William McCulloch

Final Results From a Multicenter, International, Pivotal Study of Romidepsin in Refractory Cutaneous T-Cell Lymphoma

PURPOSE The primary objective of this study was to confirm the efficacy of romidepsin in patients with treatment refractory cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS This international, pivotal, single-arm, open-label, phase II study was conducted in patients with stage IB to IVA CTCL who had received one or more prior systemic therapies. Patients received romidepsin as an intravenous infusion at a dose of 14 mg/m(2) on days 1, 8, and 15 every 28 days. Response was determined by a composite assessment of total tumor burden including cutaneous disease, lymph node involvement, and blood (Sézary cells). RESULTS Ninety-six patients were enrolled and received one or more doses of romidepsin. Most patients (71%) had advanced stage disease (≥ IIB). The response rate was 34% (primary end point), including six patients with complete response (CR). Twenty-six of 68 patients (38%) with advanced disease achieved a response, including five CRs. The median time to response was 2 months, and the median duration of response was 15 months. A clinically meaningful improvement in pruritus was observed in 28 (43%) of 65 patients, including patients who did not achieve an objective response. Median duration of reduction in pruritus was 6 months. Drug-related adverse events were generally mild and consisted mainly of GI disturbances and asthenic conditions. Nonspecific, reversible ECG changes were noted in some patients. CONCLUSION Romidepsin has significant and sustainable single-agent activity (including improvement in pruritus) and an acceptable safety profile, making it an important therapeutic option for treatment refractory CTCL.

Clinically meaningful reduction in pruritus in patients with cutaneous T-cell lymphoma treated with romidepsin

Abstract Patients with cutaneous T-cell lymphoma (CTCL) frequently experience severe pruritus that can significantly impact their quality of life. Romidepsin is approved by the US Food and Drug Administration (FDA) for the treatment of patients with CTCL who have received at least one prior systemic therapy, with a reported objective response rate of 34%. In a phase 2 study of romidepsin in patients with CTCL (GPI-04-0001), clinically meaningful reduction in pruritus (CMRP) was evaluated as an indicator of clinical benefit by using a patient-assessed visual analog scale. To determine the effect of romidepsin alone, confounding pruritus treatments including steroids and antihistamines were prohibited. At baseline, 76% of patients reported moderate-to-severe pruritus; 43% of these patients experienced CMRP, including 11 who did not achieve an objective response. Median time to CMRP was 1.8 months, and median duration of CMRP was 5.6 months. Study results suggest that the clinical benefit of romidepsin may extend beyond objective responses.

Clinically significant responses achieved with romidepsin across disease compartments in patients with cutaneous T-cell lymphoma

Cutaneous T-cell lymphoma (CTCL) is a rare heterogeneous group of non-Hodgkin lymphomas that arises in the skin but can progress to systemic disease (lymph nodes, blood, viscera). Historically, in clinical trials of CTCL there has been little consistency in how responses were defined in each disease “compartment”; some studies only assessed responses in the skin. The histone deacetylase inhibitor romidepsin is approved by the US Food and Drug Administration for the treatment of CTCL in patients who have received at least one prior systemic therapy. Phase II studies that led to approval used rigorous composite end points that incorporated disease assessments in all compartments. The objective of this analysis was to thoroughly examine the activity of romidepsin within each disease compartment in patients with CTCL. Romidepsin was shown to have clinical activity across disease compartments and is suitable for use in patients with CTCL having skin involvement only, erythroderma, lymphadenopathy and/or blood involvement.

Responses to romidepsin in patients with cutaneous T-cell lymphoma and prior treatment with systemic chemotherapy

Abstract Cutaneous T-cell lymphomas (CTCL) are a group of non-Hodgkin lymphomas that typically present in the skin but can progress to systemic involvement. The optimal treatment for patients who relapse from or are refractory to systemic chemotherapy remains unclear. Romidepsin is a potent, class-I selective histone deacetylase inhibitor approved for the treatment of patients with CTCL who have had ≥1 prior systemic therapy. Here, we present a subanalysis of two phase-2 trials (NCT00106431, NCT00007345) of romidepsin in patients with CTCL who had prior treatment with systemic chemotherapy. Patients with prior chemotherapy were able to achieve durable responses to romidepsin, and response rates were similar to those in patients who were chemotherapy naïve. Overall, no new safety signals emerged in patients who had received prior chemotherapy. The data presented here suggest that romidepsin is safe and effective in patients with CTCL who received prior systemic chemotherapy.

