Tolinapant

Dose escalation of tolinapant (ASTX660) in combination with standard radical chemoradiotherapy in cervical cancer : a study protocol for a phase 1b TiTE-CRM clinical trial (CRAIN) in UK secondary care centres

**Background:** Cervical cancer is the fourth most common cancer affecting women, with approximately 342,000 deaths worldwide in 2020. In the UK, the current standard treatment for locally advanced cervical cancer is concurrent chemoradiotherapy (CRT) with weekly cisplatin. However, the 5-year overall survival rate is only 65%, and the rate of distant relapse remains at 50%. Inhibitors of Apoptosis Proteins (IAPs) are often overexpressed in cancer cells, contributing to tumor progression and treatment resistance. Tolinapant, developed by Astex Pharmaceuticals, is an IAP antagonist with an additional action mechanism involving the down-regulation of NF-kB, a key regulator in cervical cancer. Preclinical studies of tolinapant in combination with cisplatin and radiotherapy have shown promising results in inhibiting tumor growth and improving survival. This provides a strong rationale for combining tolinapant with CRT.

**Methods:** The CRAIN study is a phase Ib, open-label, dose-escalation trial designed to evaluate the safety, tolerability, and initial clinical activity of tolinapant in combination with cisplatin-based CRT. Up to 42 patients with newly diagnosed cervical cancer will be recruited from six secondary care sites in the UK. The trial duration and participant numbers will be determined by observed toxicities and dose-escalation decisions using a TiTE-CRM statistical design. Patients will receive standard CRT consisting of 45 Gy external beam radiotherapy delivered in 25 daily fractions over 5 weeks, alongside weekly cisplatin (40 mg/m²). Following this, brachytherapy will be administered, with typical schedules being either 28 Gy in 4 fractions (high-dose-rate) or 34 Gy in 2 fractions (pulsed-dose-rate). Tolinapant will be given as fixed-dose oral capsules for seven consecutive days on alternate weeks (weeks 1, 3, and 5) during chemoradiation. The tolinapant dose levels to be evaluated include: 60 mg, 90 mg (starting level), 120 mg, 150 mg, and 180 mg, with dose escalation guided by safety data and the Safety Review Committee.

**Discussion:** If this trial identifies a recommended phase II dose and demonstrates the safety and efficacy of tolinapant in combination with CRT, it would support further phase trials. The ultimate goal is to offer a synergistic treatment option that improves outcomes for patients with cervical cancer.