Short summary

A multicentre, single-arm, phase II study to investigate the safety and antiemetic efficacy of Akynzeo® (a fixed dose combination of palonosetron and netupitant) plus dexamethasone in patients receiving concomitant chemo-radiotherapy with weekly cisplatin for at least five weeks.

The purpose of this study is to investigate the safety and the antiemetic efficacy of Akynzeo during weekly administration for five weeks in women with cervical cancer treated with fractionated radiotherapy and concomitant weekly cisplatin.

Rationale

Chemotherapy-induced nausea and vomiting (CINV) are some of the most feared side-effects to cancer treatment and improved control of emesis is highly effective in reducing the impact of CINV on patients' daily lives. About 40% of patients receiving radiotherapy will experience nausea and/or vomiting (RINV). In order to enhance the efficacy of radiotherapy and to treat micrometastatic disease, a number of cancer diseases are treated with concomitant chemotherapy. It is reasonable to believe that concomitant chemotherapy increases the risk of nausea and vomiting.

The first randomised study investigating the role of a neurokinin (NK)1-receptor antagonist (RA) in fractionated radiotherapy and concomitant chemotherapy was published in 2016. This was a multinational, randomised, double blind, phase III trial (GAND-emesis study) in patients treated with radiotherapy and concomitant weekly cisplatin (40 mg/m²), and the study showed, that the NK1-RA, fosaprepitant (a prodrug of aprepitant), was able to increase the number of patients with sustained no emesis (i.e. no emesis during 5 weeks of treatment) by 17%, when added to a combination of palonosetron plus dexamethasone (subhazard ratio 0.58; p = 0.008). The study also demonstrated that there was no increased toxicity when fosaprepitant (150 mg as a single intravenous dose on the day of chemotherapy) was administered weekly compared to the placebo regimen.

At the time the GAND-emesis study was conducted, aprepitant/fosaprepitant were the only NK1-RAs approved by FDA and EMA. Since then two other NK1-RAs have been approved. Netupitant and rolapitant are both approved by FDA and EMA. Netupitant and rolapitant have not been investigated for toxicity when administered weekly and furthermore they have not been investigated in antineoplastic treatment including radiotherapy. Given the considerable differences in plasma half-life between fosaprepitant/aprepitant (  ?9-13 hours), netupitant  (  ?88 hours), and rolapitant (  ?180 hours), the safety during weekly administration of fosaprepitant/aprepitant does not necessarily apply to netupitant and rolapitant.

The single day dosing of the NK1-RA will in theory enhance compliance and hence may improve antiemetic prophylaxis. Therefore, it is clinically relevant to investigate the safety of weekly administration of the new single day NK1-RA treatment options.

Akynzeo (hard capsule for oral use) is a fixed dose combination of the NK1-RA netupitant (300 mg) and the 5-HT3-RA palonosetron (0.5 mg). The antiemetic efficacy of netupitant  300 mg plus oral palonosetron 0.5 mg administered 1 hour before chemotherapy seems to be  comparable to that of aprepitant 125 mg administered 1 hour before chemotherapy (Day 1), 80 mg Day 2, and 80 mg Day 3 plus ondansetron 32 mg before chemotherapy, both combined with dexamethasone.

The purpose of this study is to investigate the safety and the antiemetic efficacy of Akynzeo during weekly administration for 5 weeks in patients receiving fractionated radiotherapy and concomitant weekly cisplatin.

The co-primary objectives of this study are to explore the safety and efficacy of an antiemetic regimen consisting of Akynzeo and dexamethasone during five weeks of fractionated (5 days a week) radiotherapy and concomitant weekly cisplatin at a dose of ? 40 mg/m2.

The secondary objectives are to investigate Akynzeo and dexamethasone in terms of 1) the proportion of subjects with complete response (defined as no vomits, no dry retches and no need for rescue medication), 2) the proportion of subjects with no significant nausea (none or mild nausea), and 3) the proportion of subjects with no nausea, all in the 5 days and the 35 days following initiation of fractionated radiotherapy and concomitant weekly cisplatin at a dose of ? 40 mg/m². Finally, 4) to investigate Akynzeo and dexamethasone in terms of time to first emetic episode.

Description of the cohort

Patients diagnosed with cervical cancer and scheduled to receive fractionated radiotherapy and concomitant weekly cisplatin.

Data and biological material

We will collect data from patient diaries specified for this study and adverse events data prospectively collected during the study.

Collaborating researchers and departments

Klinisk Onkologisk Afdeling og Palliative Enheder, Sjællands Universitetshospital Roskilde

• Jørn Herrstedt, Professor, MD, DMSci

Onkologisk Klinik, Rigshospitalet, Copenhagen University Hospital

• Trine Jakobi Nøttrup, MD, PhD