A Phase 1/2 First-in-Human Study of DCC-3116 as Monotherapy and in Combination with RAS/MAPK Pathway Inhibitors in Patients with Advanced or Metastatic Solid Tumors with RAS/MAPK Pathway Mutations
Brief description of study
Study DCC-3116-01-001 is a FIH study of DCC-3116 to evaluate safety and preliminary activity of DCC-3116 as monotherapy, and in combination with the mitogen activated protein kinase kinase (MAPK/ERK kinase=MEK) inhibitor trametinib, the MEK inhibitor binimetinib, and in combination with a KRAS G12C inhibitor, sotorasib. The objective of the study is to identify the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of DCC-3116 as monotherapy and in combination with trametinib, or binimetinib or sotorasib in the Dose Escalation Phase (Part 1). The purpose of Expansion Cohorts 1 through 3 in the Dose Expansion Phase (Part 2) is to demonstrate the antitumor activity of DCC-3116 combination with trametinib in RAS/MAPK pathway mutant tumors where autophagy has been implicated as a mechanism of resistance to MAPK pathway inhibitors such as the MEK inhibitor, trametinib. The RP2D of the combination with trametinib (RP2D-CT) will be used in 3 expansion cohorts (Figure 2) to further evaluate safety and efficacy of the combination. As described above, DCC-3116 inhibits autophagy induced by the treatment with trametinib, and the combination of DCC-3116 with trametinib showed antitumor activity in various xenograft models with RAS/MAPK pathway mutant tumors including pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and melanoma. The purpose of Expansion Cohort 4 in the Dose Expansion Phase (Part 2) is to demonstrate the antitumor activity of DCC-3116 in combination with binimetinib in NRAS mutant melanoma. The RP2D of the combination with binimetinib (RP2D-CB) will be used in Expansion Cohort 4 (Figure 2) to further evaluate safety and efficacy of the combination. Like trametinib, binimetinib inhibits MEK and preclinical studies in xenograft models have demonstrated improved anticancer efficacy in combination with DCC-3116. While more clinical data exist for trametinib as monotherapy in other solid cancers, in NRAS mutant melanoma binimetinib monotherapy has been studied more (Dummer et al, 2017). Therefore, binimetinib is planned for use in Expansion Cohort 4 (NRAS mutant melanoma), while trametinib is planned for use in Expansion Cohorts 1 to 3. However, if preliminary PK, PD, safety, and efficacy analyses suggest a more favorable profile for the combination of DCC-3116 with trametinib or binimetinib, Expansion Cohorts 1 to 4 may use the same MEK inhibitor. The purpose of Expansion Cohort 5 (Figure 2) in the Dose Expansion Phase (Part 2) is to demonstrate the antitumor activity of DCC-3116 in combination with sotorasib, a small molecule covalent inhibitor of KRAS G12C. The RP2D of the combination with sotorasib (RP2D-CS) will be used in Expansion Cohort 5 to further evaluate safety and efficacy of the combination. Sotorasib is a small molecule covalent inhibitor of KRAS G12C, with demonstrated efficacy in treatment of patients with KRAS G12C-mutated locally advanced or metastatic NSCLC. Sotorasib blocks KRAS signaling, inhibits cell growth, and promotes apoptosis in KRAS G12C tumor cell lines, but also activates autophagy which promotes cancer cell survival as a mechanism of drug resistance. DCC-3116 blocks this autophagy and thus synergizes with KRAS G12C inhibitor sotorasib, causing tumor regression in KRAS mutant NSCLC xenograft models.
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