Brian Simmons

Safety and efficacy of vismodegib in relapsed/refractory acute myeloid leukaemia: results of a phase Ib trial

lymphoma kinase positive anaplastic large cell lymphoma with extranodal involvement: an analysis of 1306 cases from the US National Cancer Database. British Journal of Haematology, 181, 196–204. Su, C., Nguyen, K.A., Bai, H.X., Cao, Y., Tao, Y., Karakousis, G., Zhang, P.J., Zhang, G. & Xiao, R. (2017) Disease site as a determinant of survival outcome in patients with primary cutaneous peripheral T-cell lymphoma, unspecified: an analysis of 4057 cases from the US National Cancer Database. Leukemia & Lymphoma, 59, 2105–2112. Wilson, L.D., Hinds, G.A. & Yu, J.B. (2012) Age, race, sex, stage, and incidence of cutaneous lymphoma. Clinical Lymphoma, Myeloma & Leukemia, 12, 291–296.

Abstract P4-22-22: Cobimetinib (C) combined with paclitaxel (P) as a first-line treatment in patients (pts) with advanced triple-negative breast cancer (COLET study): Updated clinical and biomarker results

Resistance to standard taxane-based chemotherapy is common in triple-negative breast cancer (TNBC). Mutations and gene amplifications in the MAPK pathway that upregulate MAPK signaling are present in many TNBC tumors. Upregulation of the MAPK signaling pathway can result in degradation of the pro-apoptotic protein BIM and upregulation of anti-apoptotic proteins, including BCL-2, BCL-XL, and MCL-1, thus promoting cell survival and desensitizing tumor cells to the pro-apoptotic effects of taxane chemotherapy. Updated data on clinical safety and efficacy are presented along with biomarker data evaluating the effects of treatment on induction of apoptosis.The COLET study (ClinicalTrials.gov ID, NCT02322814; EudraCT number, 2014-002230-32) consisted of a safety run-in (n∼12) followed by a blinded 1:1 randomized expansion stage (n∼90) to C + P or placebo (PBO) + P. The safety stage is complete and the randomized stage is enrolling pts. Two additional cohorts investigating the effect of adding atezolizumab will be recruiting and are out of scope of this submission. Pts in cohort I were treated with P 80 mg/m2 on days 1, 8, and 15 and C/PBO 60 mg/day on days 3–23 of each 28-day cycle until disease progression or unacceptable toxicity. Gene expression and apoptotic index were measured by RNA-Seq and TUNEL staining, respectively, to assess the biologic activity of C + P.Sixteen women (median age, 55.5 years) were enrolled in the safety run-in stage. At data snapshot (April 22, 2016), all 16 pts had received ≥1 dose of study treatment. Median time on treatment was 116 days (range, 7-336) for C and 84 days (range, 0-351) for P. Fifteen (94%) pts had ≥1 adverse event (AE); 5 (31%) pts had grade 1/2 AEs and 10 (63%) pts had grade 3 AEs (Table). No pts experienced grade 4–5 AEs. Among the 16 safety run-in patients, responses to date include partial response (PR; n = 8 [50.0%]), stable disease (SD, n = 4 [25.0%]), and progressive disease (n = 2 [12.5%]), as well as 2 pts with no post-baseline tumor assessment. Six pts maintained a PR at ∼20 weeks and three maintained a PR at ≥40 weeks. To date, matched pre- and on-treatment biopsies were evaluable for 2 pts, 1 with a PR and 1 with SD. In the patient who attained a PR, increased expression of pro-apoptosis genes, including BIM, was observed; but this was not seen in the patient experiencing SD. The PR patient also had an increase in apoptotic index. Updated biomarker data will be reported.This is the first study to evaluate C + P in TNBC. The safety profile of C + P is consistent with that of known safety profiles. Efficacy and safety will be further evaluated in the ongoing randomized stage. Citation Format: Brufsky A, Kim S-B, Velu T, Garcia-Saenz JA, Tan-Chiu E, Sohn JH, Dirix L, Borms MV, Liu M-C, Moezi MM, Kozloff MF, Sparano JA, Xu N, Wongchenko M, Simmons B, McNally V, Miles D. Cobimetinib (C) combined with paclitaxel (P) as a first-line treatment in patients (pts) with advanced triple-negative breast cancer (COLET study): Updated clinical and biomarker results [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-22.

Abstract CT308: Pharmacokinetics and safety of vismodegib in patients with advanced solid malignancies and hepatic dysfunction

Background: Vismodegib is an inhibitor of the hedgehog signaling pathway approved for treatment of advanced basal cell carcinoma. Pharmacokinetics (PK) and safety of vismodegib in patients (pts) with hepatic dysfunction are unknown. Methods: Pts with advanced solid malignancies and hepatic impairment (HI) were enrolled into 4 cohorts as defined by NCI Organ Dysfunction Working Group Criteria: normal (bilirubin [bili] Results: The average concentration of vismodegib in semen on Day 8 was 1.16 μM, approximately 7% of the average C ss observed in plasma from these same male patients of the normal cohort (n = 3) (Table 1). Best response among the 21 patients with HCC was 38% stable disease, 19% disease progression, and 43% not assessed. Conclusion: HI does not appear to impact vismodegib PK. However, the study is influenced by the high number of patients with HCC with advanced cirrhosis, rendering it difficult to draw any causality relationships between DLT and SAE, and vismodegib. This is confirmed by inability to deduce any correlation between C ss values and AST or total bilirubin concentrations. Stable disease is reported in 38% of patients with HCC. Further study of vismodegib in pts with severe HI and HCC should be carefully considered within the context of the DLT and SAE events reported herein. Citation Format: Ghassan K. Abou-Alfa, Lionel D. Lewis, Patricia LoRusso, Michael Maitland, Sravanthi Cheeti, Dawn Colburn, Sarah Williams, Brian Simmons, Richard A. Graham, Priya Chandra. Pharmacokinetics and safety of vismodegib in patients with advanced solid malignancies and hepatic dysfunction. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT308. doi:10.1158/1538-7445.AM2015-CT308