123P - A phase II study of nivolumab (N) plus ipilimumab (I) and ASTX727 or N plus I in PD-1/PD-L1 resistant melanoma or NSCLC patients: the run-in phase of the NIBIT Foundation ML1 Study

Background

Our phase Ib NIBIT Foundation M4 study firstly reported that administration of the hypomethylating agent (DHA) guadecitabine (guade), a prodrug of decitabine (D), followed by I in metastatic melanoma (MM) patients (pts) is safe and has promising clinical and tumor immune-modulating activity (Di Giacomo, CCR 2019). To further explore the activity of DHA combined with immune-checkpoints blockade, the NIBIT-ML1 trial is investigating the efficacy of guade plus I and N in PD-1/PD-L1 resistant MM or NSCLC pts. The run-in phase of the study is reported.

Methods

The NIBIT-ML1 is a randomized, phase II study (Simon two stages optimal design), in unresectable Stage III/IV MM (Cohort A) or NSCLC (Cohort B) pts progressing to anti-PD-1/PD-L1. A trial amendment substituted guade with ASTX727, an oral formulation of D with cedazuridine. Following the safety run-in of 6 subjects per Cohort, eligible pts are randomized to ASTX727 plus I and N or I and N. Primary objective is immune(i)-ORR; secondary are safety, DCR, PFS, median OS, survival rate at 1- and 2-year. For PK analyses D was measured in plasma as active drug after oral ASTX727 or as active metabolite after s.c. guade. Extensive cellular and molecular immunocorrelates are also explored.

Results

Cohort A. Six pts [4 male; median age 71 years, ECOG 0-1] with Stage III/IVMM, received guade (2 pts) or ASTX727 (4 pts) plus I and N. No DLT or overlapping toxicities occurred. Any grade (G) treatment-related AEs occurred in 6 (100%) pts, 50% were G3/4. Three PR, 2 SD, and 1 PD were observed. Cohort B. Six pts [2 male; median age 70 ECOG 0-1] with Stage III/IV NSCLC received guade (2 pts) or ASTX727 (4 pts) plus I and N. Two DLTs occurred. Any G treatment-related AEs occurred in 5 (83.3%) pts, 67% were G3/4. One CR, 2 SD and 3 PD were observed. PK analyses showed that D systemic exposures (mean AUC) dosed as 20mg ASTX727 and dosed at 80mg guade (∼45 mg/m²) were similar. Mean (% CV) D AUC 0-24 for combined Cohorts A and B after ASTX727 was 114 (90%) ng*hr/mL (n=8), and after guade was 110 (21%) ng*hr/mL (n=4).

Conclusions

Treatment with ASTX727 plus I and N is feasible in PD-1/PD-L1 refractory MM and NSCLC pts. The Stage 1 of the NIBIT-ML1 study is recruiting.

Clinical trial identification

NCT04250246, EudraCT 2019-002986-36.

Legal entity responsible for the study

NIBIT Foundation Onlus.

Funding

NIBITFoundation Onlus with unresctricted grant from Astex Pharmaceuticals and Bristol Myers Squibb.

Disclosure

A.M. Di Giacomo: Financial Interests, Personal, Advisory Board: Incyte, Pierre Fabre, GSK, Bristol Myers Squibb, Merck Sharp Dohme, Sanofi; Financial Interests, Personal, Other, Educational activities: Bristol Myers Squibb, Merck Sharp Dohme, Pierre Fabre, Sanofi. L. Calabro: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck Sharp and Dohme, Roche; Financial Interests, Personal, Other, Educational activities: Bristol Myers Squibb, AstraZeneca, Sanofi. M. Valente: Financial Interests, Personal, Advisory Board: Novartis. H.N. Keer, A. Oganesian, D. Chan: Financial Interests, Personal, Full or part-time Employment: Astex Pharmaceuticals. M. Ceccarelli: Financial Interests, Personal, Advisory Board: Moderna Therapeutics; Financial Interests, Personal, Funding: Immunomica srl. M. Maio: Financial Interests, Personal, Advisory Board: Roche, Bristol Myers Squibb, Merck Sharp Dohme, Incyte, AstraZeneca, Amgen, Pierre Fabre, Eli Lilly, GSK, Sciclone, Sanofi, Alfasigma, Merck Serono; Financial Interests, Personal, Ownership Interest: Theravance, Epigen Therapeutics, Srl. All other authors have declared no conflicts of interest.