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The INCB 24360-202 study is a randomized, double-blind, placebo-controlled Phase 1/2 study of INCB024360 or placebo administered in combination with MK-3475. Phase 1 will be open-label and will include subjects with Stage IIIB, IV, or recurrent non--small cell lung cancer (NSCLC), melanoma, transitional carcinoma of the genitourinary (GU) tract, renal cell cancer, triple negative breast cancer, adenocarcinoma of the endometrium, or squamous cell carcinoma of the head and neck, and Phase 2 will be randomized, double-blind, and placebo-controlled in subjects with Stage IIIB, IV, or recurrent NSCLC. INCB024360 represents a novel, potent, and selective inhibitor of the enzyme indoleamine 2,3 dioxygenase-1 (IDO1) in both human tumor cells and human dendritic cells (DCs). MK-3475 is a potent and highly selective humanized monoclonal antibody of the immunoglobulin (Ig) G4/kappa isotype directed against programmed death receptor 1 (PD-1). For a thorough discussion of the pharmacology of MK-3475 and INCB024360, refer to the INCB024360 Investigator’s Brochure (iIB) and the MK-3475 Investigator’s Brochure (mIB). The goal of cancer immunotherapy is to initiate or reinitiate a self-sustaining cycle of cancer immunity, enabling it to amplify and propagate. Cancer immunotherapies must overcome the negative feedback mechanisms inherent in most cancers. The current approach will attempt to further amplify an immune response by targeting multiple nonredundant immune checkpoints. Expression of IDO1 represents an early checkpoint that results in a diminished immune response and tolerance to tumor antigen. Many recent clinical results suggest that another common rate-limiting step is the expression of PD-L1 as a distal immune modulator expressed in 20% to 50% of human cancer (Hiraoka 2010, Herbst et al 2013), including but not limited to the ones selected for investigation in the Phase 1 portion of this study: advanced or metastatic NSCLC, melanoma, transitional carcinoma of the GU tract, renal cell cancer, triple negative breast cancer, endometrial cancer, or squamous cell carcinoma of the head and neck. Expression of IDO and PD-1/L1 have been found to be increased in NSCLC as the disease progresses, and expression of these markers in tumor cells has been associated with shorter subject survival (Iversen et al 2013). Anti-PD-L1 and anti-PD-1 monotherapy response rates of 17% to 24% have been reported in refractory NSCLC (Garon et al 2013, Brahmer et al 2013) with survival medians of 8 to 18 months; however, MK-3475 has not yet reached the median in its study (Garon et al 2013). Thus, there is a strong rationale for therapies aimed at restoring antitumor immunocompetence in NSCLC and establishing a rationale for inhibiting IDO1 and the PD-1/L1 pathways in this disease. 2. STUDY OBJECTIVES AND PURPOSE 2.1. Primary Objectives ? Phase 1: To evaluate the safety, tolerability, and DLTs of a pharmacologically active dose (PAD) of INCB024360 administered in combination with MK-3475 in advanced or metastatic solid tumors, and to select doses for further evaluation. ? Phase 2: To evaluate and compare the PFS of subjects with Stage IIIB, IV, or recurrent NSCLC when treated with INCB024360 in combination with MK-3475 versus MK-3475 alone as determined by investigator assessment of objective radiographic disease assessments per modified RECIST v1.1. 2.2. Secondary Objectives (Phase 2) ? To evaluate and compare the efficacy of the 2 treatment groups with respect to ORR utilizing modified RECIST v1.1 ? To evaluate and compare the efficacy of the 2 treatment groups with respect to ordinal categorical response score, calculated as the following: - 1 = Complete response per modified RECIST v1.1 - 2 = Very good response, defined as > 60% tumor reduction - 3 = Minor response, defined as > 30% to 60% tumor reduction
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