Characterization of the overall survival benefit in ENCORE 301, a randomized placebo-controlled phase II study of exemestane with and without entinostat in ER+ postmenopausal women with metastatic breast cancer.

128 Background: Histone deacetylase inhibitors (HDACi) prevent the emergence of drug tolerant clones and sensitize cells to a variety of anti-cancer therapies. We previously reported ENCORE 301, a randomized placebo controlled phase II study comparing exemestane with (EE) and without (EP) the HDACi entinostat met its primary endpoint of prolonging progression free survival (PFS) (4.3 months vs 2.3 months) and extending overall survival (OS) benefit (26.9 vs 19.8 months). In order to characterize and better understand the OS benefit, exploratory analyses were conducted. METHODS Hazard ratios (HR) for treatment were estimated from the Cox proportional hazards model, with EP serving as the reference treatment in the calculations. Inferential comparisons between treatment groups were made using the log-rank test. RESULTS Analysis of OS across multiple subsets of interest demonstrated a consistent benefit in EE group versus EP. Sensitivity analysis of baseline characteristics potentially impacting OS did not identify any factors that influenced the effect of EE on OS. Examination of treatments received during follow-up after discontinuation of EE and EP demonstrated balance between treatment group for patients receiving chemotherapy (48% EE: 44% EP), hormone therapy (37% EE: 35% EP), bisphosphonates (2% EE; 0% EP), radiation (6% EE; 5%EP), and surgery (0% EE: 2% EP). Compared to EP, OS was longer in EE group for patients whose first subsequent treatment was a hormone therapy (EE median not reached vs EP median 20.5 months; HR 0.65 [95% CI 0.26, 1.58]) or chemotherapy (EE median 26.9 months vs EP median 17.6 months; HR 0.51 [95% CI 0.25, 1.04]). Updated PFS and OS data will also be presented along with correlation analysis of PFS and OS. CONCLUSIONS Analyses of baseline characteristics, subsequent treatment and subsets of prognostic factors in ENCORE 301 did not identify any contributing factors that account for the extended OS benefit in the EE treatment group. Long lasting effects of entinostat on progenitor cells, emergence of drug tolerant cells and or priming to subsequent therapies cannot be ruled out.

Fatty acid synthase – Modern tumor cell biology insights into a classical oncology target

Decades of preclinical and natural history studies have highlighted the potential of fatty acid synthase (FASN) as a bona fide drug target for oncology. This review will highlight the foundational concepts upon which this perspective is built. Published studies have shown that high levels of FASN in patient tumor tissues are present at later stages of disease and this overexpression predicts poor prognosis. Preclinical studies have shown that experimental overexpression of FASN in previously normal cells leads to changes that are critical for establishing a tumor phenotype. Once the tumor phenotype is established, FASN elicits several changes to the tumor cell and becomes intertwined with its survival. The product of FASN, palmitate, changes the biophysical nature of the tumor cell membrane; membrane microdomains enable the efficient assembly of signaling complexes required for continued tumor cell proliferation and survival. Membranes densely packed with phospholipids containing saturated fatty acids become resistant to the action of other chemotherapeutic agents. Inhibiting FASN leads to tumor cell death while sparing normal cells, which do not have the dependence of this enzyme for normal functions, and restores membrane architecture to more normal properties thereby resensitizing tumors to killing by chemotherapies. One compound has recently reached clinical studies in solid tumor patients and highlights the need for continued evaluation of the role of FASN in tumor cell biology. Significant advances have been made and much remains to be done to optimally apply this class of pharmacological agents for the treatment of specific cancers.

