Morris, Shannon R.

Abstract Background Langerhans cell histiocytosis (LCH) is a heterogeneous disease whose myriad manifestations result from accumulation of Langerhans cells in a variety of organs most commonly including skin, bone, central nervous system, liver, lymph nodes, and bone marrow. The disease can affect people of any age. Treatment is primarily driven by disease extent and organ involvement and can range from focused radiation or surgery to multi-agent chemotherapy. There is a relatively high recurrence rate following complete remissions with conventional chemotherapy. In the first-time-in-human (FTIH) study of the oral pan-AKT inhibitor afuresertib (GSK2110183), in patients with hematologic malignancies, a patient with refractory multi-system LCH experienced a prolonged period (> 3 years) of clinical benefit on 125mg oral once daily afuresertib. This observation led to the evaluation of the use of afuresertib in patients with LCH. Methods This single-arm, open-label trial was designed to evaluate the efficacy and safety of afuresertib, administered at 125 mg once daily, in adults and adolescents with relapsed/refractory LCH and adults with treatment-naïve LCH. Secondary objectives included pharmacokinetics. Diagnosis of LCH was confirmed by pathology review of archival tissue. The Histiocyte Society criteria were used for response evaluation at three and six months with safety and pharmacokinetic assessments performed at pre-specified intervals. BRAF status from archival tissue was evaluated by Sanger sequencing. Results 17 patients (16 adults, 10 females) were enrolled; median age was 38 years (15-75). 3/17 patients had isolated pulmonary disease, 1/17 had single-system multifocal-bone disease, 1/17 had single-system skin disease, and 12/17 had multi-system disease. Seven patients were treatment-naïve; 10 had relapsed/refractory disease, including the one adolescent. The most frequent (>20% of patients) adverse events (AEs), regardless of causality, were nausea (59%), fatigue (59%), upper respiratory infection (47%), diarrhea (47%), dyspepsia (35%), bone pain (39%), asthenia (24%), memory impairment (24%), decreased appetite (24%) and vomiting (24%). Most AEs were Grade 1 or 2 in severity; no Grade 4 AEs were reported and no Grade 3 AEs occurring in more than 1 subject were reported. 6/17 (35%) had afuresertib dose modifications (interruption or reduction). Afuresertib plasma concentrations in the adult patients were similar to values seen in adult patients with other hematologic malignancies in the FTIH study. Following a single dose, the concentration-time profile in the adolescent patient was similar to adults in the FTIH study (Tmax = 3h: Cmax 229 ng/ml: AUC24 = 3893 ng*h/mL). 15 patients had archival tissues collected for BRAF testing; 13 had DNA suitable for analysis. 2/13 was BRAF V600E mutant and 11/13 were BRAF wild type. Upon evaluation of the all-treated patient population, 5/17 (29%) patients were reported as better at the three and/or six month disease assessment. Among the 5 responders, three were treatment-naïve and two had relapsed/refractory disease. The median duration on study for all patients was 214 (44-426) days. For the 5 patients who responded, the median duration on study was 372 (255-426) days. Conclusion The pharmacokinetic and safety profile of afuresertib in patients with LCH was consistent with that observed in patients with other hematologic malignancies evaluated in the FTIH study. Afuresertib was active in patients with both treatment-naïve and relapsed/refractory disease. Additional evaluation, including molecular profiling, may be warranted alone or in combination with BRAF inhibitors or established therapies for LCH to determine the optimal population of patients with LCH who might benefit from afuresertib Disclosures: Vassallo: GlaxoSmithKline: Research Funding. Oliff:GlaxoSmithKline: Employment. Morris:GlaxoSMithKline: Employment. Reedy:GlaxoSmithKline: Employment. Portnoy:GlaxoSmithKline: Stock, prior employee Other. Smith:GlaxoSmithKline: Employment, Equity Ownership. Noble:GlaxoSmithKline: Employment, stock Other. Murnane:GlaxoSmithKline: Employment, stock Other. Szabo:GlaxoSmithKline: Employment. Heaney:Novartis: Research Funding; Sanofi-Aventis: Consultancy, Research Funding; Onconova: Research Funding; Incyte: Consultancy, Research Funding.

4073 Background: Durvalumab and tremelimumab, investigational monoclonal antibodies against PD-L1 and CTLA-4 immune checkpoints, respectively, have shown efficacy in monotherapy and offer promise in combination for patients (pts) with HCC. This is a phase I/II, open-label, randomized study of durvalumab combined with tremelimumab in unresectable HCC. Methods: Phase I part of this study is a safety run-in cohort treated at the recommended phase II doses of the durvalumab/tremelimumab combination (20 and 1 mg/kg IV Q4W respectively for 4 doses followed by 20 mg/kg Q4W durvalumab alone) in pts with unresectable HCC with or without concomitant HBV or HCV infection who progress on, are intolerant to, or have refused sorafenib therapy. Secondary objectives include evaluation of antitumor activity. Here we present results of a preplanned analysis from the completed phase I part of the study. Results: As of 10 January 2017, 40 pts have been enrolled (11 HBV+, 9 HCV+, 20 uninfected). 30% had no prior systemic therapy; 93% were Child Pugh Class A. 24 (60%) had ≥1 treatment-related AE; 20% had ≥1 grade ≥3 related AE. Most common (≥15%) treatment-related AEs: fatigue (20%), increased ALT (18%), pruritus (18%), and increased AST (15%). Most common grade ≥3 related AE was asymptomatic increased AST (10%). 24 pts have discontinued treatment: 3 due to treatment-related AEs (grade 3 pneumonitis, grade 3 colitis/diarrhea, asymptomatic grade 4 elevated AST and ALT), 16 due to progressive disease, 4 due to death unrelated to treatment (cardiac arrest, variceal bleed, progressive disease, probable HCC rupture), and 1 other (pt entered hospice care). 40 pts were evaluable for response at ≥16 weeks follow-up. Conclusions: No unexpected safety signals with durvalumab and tremelimumab were seen in this unresectable HCC population. Clinical activity observed predominantly in uninfected pts though interpretation limited by small subsets. Enrollment to the phase II portion of the study is ongoing. Clinical trial information: NCT02519348. [Table: see text]

AbstractBackgroundLangerhans cell histiocytosis (LCH) is a clonal neoplasm characterized by widely varied clinical presentations, including multisystem involvement and systemic inflammatory symptoms. The AKT pathway is relevant to survival and proliferation of dendritic cells, and is also often upregulated in hematopoietic malignancies. A clinical response in an adult patient with LCH participating in the first‐in‐human trial of afuresertib prompted this prospective trial.ProcedureThe population in the current study included treatment‐naïve (n = 7) and recurrent/refractory patients with LCH (n = 10), who received oral afuresertib (125 mg). The majority of patients were treated for > 24 weeks, with four patients receiving treatment for > 48 weeks.ResultsPharmacokinetic analysis showed similar exposures in previously reported patients with other hematologic malignancies. Primary drug‐related toxicities included Grade 1/2 nausea, diarrhea, dyspepsia, and vomiting. Grade 3 toxicities included fatigue, diarrhea, and pain (one of each). Another severe adverse event involved soft tissue necrosis. The overall response rate in evaluable subjects was 33% in treatment‐naïve patients and 28% in patients with recurrent/refractory disease, which did not meet the predefined Bayesian criteria for efficacy.ConclusionAfuresertib has clinical activity in some patients with newly diagnosed and advanced LCH.