhibition, and gamma-H2AX as a marker of radiosensitization.
• To observe and record anti-tumor activity (objective response rate) by Response Evaluation Criteria in Solid Tumours (RECIST) criteria, locoregional control, relapse-free survival, and overall survival) of the combination of ipatasertib, cisplatin, and radiation therapy in patients with HNSCC.
• To correlate efficacy outcomes with tumour genotype, based on whole exome sequencing of pre-treatment biopsy specimens.

OUTLINE: This is a phase I, dose-escalation study of ipatasertib in combination with fixed-dose cisplatin and radiation therapy followed by a dose-expansion study.

DOSE ESCALATION:

Patients receive ipatasertib orally (PO) once daily (QD) on days 1-28 of each cycle. Patients also receive cisplatin intravenously (IV) on days 1, 8, 15, and 22 of cycle 1 and days 1, 8, and 15 of cycle 2. Patients undergo radiation therapy (RT) daily (Monday-Friday) during weeks 1-7. Treatment repeats every 28 days for a total of 2 cycles in the absence of disease progression or unacceptable toxicity.

DOSE EXPANSION:

Patients receive ipatasertib PO QD on days 2-28 or 3-28 of cycle 1 and 1-28 of subsequent cycles. Patients also receive cisplatin IV on days 1, 8, 15, and 22 of cycle 1 and days 1, 8, and 15 of cycle 2. Patients undergo RT daily (Monday-Friday) during weeks 1-7. Treatment repeats every 28 days for a total of 2 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days, and then for up to 2 years.

Voir cet essai sur ClinicalTrials.gov