This is a randomized, controlled, open-label, multicenter study to characterize the
safety, tolerability, and antitumor effects of LNS8801 alone and in combination with
pembrolizumab in treatment refractory, unresectable cutaneous melanoma patients who are
homozygous for the consensus GPER protein-coding amino acid sequence (C/C) and have
progressed on prior immune checkpoint inhibitor therapy, including an anti-PD-1 therapy.
The C/C form of GPER is present in approximately 55% of patients.
Patients must initially consent to a prescreening blood-based genetic test only. Patients
with the required genotype will then consent to full screening and treatment, and the
potential physician's choice (PC) treatment will be identified. Patients will be
randomized 1:1:1 between LNS8801 + pembrolizumab, LNS8801 monotherapy, and PC treatment.
In the LNS8801 + pembrolizumab arm, LNS8801 will be administered every day per week, and
pembrolizumab will be administered 200 mg Q3W for up to 35 cycles (approximately 2 years;
Note: Physicians may modify the pembrolizumab regimen to 400 mg Q6W pembrolizumab after 6
months of treatment if appropriate). In the monotherapy arm, LNS8801 will be administered
every day per week. In the PC arm, patients may receive chemotherapy (dacarbazine,
temozolomide) or immunotherapy (pembrolizumab, nivolumab/relatlimab,
nivolumab/ipilimumab).
Patients' randomization will be stratified by normal or elevated baseline LDH, <3 or ≥3
disease sites, and physician's determination of primary vs secondary anti-PD-1 therapy
resistance per SITC guidelines; prior to randomization, the preferred PC treatment for
each patient will be identified, and the patient must be willing to receive this therapy
if assigned to the PC arm. At least one-third of patients in each arm must have had
secondary resistance to prior anti-PD-1 therapy. Patients who are on LNS8801 +
pembrolizumab combination therapy may drop one of the study medications and continue on
the other for tolerability or safety reasons. For example, if a patient has an
immune-related AE that warrants discontinuation of pembrolizumab, they should continue
LNS8801 monotherapy. Patients may choose to remain on study drugs past progression if
they are clinically stable and the treating physician believes that continued therapy is
likely to benefit the patient.
Patients may continue on LNS8801 therapy past progression and initiate localized therapy
if they are clinically stable and the treating physician believes that continued LNS8801
therapy is likely to benefit the patient. Safety assessments will be performed on all
patients at screening, throughout their participation in the study, and at either 30 days
following the last dose of study drugs if they are not taking an immune checkpoint
inhibitor (ICI) or 90 days following the last dose if their treatment included an ICI.
Measures of metabolic health (eg, circulating lipids, blood pressure, HbA1C) will also be
recorded throughout the study.
Overall survival and reason for mortality should be assessed after the last dose of study
medication, every 6 months for the first year, and then annually, until it has been 2
years since any patient has taken study medication. Any anti-cancer therapies should be
recorded.
Imaging of tumors for evidence of tumor response and/or progression will be performed at
screening (within 21 days of the first dose of study drug) and then every 8 weeks for the
first year, every 12 weeks for the second year, and every 6 months thereafter.
Up to 135 patients will be randomized in this study.
