Kuzel, Timothy M.

Background SEA-CD40 is an investigational, non-fucosylated, humanized monoclonal IgG1 antibody that activates CD40, an immune-activating tumor necrosis factor receptor superfamily member. SEA-CD40 exhibits enhanced binding to activating FcγRIIIa, possibly enabling greater immune stimulation than other CD40 agonists. A first-in-human phase 1 trial was conducted to examine safety, pharmacokinetics, and pharmacodynamics of SEA-CD40 monotherapy in patients with advanced solid tumors and lymphoma. Methods SEA-CD40 was administered intravenously to patients with solid tumors or lymphoma in 21-day cycles with standard 3+3 dose escalation at 0.6, 3, 10, 30, 45, and 60 µg/kg. An intensified dosing regimen was also studied. The primary objectives of the study were to evaluate the safety and tolerability and identify the maximum tolerated dose of SEA-CD40. Secondary objectives included evaluation of the pharmacokinetic parameters, antitherapeutic antibodies, pharmacodynamic effects and biomarker response, and antitumor activity. Results A total of 67 patients received SEA-CD40 including 56 patients with solid tumors and 11 patients with lymphoma. A manageable safety profile was observed, with predominant adverse events of infusion/hypersensitivity reactions (IHRs) reported in 73% of patients. IHRs were primarily ≤grade 2 with an incidence associated with infusion rate. To mitigate IHRs, a standardized infusion approach was implemented with routine premedication and a slowed infusion rate. SEA-CD40 infusion resulted in potent immune activation, illustrated by dose dependent cytokine induction with associated activation and trafficking of innate and adaptive immune cells. Results suggested that doses of 10–30 µg/kg may result in optimal immune activation. SEA-CD40 monotherapy exhibited evidence of antitumor activity, with a partial response in a patient with basal cell carcinoma and a complete response in a patient with follicular lymphoma. Conclusions SEA-CD40 was tolerable as monotherapy and induced potent dose dependent immune cell activation and trafficking consistent with immune activation. Evidence of monotherapy antitumor activity was observed in patients with solid tumors and lymphoma. Further evaluation of SEA-CD40 is warranted, potentially as a component of a combination regimen. Trial registration number NCT02376699.

Importance Given that mycosis fungoides−cutaneous T-cell lymphoma (MF/CTCL) is chronic, there is a need for additional therapies with minimal short- and long-term adverse effects. Topical synthetic hypericin ointment, 0.25%, activated with visible light is a novel, nonmutagenic photodynamic therapy (PDT). Objectives To determine the efficacy and safety of topical synthetic hypericin ointment, 0.25%, activated with visible light as a nonmutagenic PDT in early-stage MF/CTCL. Design, Settings, and Participants This was a multicenter, placebo-controlled, double-blinded, phase 3 randomized clinical trial (FLASH study) conducted from December 2015 to November 2020 at 39 academic and community-based US medical centers. Participants were adults (≥18 years) with early-stage (IA-IIA) MF/CTCL. Interventions In cycle 1, patients were randomized 2:1 to receive hypericin or placebo to 3 index lesions twice weekly for 6 weeks. In cycle 2, all patients received the active drug for 6 weeks to index lesions. In cycle 3 (optional), both index and additional lesions received active drug for 6 weeks. Main Outcomes and Measures The primary end point was index lesion response rate (ILRR), defined as 50% or greater improvement in modified Composite Assessment of Index Lesion Severity (mCAILS) score from baseline after 6 weeks of therapy for cycle 1. For cycles 2 and 3, open label response rates were secondary end points. Adverse events (AEs) were assessed at each treatment visit, after each cycle, and then monthly for 6 months. Data analyses were performed on December 21, 2020. Results The study population comprised 169 patients (mean [SD] age, 58.4 [16.0] years; 96 [57.8%] men; 120 [72.3%] White individuals) with early-stage MF/CTCL. After 6 weeks of treatment, hypericin PDT was more effective than placebo (cycle 1 ILRR, 16% vs 4%; P = .04). The ILRR increased to 40% in patients who received 2 cycles of hypericin PDT ( P < .001 vs cycle 1 hypericin) and to 49% after 3 cycles ( P < .001 vs cycle 1 hypericin). Significant clinical responses were observed in both patch and plaque type lesions and were similar regardless of age, sex, race, stage IA vs IB, time since diagnosis, and number of prior therapies. The most common treatment-related AEs were mild local skin (13.5%-17.3% across cycles 1-3 vs 10.5% for placebo in cycle 1) and application-site reactions (3.2%-6.9% across cycles 1-3 vs 4% for placebo in cycle 1). No drug-related serious AEs occurred. Conclusion and Relevance The findings of this randomized clinical trial indicate that synthetic hypericin PDT is effective in early-stage patch and plaque MF/CTCL and has a favorable safety profile. Trial Registration ClinicalTrials.gov Identifier: NCT02448381

