Date: 2014-06-02
Type of information: Presentation of results at a congress
phase: 1-2
Announcement: presentation of results at the 50th American Society of Clinical Oncology (ASCO) Annual Meeting, May 30 to June 3, 2014, in Chicago
Company: Incyte (USA)
Product: INCB24360 and ipilimumab
Action
mechanism: INCB24360 is an oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor. IDO1 is an immunosuppressive enzyme that has been shown to induce regulatory T cell generation and activation, and allow tumors to escape immune surveillance. This small molecule inhibitor has nanomolar potency in both biochemical and cellular assays and has demonstrated potent activity in enhancing T lymphocyte, dendritic cell and natural killer cell responses in vitro, with a high degree of selectivity. INCB24360 has been shown to be active in mouse models of cancer as a single agent and in combination with cytotoxic and immunotherapy agents, and its ability to reduce tumor growth is dependent on a functional immune system - consistent with its proposed mechanism of action. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The mechanism of action of ipilimumab’s effect in patients with melanoma is indirect, possibly through T-cell mediated anti-tumor immune responses.
Disease: unresectable or metastatic melanoma
Therapeutic area: Cancer - Oncology
Country: USA
Trial
details: This Phase 1/2 randomized, blinded, placebo controlled study evaluates ipilimumab in combination with INCB024360 or placebo in subjects with unresectable or metastatic melanoma. The study design includes an open-label, dose escalation phase followed by a blinded, randomized phase, which combines INCB024360 (an oral IDO inhibitor) with an approved therapy and compares to approved therapy plus placebo in metastatic melanoma patients. (NCT01604889)
Latest
news: * On June 2, 2014, Incyte Corporation announced that preliminary results from an ongoing Phase I/II study of INCB24360, an oral indoleamine 2,3dioxygenase 1 (IDO1) inhibitor, combined with ipilimumab in patients with unresectable or metastatic melanoma were presented at the 50th Annual Meeting of the American Society of Clinical Oncology ( ASCO . The poster reported initial findings showing that the combination was generally well tolerated and produced evidence of clinical response. In the study, 42 percent (5/12) of immunotherapy-naïve patients who received ipilimumab with INCB24360 at 25 mg or 50 mg twice-daily demonstrated an objective response (complete response + partial response) and 75 percent (9/12) achieved disease control (complete response + partial response + stable disease) as assessed using immune-related response criteria (irRC). One patient with pulmonary metastases treated with ipilimumab and INCB24360 50 mg twice-daily experienced a complete response. Immune-related adverse events observed in these cohorts were generally mild-to-moderate (Grade 1 or Grade 2). Grade 3 or 4 immune related adverse events were qualitatively similar to ipilimumab monotherapy and were generally manageable and reversible.
The ASCO presentation described results from the open-label, dose escalation portion of the ongoing Phase I/II study evaluating the combination of a standard regimen of ipilimumab with oral INCB24360. Study endpoints included safety and tolerability, objective response rate (assessed using irRC and RECIST 1.1 criteria every nine weeks), duration of response, overall and progression-free survival, and IDO1 inhibition.
Initially, seven patients were enrolled in a cohort receiving ipilimumab with INCB24360 300 mg twice-daily. Five of these patients developed clinically significant (Grade 3 or 4) alanine aminotransferase (ALT) elevations and enrollment was stopped. The ALT elevations observed in the patients receiving the 300 mg dose were reversible with corticosteroids and treatment discontinuation. Although all patients in the 300 mg twice-daily cohort were discontinued before response could be fully evaluated, six of the seven patients were alive after one year, including three who have not received subsequent checkpoint inhibitor immunotherapy. The study was amended to evaluate lower doses of INCB24360.
Seventeen patients were enrolled in the INCB24360 25 mg twice-daily and 50 mg twice-daily cohorts. During the dose limiting toxicity (DLT) observation periods, one patient in the 25 mg cohort who had extensive liver metastases prior to entering the trial experienced a DLT (Grade 3 AST elevation), and two patients in the 50 mg cohort experienced a DLT (Grade 3 diarrhea and Grade 3 ALT elevation). In both cohorts, immune-related treatment-emergent adverse events were generally Grade 1 or Grade 2 and manageable with continued dosing or temporary dose interruption.
Twelve patients who were treatment-naïve for advanced or metastatic disease were enrolled in the INCB24360 25 mg twice-daily and 50 mg twice-daily cohorts. Eight of these immunotherapy-naïve patients experienced a reduction in tumor burden, and most reductions were durable with continued therapy. As of the data cutoff, the majority of immunotherapy-naïve patients are continuing on study therapy or have experienced a prolonged period without the need for subsequent therapy.
Of the five patients who received prior immunotherapy for advanced or metastatic disease, two (40 percent) achieved stable disease by irRC.
Duration of disease control ranged from 60 to more than 379 days (ongoing).
Pharmacodynamic effects with INCB24360 25 mg BID and 50 mg BID were similar to those that were sufficient in preclinical models to achieve maximal therapeutic effect. IDO1 inhibition in this study was consistent with that observed in the phase I open-label study,1 suggesting that there was no pharmacodynamic interaction with ipilimumab.