Abstract LB-214: FASN inhibitor TVB-2640 shows pharmacodynamic effect and evidence of clinical activity in KRAS-mutant NSCLC patients in a phase I study

TVB-2640 is an oral, first-in-class, selective and reversible inhibitor of fatty acid synthase (FASN) in Phase 1 testing in solid tumor patients (study 3V2640-CLIN-002). FASN is a central mediator of neoplastic lipogenesis and uniquely catalyzes the production of palmitate, a key signaling molecule and the building block for long chain fatty acids. Tumor cells frequently increase FASN expression compared to normal cells to support an increased dependence on de novo lipogenesis to produce palmitate, phospholipids, lipid second messengers, membranes and lipid rafts for oncogenic signaling. High FASN correlates with poor prognosis in several tumor types including NSCLC. Palmitoylation, the reversible attachment of palmitate to proteins regulates membrane interactions and dynamically alters protein trafficking and function. RAS proteins require palmitoylation for plasma membrane localization and signaling, and KRAS4A mutated at G12 specifically requires palmitoylation for oncogenic activity. FASN inhibitors may therefore provide a novel approach to target KRAS which to date has eluded many drug development approaches. In vitro viability assays showed that KRAS mutant NSCLC cell lines show greater sensitivity to FASN inhibitors than KRAS WT. Furthermore gene expression analysis of TCGA NSCLC tumors and PDX models showed that KRAS mutant cases are associated with a higher incidence of lipogenic features than KRAS WT. The ongoing Phase 1 study includes 2 NSCLC expansion cohorts; TVB-2640 as monotherapy or in combination with paclitaxel. Several biomarker approaches are ongoing to investigate pharmacodynamic activity and patient enrichment strategies. Metabolomic profiling of serum from 12 NSCLC patients showed increased serum malonyl carnitine and decreased palmitate- derived lipids after 8 or 15 days of TVB-2640 treatment. These changes are consistent with FASN inhibition, and also observed in preclinical models. A novel non-invasive approach using Sebutape patches to collect forehead sebum showed inhibition of de novo lipogenesis in 7/7 patients including 2 NSCLC. Decreases in wax esters, saturated and monounsaturated triglycerides were observed, indicating that these lipids are not restored by diet. To date, 16 NSCLC patients are considered evaluable for clinical activity; 6 have KRAS mutant tumors, 2 have wild type KRAS and 8 are unknown. Of the 6 known KRAS mutant patients, 3 are in the monotherapy cohort and all 3 have stable disease for 20, >25 and >37 weeks respectively. The remaining 3 KRAS mutant patients are on combination therapy; one achieved a partial response and remains on therapy (>22 weeks), 1 had stable disease (24 weeks), and 1 progressed. This study shows that TVB-2640 1) inhibits palmitate production and lipogenesis, and 2) shows evidence of clinical activity in KRAS mutant NSCLC patients. Additional biomarker and clinical analyses are ongoing in NSCLC and other tumor types. Citation Format: Marie O’Farrell, Tim Heuer, Katharine Grimmer, Richard Crowley, Joanna Waszczuk, Marina Fridlib, Richard Ventura, Claudia Rubio, Julie Lai, Doug Buckley, William McCulloch, George Kemble. FASN inhibitor TVB-2640 shows pharmacodynamic effect and evidence of clinical activity in KRAS-mutant NSCLC patients in a phase I study. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-214.

Abstract CT153: First in human study of the first-in-class fatty acid synthase (FASN) inhibitor TVB-2640

