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|Incyte Announces Preliminary Results of a Phase I/II Study of Combination Immunotherapy in Patients with Melanoma|
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.
“In addition to seeing disease control among the 12 immunotherapy-naïve
patients, many of these patients also experienced substantial reduction
in tumor burden,” said
“Immune-targeted combination therapy represents one of the most
promising approaches in oncology and our preclinical data suggested that
combination of an IDO1 inhibitor with checkpoint inhibitors could have
significant anti-tumor synergy,” said Hervé Hoppenot, President and
Chief Executive Officer,
The poster for this presentation can be accessed at 2014
About the Study
Additional Safety and Efficacy Findings
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.
Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive enzyme that has been shown to induce regulatory T cell generation and activation, and allow tumors to escape immune surveillance. INCB24360 is an orally bioavailable small molecule inhibitor of IDO1 that 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. A Phase I dose-escalation trial demonstrated that INCB24360 results in greater than 90 percent inhibition of IDO1 activity at generally well-tolerated doses.
In addition to the Phase I/II study in metastatic melanoma in
combination with ipilimumab (www.clinicaltrials.gov
Identifier: NCT01604889), described in the
About the Webcast
Except for the historical information set forth herein, the matters set
forth in this press release, including without limitation statements
with respect to the potential efficacy, safety and therapeutic value of,
and Incyte’s plans for, INCB24360, including that INCB24360 may improve
patient outcomes with manageable toxicity when combined with ipilimumab,
contain predictions and estimates and are forward-looking statements
within the meaning of the "safe harbor" provisions of the Private
Securities Litigation Reform Act of 1995. These forward-looking
statements are based on Incyte’s current expectations and subject to
risks and uncertainties that may cause actual results to differ
materially, including unanticipated developments in and risks related to
the efficacy or safety of INCB24360, the results of further research and
development, the high degree of risk and uncertainty associated with
drug development, clinical trials and regulatory approval processes,
other market or economic factors, competitive and technological
advances, and other risks detailed from time to time in
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