Abstract CD40 is a co-stimulatory receptor of the TNF receptor superfamily expressed on antigen presenting cells (APCs). Antibodies targeting CD40 may have therapeutic benefit via multiple mechanisms including innate immune activation that can support generation of antigen-specific, antitumor T cell responses, and binding to CD40-expressing cancer cells leading to antibody-mediated target cell killing. Multiple CD40-directed antibodies are in clinical development and differ by immunoglobulin isotype, affinity to CD40, and selectivity for FcγR-binding. These alterations could lead to differences in pharmacodynamic and antitumor activity. SEA-CD40 is an agonistic non-fucosylated, humanized IgG1 monoclonal antibody directed against CD40. SEA-CD40 has enhanced FcγRIIIa binding (~10x greater than parent IgG1 antibody) that drives increased effector function, resulting in more potent immune stimulatory activity than antibodies with muted or selective FcγR binding. The enhanced effector function of SEA-CD40 may confer greater immune stimulation and antitumor activity relative to other CD40-directed therapeutics. Preclinically, SEA-CD40 exposure results in a distinct signature of responses including activation of APCs, CD8+ and CD4+ T cells and NK cells, and targeted depletion of CD40+ B cells. SEA-CD40 demonstrates superior activity compared to other CD40-targeted antibodies in vitro and in vivo, suggesting that the enhanced effector function is critical for optimal immune cell agonism. For example, SEA-CD40 drove in vitro ADCC activity 100-fold above the parent antibody and exhibited robust ADCC with the low and high affinity FcγRIIIA genotype. At matched dose levels in cynomolgus monkeys, SEA-CD40 induced circulating cytokines and sustained B cell depletion that were up to 50-fold above that induced with the parent antibody. The SEA-CD40 signature of activation translates to increased antitumor activity as a single agent and in combination with standard of care treatments in preclinical models, suggesting the potential for beneficial combination therapy in the clinic. The SEA-CD40 immune signature was confirmed by pharmacodynamic changes in an ongoing phase 1 clinical trial in patients with relapsed/refractory metastatic solid tumors (NCT02376699). SEA-CD40 treatment induced dose-dependent increases in circulating cytokines and chemokines associated with myeloid and lymphoid immune activation and trafficking. SEA-CD40 treatment also resulted in activation of CD4+ and CD8+ T cells and CD40-targeted B cell depletion in the periphery. These findings support continued clinical evaluation of SEA-CD40. The ongoing phase 1 clinical trial is actively enrolling and includes a cohort in pancreatic cancer assessing the combination of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab. Citation Format: Haley Neff-LaFord, Juneko E. Grilley-Olson, David C. Smith, Brendan Curti, Sanjay Goel, Timothy M. Kuzel, Svetomir N. Markovic, Olivier Rixe, David L. Bajor, Thomas F. Gajewski, Martin Gutierrez, Elisabeth I. Heath, John Thompson, Sahar Ansari, Shyra Gardai, Celine Jacquemont, Michael Schmitt, Andrew L. Coveler. SEA-CD40 is a non-fucosylated anti-CD40 antibody with potent pharmacodynamic activity in preclinical models and patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5535.

