A Single-Arm PHASE 2A Study of NM-IL-12 (rHu-IL12) in Patients with Mycosis Fungoides-Type CTCL (MF) Undergoing Low-Dose TOTAL Skin Electron BEAM Therapy (LD-TSEBT)

Autor: Vladimir Vainstein, Alain H. Rook, Michael S. Khodadoust, Larisa J. Geskin, Richard T. Hoppe, Wen-Kai Weng, Hue Kha, Genet Finnegan, Marie Buchanan, Vernon Ma, David P. Horowitz, Analuisa Lares, E. Hong, Youn H. Kim, Amit Maity, Lena A. Basile, Chris E Lawrence
Rok vydání: 2016
Předmět:
Zdroj: Blood. 128:4165-4165
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood.v128.22.4165.4165
Popis: Multiple treatment modalities are available for MF, but most result in inevitable relapse. Therefore, new treatment strategies that improve response rate and prolong response duration are greatly needed. TSEBT is a highly effective therapy in MF. LD-TSEBT (12 Gy) is much more tolerable than the conventional 36+ Gy dose, thereby allowing for re-treatment; however, LD-TSEBT has a less favorable complete response rate and response duration. Combining LD-TSEBT with immunostimulatory modalities in MF has a strong biological rationale, since radiation-induced exposure of cancer-specific antigens should be synergistic with concomitant stimulation of anti-cancer immune responses. Interleukin-12 is a robust candidate for radioimmunotherapy, as IL-12 has significant anti-MF activity as monotherapy, is very well tolerated without overlapping toxicity with TSEBT, and is a potent stimulator of innate and adaptive immunity. We report on a single-arm open-label phase 2a trial of combination of LD-TSEBT and NM-IL-12. Ten patients are planned for enrollment. Eligibility includes MF-type CTCL stages IB-IIIB and patients must be eligible for LD-TSEBT. TSEBT is started on study day 1 (fractionated 4 Gy/week, up to 12 Gy). NM-IL-12 is administered subcutaneously at 150 ng/kg on days 2 and 15, followed by 6 maintenance doses q4w at 100 ng/kg. The primary endpoint is safety with secondary endpoints being response rate and PFS. Currently, 6 patients are enrolled, 5 evaluable for response; 4 male; median age 55; three have stage IB, one IIB and one IIIB. Median number of previous therapies is 2 (0-6). The treatment was well-tolerated with only grade 1 or 2 AEs; most common AEs include grade 1 headache and chills. One patient achieved CR, 2 PR, and 2 SD. Median follow-up is so far 15 weeks and 5 patients remain on study. One patient has been withdrawn from the study due to development of a suspected PLC (pityriasis lichenoides chronica)-like skin reaction requiring topical steroid therapy. PK and PD analysis was completed in the first 4 patients. It demonstrated measurable drug levels in all patients studied, Cmax being 10.8-56.1 pg/ml achieved at 5-24 hours post injection. Interferon-γ and IP-10 (hallmark PD markers of IL-12 activity) were measurable after the first and the second injections in all patients. Levels of the inhibitory cytokine IL-10 were generally measurable after NM-IL-12 injections, but were very low ( Total RNA was extracted from patient blood samples and subjected to qRT-PCR. Gene specific primers were used to analyse intracellular expression of the IL-12 receptor and immune cell markers. Ongoing work investigates an activated cellular phenotype at week 15 of LD-TSEBT and NM-IL-12 treatment compared with the respective baseline samples. Overall these early results demonstrate that NM-IL-12 can be safely administered together with LD-TSEBT in CTCL patients. Encouraging clinical activity is observed including a CR. Enrollment is currently ongoing and planned PD and correlative biomarker studies are in progress. A phase 2B randomized trial of NM-IL-12 and low dose TSEBT compared against low-dose TSEBT alone in patients with MF is being developed based on the apparent benign AE profile as compared to approved systemic therapies. Disclosures Kim: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic: Research Funding; Neumedicine: Research Funding; Merck: Research Funding; Kyowa Kirin Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Consultancy; miRagen: Research Funding; Innate: Research Funding; Horizon Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Soligenix: Research Funding. Ma:Neumedicines: Employment. Kha:Neumedicines: Employment. Lawrence:Neumedicines: Employment, Patents & Royalties. Vainstein:Neumedicines: Employment. Basile:Neumedicines: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
Databáze: OpenAIRE
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