Neumedicines Inc. — Department of Health and Human Services SBIR Phase II: 102

Description

DESCRIPTION provided by applicant Cutaneous T cell lymphoma CTCL is a chronic incurable disease with significant morbidity and mortality Treatment of CTCL depends on clinical stage and includes both topical and systemic therapies including psoralene plus UVA irradiation PUVA total skin electron beam therapy TSEBT systemic chemotherapy and newly approved drugs vorinostat romidepsin and pralatrexate which have been FDA approved based on overall response rates of to These interventions are associated with sometimes debilitating and dose limiting side effects and are not curative Partial responses progression and relapses do often occur and prolonged disease free survival is rare except in patients with early stage CTCL CTCL is highly responsive to radiotherapy and TSEBT has evolved as a powerful treatment regimen Current low dose Gy TSEBT treatment regimens can generate very good responses with minimal toxicity However relapses occur and doses are gradually increased High dose Gy treatment regimens of are commonly used resulting in complete response CR rates ranging from in limited plaque stage to in tumor stage The CR rate is correlated with total radiation dose but most patients will eventually relapse However high dose TSEBT is generally not repeated more than twice due to the concern of causing significant toxicity such as skin atrophy and necrosis In phase I and phase II clinical studies interleukin IL monotherapy was shown to be effective in CTCL inducing tumor regression and achieving some complete responses Recombinant human interleukin rHuIL has also been shown to be effective as a mitigator of radiation induced hematopoietic and skin toxicity Figures With rHuIL we propose to induce significant antitumor clinical responses in synergy with the radiation therapy while providing radiation protection to normal tissues rHuIL is an optimal adjuvant for radiation therapy in CTCL for several reasons rHuIL effectively mitigates radiation side effects Figures rHuIL exhibits independent antitumor activity in CTCL Fig and together with radiation induced immunogenic tumor cell death rHuIL modulates tumor microenvironment to potentiate tumor antigen uptake and presentation by APCs blocks activity of cells capable of immune suppression resulting in a Th skewing and antitumor stimulating immune environment leading to long lasting antitumor immunity likely via an endogenous vaccine effect Fig The proposed project is a phase I clinical study of rHuIL in combination with TSEBT in patients with CTCL The specific aims or objectives of the project are Determine the safety of rHuIL in patients with CTCL treated with low dose TSEBT Establish a recommended phase II dose RP D of rHuIL and Explore efficacy endpoints of rHuIL in patients with CTCL treated with low dose TSEBT PUBLIC HEALTH RELEVANCE CTCL has no cure In the past years new drugs vorinostat romidepsin and pralatrexate have been approved for use in CTCL treatment but all have substantial sometimes debilitating adverse effects have limited efficacy response rate and do not provide long term remissions from the disease We propose that a novel immunotherapy recombinant human interleukin rHuIL in combination with radiation therapy total skin electron beam therapy or TSEBT has potential to significantly improve the current CTCL treatment paradigm by improving rates of complete response and relapse free survival via simultaneously stimulating oneandapos s own immune system against cancer cells and protecting healthy skin tissue against the toxicity of standard use radiation therapy The proposed project is a phase I clinical study of rHuIL in combination with radiation therapy TSEBT in patients with CTCL