NCT04250246

A Study of NIVO Plus IPI and Guadecitabine or NIVO Plus IPI in Melanoma and NSCLC Resistant to Anti-PD1/PDL1

A Randomized, run-in, Multi-center, Phase II Study of Nivolumab Combined With Ipilimumab and Guadecitabine or Nivolumab Combined With Ipilimumab in Melanoma and NSCLC Patients Resistant to Anti-PD-1/PD-L1 (NIBIT-ML1)

• Status: Unknown
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 184 (estimated)
• Sponsor: Italian Network for Tumor Biotherapy Foundation · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

This is a run-in, randomized, non-comparative, phase II study designed according to a two stages optimal design by Simon. This phase II design will be preceded by a safety evaluation after the first cohort of 6 patients to preserve a high-grade of overlapping and/or unexpected toxicity rate. The study will assess the immune-objective response rate (iORR) (assessed using iRECIST criteria) of nivolumab combined with ipilimumab and guadecitabine or nivolumab combined with ipilimumab, in Melanoma and non-small cell lung cancer (NSCLC) patients resistant to anti-PD-1/PD-L1 therapy. Immune biologic correlates to treatment will be assessed as exploratory endpoints.

Detailed description

Epigenetic alterations play a pivotal role in cancer development and progression. Pharmacologic reversion of such alterations is feasible, second generation "epigenetic drugs" are in development and have demonstrated to possess significant immunomodulatory properties. This knowledge, together with the availability of new and highly effective immuno-therapeutic agents including immune check-point(s) blocking monoclonal antibodies, allows the investigators to plan for highly innovative proof-of-principle combination studies that will likely open the path to more effective anti-cancer therapies. Targeting immune check-point(s) with immunomodulatory monoclonal-antibodies is a novel and rapidly evolving strategy to treat cancer, that is rapidly spreading to different tumor histologies. The prototype approach of this therapeutic modality relies on the inhibition of negative signals delivered by CTLA-4 expressed on T lymphocytes. CTLA-4 blockade has profoundly changed the therapeutic landscape of melanoma, significantly improving the survival of patients; however, objective clinical responses are limited, and only a minority of patients achieves long-term disease control. Therefore, several combination approaches are being explored to improve the efficacy of CTLA-4 blockade. The anti-PD-1 monoclonal antibodies, nivolumab and pembrolizumab, have significantly increased the survival of melanoma and NSCLC patients. Despite this unprecedented efficacy, a significant proportion of melanoma and NSCLC patients fails to respond (primary resistance) or develops secondary resistance to anti-PD-1 treatment over time. Therefore, identifying new mechanism(s) underlying treatment failure(s), and designing novel combination/sequencing therapeutic approaches to overcome primary/secondary resistance is mandatory to improve the overall efficacy of anti-PD-1 therapy. The investigators have first demonstrated that epigenetic immune-modeling of cancer cells represents a key hallmark of cancer, as it impairs functional host's immune recognition of malignant cells; on the other hand, the investigators have shown the potential of epigenetic drugs, including DNA hypomethylating agents (DHA), to sensitize tumor cells to emerging immunotherapies. Based on these pre-clinical in vitro and in vivo findings, the investigators have most recently promoted the clinical translation of the immunomodulatory potential of epigenetic drugs through highly-innovative, hypothesis-driven, clinical trials. Along this line, the ongoing, exploratory, Investigator Initiated Trial (IIT) phase Ib NIBIT-M4 study, has evaluated safety and immunobiologic activities of the epigenetic priming with the next generation DHA guadecitabine followed by CTLA-4 blockade in MM patients (NCT02608437). The results of NIBIT-M4 study support the notion that DHA represent ideal "partner drugs" to improve the therapeutic efficacy of immune-checkpoint blockade, including the foreseeable role in reverting resistance to treatment. The NIBIT-ML1 study will assess the therapeutic efficacy of nivolumab combined with ipilimumab and guadecitabine or nivolumab combined with ipilimumab, in metastatic melanoma and NSCLC patient with primary resistance to anti-PD-1/PD-L1 therapy. Exploratory translational objectives will extensively investigate, on neoplastic cells, tumor microenveroinment and peripheral blood, immune-biologic correlates to treatment.

Conditions

• Melanoma
• Non Small Cell Lung Cancer

Interventions

Type	Name	Description
DRUG	Ipilimumab plus nivolumab plus guadecitabine	Cohort A Melanoma ARM A Guadecitabine: 30-45 mg/m2 s.c./day 1-5 q21 x 4 cycles and from W13 q28 x 6 cycles Ipilimumab: 3 mg/Kg i.v. plus nivolumab 1 mg/Kg i.v. on W1, 4, 7 and 10 and from W14 nivolumab 480 mg i.v. q4 wks for 2 years Cohort B NSCLC ARM A Guadecitabine: 30-45 mg/m2 s.c./day 1-5 q21 x 4 cycles and from W13 q28 x 6 cycles Ipilimumab: 1 mg/Kg i.v.q 6wks plus nivolumab 3 mg/Kg i.v. q2 wks until W13, then ipilimumab: 1 mg/Kg i.v. q 6wks plus nivolumab 480mg i.v. q4wks for 2 years
DRUG	Ipilimumab plus nivolumab	Cohort A Melanoma ARM B Ipilimumab: 3 mg/Kg i.v. plus nivolumab 1 mg/Kg i.v. on W1, 4, 7 and 10 and from W14 nivolumab 480 mg i.v. q4 wks for 2 years Cohort B NSCLC ARM B Ipilimumab: 1 mg/Kg i.v. q 6wks plus nivolumab 3 mg/Kg i.v. q2 wks until W13, then ipilimumab: 1 mg/Kg i.v. q6 wks plus nivolumab 480mg i.v. q4wks for 2 years.

Timeline

• Start date: 2020-03-01
• Primary completion: 2023-03-01
• Completion: 2025-03-01
• First posted: 2020-01-31
• Last updated: 2020-01-31

Locations

1 site across 1 country: Italy