Introduction FASN inhibition causes selective disruption of palmitate biosynthesis that, in tumor cells, leads to apoptosis. TVB-2640 is an oral, first-in-class, small molecule reversible inhibitor of FASN that demonstrated in vivo antitumor effects. We previously reported the results of dose escalation and now present evidence of activity in patients (pts) treated in the dose expansion cohorts. Methods This fully enrolled multicenter phase I trial included pts with advanced solid tumors. TVB-2640 was given PO once daily at the MTD (100 mg/m2) as monotherapy (mono) or in combination (combo) with weekly IV paclitaxel (80 mg/m2). Results The most common related AEs observed in both groups (mono, N=44, combo, N=43) included alopecia (41%), palmar-plantar erythrodysesthesia (PPE) (47%), and decreased appetite (13%). Additional common AEs in the mono group included dry skin (19%) and in the combo group included nausea (28%). Gr3 related AEs included decreased appetite (8%) and PPE (9%); all other related AEs were ≤ Gr2. All related AEs were reversible on dose interruption. No enhancement of paclitaxel toxicity was observed with TVB-2640. Pneumonitis in the combo arm was observed uncommonly (9%), but the contribution of TVB-2640 to this effect is uncertain. Pharmacokinetic analyses showed that TVB-2640 had a similar half-life whether given alone or in combo with paclitaxel. Clearance rates were similar on days 1 and 8 (or day 15 for combo). Multiple pharmacodynamic markers demonstrated potent inhibition of FASN and lipogenesis in pts. With respect to clinical activity, overall, 5 confirmed RECIST partial responses (cPR) were seen. Among pts with NSCLC, 18 of 31 were KRASmut, and KRASmut pts achieved longer progression-free survival on TVB-2640 monotherapy, with 60% of KRASmut pts vs. 0% of KRASwt pts on study > 12 wks. Among 18 KRASmut pts, 11 achieved prolonged SD (≥16 wks), including 6 mono pts (SD=19-46 wks) and 5 combo pts (SD=23-54 wks), whereas no KRASwt pts achieved prolonged SD. One NSCLC combo pt achieved cPR at wk 12 and remained on study for 39 wks. Of 14 breast cancer pts, 3 pts achieved cPR and 8 pts achieved prolonged SD (≥16 wks), despite extensive previous treatment, including taxane resistance. One ongoing breast cancer pt with SD, entering her 78th wk of treatment, discontinued paclitaxel at wk 35 and remains on monotherapy . One pt with peritoneal carcinoma (combo) achieved cPR and a 58% decrease in CA125. Reductions in CA125 were seen in 5 out of 12 ovarian cancer pts, who were typically heavily pretreated and taxane-resistant. Summary TVB-2640 demonstrated antitumor activity, including objective responses when combined with weekly paclitaxel, as well as prolonged SD as monotherapy or in combination with paclitaxel. Further studies are planned to evaluate the efficacy of TVB-2640 in NSCLC and breast cancer pts. Citation Format: Gerald Falchook, Manish Patel, Jeffrey Infante, Hendrik-Tobias Arkenau, Emma Dean, Andrew Brenner, Erkut Borazanci, Juanita Lopez, Kathleen Moore, Peter Schmid, Arthur Frankel, Suzanne Jones, William McCulloch, George Kemble, Howard Burris. First in human study of the first-in-class fatty acid synthase (FASN) inhibitor TVB-2640 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT153. doi:10.1158/1538-7445.AM2017-CT153

Targeting of endocrine therapy resistance through combined mTOR and histone deacetylase inhibition.

130 Background: Primary and acquired resistance to endocrine therapy in advanced breast cancer presents a significant barrier to maximizing the clinical effectiveness of these agents. We recently reported in a randomized, placebo controlled phase II study that entinostat (ENT), a class 1 selective HDAC inhibitor, combined with exemestane extended PFS and OS in postmenopausal women with ER+ positive breast cancer that had progressed on a prior nonsteroidal aromatase inhibitor. Likewise, everolimus (EVE), a mTORi, combined with exemestane or tamoxifen (TAM) also significantly extended PFS in a similar patient population. In order to determine the potential benefit of combining ENT with EVE plus hormone therapy we have piloted a series of xenograft studies in primary human tumor models of TAM sensitivity and resistance. METHODS Athymic nude mice bearing xenografts of tissue derived directly from patient tumors (MaCa4049 - TAM sensitive; MaCa3366/TAM - TAM resistant) were treated with A) vehicle B) 2 mg/kg EVE C) 2 mg/kg EVE + 10 mg/kg TAM D) 15 mg/kg ENT E) 2 mg/kg EVE + 10 mg/kg TAM + 15 mg/kg ENT. Tumor samples taken at the end of the study were cryoconserved for analysis of gene and protein expression and protein phosphorylation. RESULTS Growth of MaCa4049 tumors was inhibited in all treatment groups relative to vehicle in two independent studies conducted in this tumor model. Groups B, C and D demonstrated a similar level of activity while maximal inhibition was observed in Group E. All treatments were generally well tolerated with weight loss similar in groups C and E. Treatment of MaCa3366/TAM tumors is ongoing with similar levels of tumor growth inhibition in all groups observed relative to vehicle at week 7. Analysis of tumor samples from completed studies will be presented to provide insight into mechanism of action for the enhanced activity observed with the triple combination. CONCLUSIONS Preclinical data demonstrating enhanced activity of entinostat combined with everolimus and hormone therapy provides the rationale for clinical investigation of this novel therapeutic approach to targeting hormone therapy resistance.