Background: Eribulin mesylate, a synthetic analog of halichondrin B, is a novel tubulin-binding agent that inhibits cancer cell proliferation at low-nanomolar levels. Methods: In a multicenter ECOG trial, patients with progressive metastatic CRPC, ECOG 0-2 were treated with eribulin 1.4 mg/m2 as an IV bolus over 5 minutes on days 1 and 8 of a 21-day cycle. This noncomparative study stratified points to either a chemonaive (CN), prior-taxane (Tax) only, or 2 prior cytotoxic (TCx) chemotherapy arm. The trial was powered to detect a 50% PSA reduction using Consensus Criteria in at least 40% versus 20% (90% power, one-sided α=0.10) for the CN stratum and 25% versus. 10% (power 87%, one-sided α=0.10) for the Tax and TCx strata. Results: In total, 119 pts received treatment of which 116 were eligible for the primary response determination in this study. Median age 70 years (range, 45 to 88); median number of treatment cycles 4 (range, 1 to 20+); ECOG 0-1 90%. Confirmed PSA response rates (50% decline from baseline) were 29% (90% [18.2%, 41.2%]; P=0.20), 10% (90% [5.2%, 27.1%]; P=1.00), and 4% ([0.2%, 18.3%]; P=0.59) in the chemonaive stratum, the prior-taxane stratum, and the 2-prior-chemotherapy stratum, respectively. Median progression-free survival was 3.5 months (95% CI, 2.0, 5.9), 2.3 months (95% CI, 2.0, 2.9) and 3.7 months (95% CI, 2.1, 4.2) for the chemonaive stratum, the prior-taxane stratum and the 2-prior-chemotherapy stratum, respectively. Nonhematological toxicities of any grade (mainly grade 1 and 2) were fatigue (74%), neuropathy (40%), alopecia (39%), nausea (35%), and anorexia (34%). Common hematological toxicities were decreased leukocytes (75%), decreased neutrophils (72%), and decreased hemoglobin (66%). The most common grade ≥ 3 toxicities were decreased neutrophils (55%), decreased leukocytes (42%), sensory neuropathy (13%), and fatigue (11%). Overall, there was a 4% rate of febrile neutropenia. Conclusions: In summary, per the prespecified study endpoints, eribulin did not have adequate activity in chemotherapy naïve or chemotherapy pretreated patients with metastatic CRPC to support further study in this setting.

522 Background: In the METEOR study (NCT01865747), cabo demonstrated improved progression-free survival (median 7.4 vs. 3.8 mo; HR 0.58, 95% CI 0.45–0.74; p<0.0001), OS (median 21.4 vs. 16.5 mo; HR 0.66, 95% CI 0.53-0.83, p=0.0003), and objective response rate (17% vs. 3%; p<0.0001) compared with eve in patients (pts) with advanced RCC who had received prior VEGFR TKI therapy (Choueiri NEJM 2015, Lancet Oncol 2016). Here we evaluate the impact of changes in target lesion size from baseline on OS. Methods: 658 pts were randomized 1:1 to receive cabo (60 mg qd) or eve (10 mg qd). Stratification factors were MSKCC risk group and number of prior VEGFR TKIs. Target lesion size was assessed per independent radiology review by CT/MRI scans at baseline, every 8 weeks for the first 12 months, and every 12 weeks thereafter. Three subgroups were defined by best change in target lesion size from baseline: decrease ≥30%, decrease <30%, and any increase. Results: The rate of target lesion regression was higher in the cabo arm (75%) compared with the eve arm (48%). A higher fraction of pts had a decrease ≥30% in target lesion size in the cabo arm, while a higher fraction of pts had an increase in target lesion size in the eve arm (Table). Medians for OS with cabo were not estimable (NE) (95% CI, NE‒NE), 20.8 mo (95% CI, 18.1‒NE), and 11.1 mo (95% CI, 7.6‒15.2) for the ≥30% decrease, <30% decrease, and any increase subgroups, respectively. Medians for OS with eve were NE (95% CI, 19.3‒NE), 18.0 mo (95% CI, 15.9‒20.4), and 14.0 mo (95% CI, 10.5‒16.3) for the ≥30% decrease, <30% decrease, and any increase subgroups, respectively. Median duration of follow-up for OS was 18.7 mo (IQR 16.1–21.1) for cabo and 18.8 mo (16.0–21.2) for eve. A higher proportion of pts received subsequent anticancer therapy in the any increase subgroup compared with the other subgroups. Conclusions: Cabo demonstrated a higher rate of tumor target lesion regression than eve, and greater target lesion regression was associated with improved OS in pts with advanced RCC. Clinical trial information: NCT01865747. [Table: see text]