Michael R. Kurman

Phase 1/2 study of mogamulizumab, a defucosylated anti-CCR4 antibody, in previously treated patients with cutaneous T-cell lymphoma

This phase 1/2 study evaluated the efficacy of mogamulizumab, a defucosylated, humanized, anti-CC chemokine receptor 4 monoclonal antibody, in 41 pretreated patients with cutaneous T-cell lymphoma. No dose-limiting toxicity was observed and the maximum tolerated dose was not reached in phase 1 after IV infusion of mogamulizumab (0.1, 0.3, and 1.0 mg/kg) once weekly for 4 weeks followed by a 2-week observation. In phase 2, patients were dosed with 1.0 mg/kg mogamulizumab according to the same schedule for the first course followed by infusion every 2 weeks during subsequent courses until disease progression. The most frequent treatment-emergent adverse events were nausea (31.0%), chills (23.8%), headache (21.4%), and infusion-related reaction (21.4%); the majority of events were grade 1/2. There were no significant hematologic effects. Among 38 evaluable patients, the overall response rate was 36.8%: 47.1% in Sézary syndrome (n = 17) and 28.6% in mycosis fungoides (n = 21). Eighteen of 19 (94.7%) patients with ≥B1 blood involvement had a response in blood, including 11 complete responses. Given the safety and efficacy of mogamulizumab, phase 3 investigation of mogamulizumab is warranted in cutaneous T-cell lymphoma patients. This trial was registered at www.clinicaltrials.gov as #NCT00888927.

Abstract B90: PFK-158 is a first-in-human inhibitor of PFKFB3 that selectively suppresses glucose metabolism of cancer cells and inhibits the immunosuppressive Th17 cells and MDSCs in advanced cancer patients

Background: 6-phosphofructo-2-kinase (PFKFB3) is an enzyme that controls the intracellular concentration of fructose-2,6-bisphosphate which is an allosteric activator of 6-phosphofructo-1-kinase (PFK-1), a key enzyme of glycolysis. PFK-1 is tightly controlled by multiple metabolic feedback mechanisms and dictates the overall rate of glycolytic flux to lactate and the TCA cycle. In human cancers, several oncogenic proteins (e.g. HIF-1α, PTEN, and AKT) converge to increase the expression and activity of PFKFB3, leading to the high glycolytic rates typically observed in cancer cells. In addition to being a promising cancer metabolism target, PFKFB3 is required for the differentiation and tumor-promoting functions of the immunomodulatory Th17 cells and myeloid derived suppressor cells (MDSCs), which are attractive cellular targets to induce tumor immunity and potentially mediate intrinsic resistance to immune checkpoint inhibitors. PFK-158 is a potent selective small molecule inhibitor of PFKFB3 that displays broad anti-tumor activity causing significant growth inhibition in human and syngeneic preclinical models. As resistance mechanisms frequently activate pathways that result in up-regulation of glycolysis and PFKFB3, combination treatments of PFK-158 with cytotoxic and targeted agents have resulted in increased efficacy and tumor regression. Results: PFK-158 is a potent selective small molecule inhibitor of PFKFB3 that displays broad anti-tumor activity and causes significant growth inhibition in multiple human and syngeneic preclinical models. The tolerability and potential clinical benefit of PFK-158 are being investigated in advanced cancer patients with solid malignancies in a Phase 1 dose-escalation, multi-center clinical trial (clinicaltrials.gov # NCT02044861). The final cohort (650 mg/m2) has been open for enrollment and PFK-158 has been well tolerated to date. Secondary end-points have been incorporated to assess peripheral F2,6BP levels and immunosuppressive and effector cells populations. Of the 15 patients evaluable for response assessment at the end of two months of treatment, 6 patients have experienced a clinical benefit associated with PFK-158 administration, including a late stage pancreatic cancer patient that had a 75% reduction in her CA19-9 levels after 1 month, a renal cell carcinoma patient currently in month 9 and an adenocystic carcinoma patient in month 12. In addition, we examined the immunomodulatory effects of PFK-158 on Th17 cells and MDSCs in vitro, in B16 melanoma-bearing mice and in advanced cancer patients and found that PFK-158: (i) suppresses human Th17 cell and MDSC differentiation in vitro; (ii) decreases splenic and tumor-infiltrating Th17 cells, γδ T17 cells and MDSCs, and increases CD4+ and CD8+ T cells in the tumors of B16-F10 melanoma-bearing mice; and (iii) decreases peripheral blood Th17 cells, γδ T17 cells and MDSCs and increases activated effector CD4+ and CD8+ T cells in advanced cancer patients. Interestingly, we are discerning a correlation between the initial level of circulating Th17 cells and clinical responses to PFK-158. Conclusion: PFK-158 is the first-in-human and first-in-class PFKFB3 inhibitor that is currently under clinical development. To date, PFK-158 has been well tolerated and shows signs of clinical activity. In addition to controlling glycolysis, over expression of PFKFB3 in key immunesuppressive cells also leads to an immunomodulatory mechanism of action, suggesting that additional clinical benefit could result from combining PFK-158 with targeted agents as well as with immunotherapeutic agents. Note: This abstract was not presented at the conference. Citation Format: Sucheta Telang, Kavitha Yaddanapudi, Jaspreet Grewal, Rebecca Redman, Siqing Fu, Paula Pohlmann, Devalingam Mahalingam, Michael Kurman, Gilles Tapolsky, Jason Chesney.{Authors}. PFK-158 is a first-in-human inhibitor of PFKFB3 that selectively suppresses glucose metabolism of cancer cells and inhibits the immunosuppressive Th17 cells and MDSCs in advanced cancer patients. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B90.

Anti-CCR4 monoclonal antibody KW-0761 (mogamulizumab) or investigator's choice in subjects with relapsed or refractory adult T-cell leukemia-lymphoma (ATL)

The receptor for macrophage derived chemokine (MDC) and thymus- and activation-regulated chemokine (TARC) CC chemokine receptor 4 (CCR4) is over expressed in several T-cell malignancies including HTLV-1 related ATL where approximately 90% of malignant cells have been shown to over express this chemokine receptor. The HTLV-1 transactivator gene (Tax) does not directly induce CCR4 expression. Rather, expression of CCR4 is controlled by the constitutive activation of several transcription factors in HTLV-1 infected cells. Inhibiting the expression of these transcription factors with small-interfering RNAs has been shown to block CCR4 expression and also reduce proliferation of the affected cells. Patients with CCR4 positive ATL are more likely to have skin involvement and shorter overall survival (OS; median 9.5 months) compared with CCR4-negative (20.6 months) patients. Mogamulizumab is a defucosylated, humanized, monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity (Potelligent®) against primary ATL cells that bind to CCR4.