Nivolumab dose optimization during nivolumab therapy in melanoma patients after achieving a complete, partial or stable response (NIVOPTIMIZE-trial)

Patients with advanced melanoma or renal cell carcinoma are, amongst others,
currently treated with nivolumab monotherapy or with nivolumab and ipilimumab
followed by nivolumab. Even though registration studies administered nivolumab
in a 3 mg/kg 2 weekly scheme, currently, nivolumab monotherapy is either
administered in a 240 mg 2-weekly scheme or in a 480 mg of 6mg/kg 4-weekly
scheme. With the current dosing regimen, steady-state is achieved after
approximately 5 to 6 months, whereas a tumor response is usually observed
earlier in patients with metastatic melanoma and renal cell carcinoma.
Moreover, PD-1 receptor occupancy is almost saturated above doses of 0.3 mg/kg,
or at nivolumab serum levels of 10 mg/L, which is a concentration that is
achieved after one treatment cycle. In melanoma patients, the additional
probability on response in patients treated with 3 mg/kg compared to 1 mg/kg
seems limited. PFS and OS for 3 mg/kg were not superior to 1 mg/kg. Therefore,
in this study, our aim is to investigate nivolumab trough levels and
pharmacokinetic parameters after 3 reduced nivolumab doses.

This study has been transitioned to CTIS with ID 2024-516718-39-00 check the CTIS register for the current data.

The primary objective is to demonstrate that the nivolumab steady-state level
after 3 cycles with a reduced nivolumab dosage (240 mg every 4 weeks) is not
lower than the nivolumab concentration 4 weeks after the first 480 mg or 6mg/kg
dose. Secondary objectives are to explore the cost-effectiveness of the
alternative dosing regimen, the pharmacokinetic profile of nivolumab, the
safety and efficacy of the alternative dosing regimen, and the PD-1 receptor
occupancy in PBMCs.

Single-centre, single-arm, pharmacokinetic intervention trial.

Three reduced doses of nivolumab 240 mg every 4 weeks in patients having a
confirmed CR, PR or SD at least 6 months after treatment start.

Patients with a confirmed response or stable disease (CR, PR or SD) and are at
least 6 months on treatment, will be asked to participate in this trial and
receive three doses of 240 mg nivolumab instead of 480 mg or 6mg/kg. Therefore,
theoretically, participation in this trial may affect clinical outcome in these
patients. However, an increasing number of physicians discontinues treatment
early at achieving CR, PR or SD, based on durable responses after treatment
discontinuation. Therefore, the additional risk of participation in this trial
is considered limited compared to daily clinical practice.