Amy Jo Chien1, Alyson Cockerill2, Craig Fancourt3, Emmett Schmidt4, Mark M Moasser2, Hope S Rugo2, Michelle E Melisko2, Andrew H Ko2, R Katie Kelley2, W Michael Korn2, Laura J Esserman5, Laura van't Veer6, Christina Yau5, Denise M Wolf6, Pamela N Munster2. 1. Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 1600 Divisadero St, Box 1710, San Francisco, CA, 94115, USA. Jo.chien@ucsf.edu. 2. Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 1600 Divisadero St, Box 1710, San Francisco, CA, 94115, USA. 3. Quantitative Pharmacology and Pharmacometrics, Merck & Co., Inc, Kenilworth, NJ, USA. 4. Merck Research Laboratories, North Wales, PA, USA. 5. Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA. 6. Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, Sanfrancisco, CA, USA.
Abstract
PURPOSE: Akt plays a key role in the aggressive pathogenesis of HER2+ malignancies, suggesting that Akt-inhibitors may be of therapeutic value in the treatment of HER2+ tumors. Preclinical studies demonstrate synergy between MK-2206, a selective allosteric Akt-inhibitor, with paclitaxel and trastuzumab. We aimed to evaluate the safety of this combination in patients with HER2+ malignancies. METHODS: We conducted a phase 1b study of weekly MK-2206 in combination with weekly paclitaxel 80 mg/m(2) and trastuzumab 2 mg/kg in patients with HER2+ malignancies. Dose escalation was performed using a modified toxicity probability interval method. Molecular profiling of archived tissue samples and limited PK analyses were performed. RESULTS: 16 patients with HER2+ tumors were enrolled (12 breast, 3 gastric, 1 esophageal). 81 and 75 % had received prior trastuzumab and taxane chemotherapy, respectively. MK-2206 135 mg/week was determined to be tolerable. Three dose-limiting toxicities were observed including two grade 3 rashes and 1 grade 3 neutropenia resulting in a > 7 day delay in treatment. Grade 3/4 adverse events include neutropenia (44 %), rash (13 %), peripheral neuropathy (6 %), and depression (6 %). 10 patients (63 %) demonstrated tumor response (3 complete, 7 partial). Median duration of response was 6 months. Exploratory analyses identified STARD3, TM7SF2, and G3BP1 as potential biomarkers of response. CONCLUSIONS: MK-2206 at a dose of 135 mg/week in combination with weekly paclitaxel and trastuzumab is safe and well tolerated, and is the recommended phase 2 dose for this combination. Preliminary data indicate significant clinical activity in patients with HER2+ tumors despite prior HER2-directed therapy.
PURPOSE:Akt plays a key role in the aggressive pathogenesis of HER2+ malignancies, suggesting that Akt-inhibitors may be of therapeutic value in the treatment of HER2+ tumors. Preclinical studies demonstrate synergy between MK-2206, a selective allosteric Akt-inhibitor, with paclitaxel and trastuzumab. We aimed to evaluate the safety of this combination in patients with HER2+ malignancies. METHODS: We conducted a phase 1b study of weekly MK-2206 in combination with weekly paclitaxel 80 mg/m(2) and trastuzumab 2 mg/kg in patients with HER2+ malignancies. Dose escalation was performed using a modified toxicity probability interval method. Molecular profiling of archived tissue samples and limited PK analyses were performed. RESULTS: 16 patients with HER2+ tumors were enrolled (12 breast, 3 gastric, 1 esophageal). 81 and 75 % had received prior trastuzumab and taxane chemotherapy, respectively. MK-2206 135 mg/week was determined to be tolerable. Three dose-limiting toxicities were observed including two grade 3 rashes and 1 grade 3 neutropenia resulting in a > 7 day delay in treatment. Grade 3/4 adverse events include neutropenia (44 %), rash (13 %), peripheral neuropathy (6 %), and depression (6 %). 10 patients (63 %) demonstrated tumor response (3 complete, 7 partial). Median duration of response was 6 months. Exploratory analyses identified STARD3, TM7SF2, and G3BP1 as potential biomarkers of response. CONCLUSIONS:MK-2206 at a dose of 135 mg/week in combination with weekly paclitaxel and trastuzumab is safe and well tolerated, and is the recommended phase 2 dose for this combination. Preliminary data indicate significant clinical activity in patients with HER2+ tumors despite prior HER2-directed therapy.
Entities:
Keywords:
Akt-inhibitor; Breast cancer; HER2+; MK-2206; Trastuzumab resistance
Authors: K Kalinsky; J A Sparano; X Zhong; E Andreopoulou; B Taback; L Wiechmann; S M Feldman; P Ananthakrishnan; A Ahmad; S Cremers; A N Sireci; J R Cross; D K Marks; P Mundi; E Connolly; K D Crew; M A Maurer; H Hibshoosh; S Lee; D L Hershman Journal: Clin Transl Oncol Date: 2018-05-07 Impact factor: 3.405
Authors: A Jo Chien; Debasish Tripathy; Kathy S Albain; W Fraser Symmans; Hope S Rugo; Michelle E Melisko; Anne M Wallace; Richard Schwab; Teresa Helsten; Andres Forero-Torres; Erica Stringer-Reasor; Erin D Ellis; Henry G Kaplan; Rita Nanda; Nora Jaskowiak; Rashmi Murthy; Constantine Godellas; Judy C Boughey; Anthony D Elias; Barbara B Haley; Kathleen Kemmer; Claudine Isaacs; Amy S Clark; Julie E Lang; Janice Lu; Larissa Korde; Kirsten K Edmiston; Donald W Northfelt; Rebecca K Viscusi; Douglas Yee; Jane Perlmutter; Nola M Hylton; Laura J Van't Veer; Angela DeMichele; Amy Wilson; Garry Peterson; Meredith B Buxton; Melissa Paoloni; Julia Clennell; Scott Berry; Jeffrey B Matthews; Katherine Steeg; Ruby Singhrao; Gillian L Hirst; Ashish Sanil; Christina Yau; Smita M Asare; Donald A Berry; Laura J Esserman Journal: J Clin Oncol Date: 2019-02-07 Impact factor: 44.544
Authors: Denise M Wolf; Christina Yau; Julia Wulfkuhle; Lamorna Brown-Swigart; Rosa I Gallagher; Mark Jesus M Magbanua; Nick O'Grady; Gillian Hirst; Smita Asare; Debu Tripathy; Don Berry; Laura Esserman; A Jo Chien; Emanuel F Petricoin; Laura van 't Veer Journal: NPJ Breast Cancer Date: 2020-10-02