Abstract A56: A dose-escalating phase 1b study assessing the safety, tolerability and efficacy of LY2780301 (a p70S6K/Akt inhibitor) in combination with gemcitabine in molecularly-selected patients with advanced or metastatic cancer
Authors: ANGEVIN ERIC , CASSIER PHILIPPE , ITALIANO ANTOINE , GONCALVES ANTHONY , GAZZAH ANAS , TERRET CATHERINE , TOULMONDE MAUD , GRAVIS GWENAELLE , VARGA ANDREA , PARLAVECCHIO CEDRIC , SORIA JEAN-CHARLES , LANOY EMILIE , HOLLEBECQUE ANTOINE 
Published: May 2016

Abstract
Background: LY2780301 is an orally available small molecule dual inhibitor of p70S6 kinase and AKT. In non-molecularly selected advanced cancer patients, the FIH study demonstrated good safety and PK/PD profiles at a recommended dose of 500 mg QD. LY2780301 has shown synergistic pre-clinical activity in combination with various targeted agents and chemotherapy, including gemcitabine.
Material and methods: This phase I study (INPAKT) evaluated the MTD, PK, safety profiles and antitumor activity in a 3+3 dose escalation and expansion design. Patients with solid tumors harboring documented molecular alterations of the PI3K/AKT/mTOR pathway including PTEN inactivation were enrolled in four sites and assessed for safety using NCI-CTCAEv4 and for efficacy using RECISTv1.1 criteria. The following QD doses of LY2780301 were explored: 400 mg (dose level/DL#1), 500 mg (DL#1.5 and #2) in combination with gemcitabine (30-min infusion) administered on days 1, 8 and 15 at 1000 mg/m2 (DL#1 and #2) and at 750 mg/m2 (DL#1.5 opened after protocol amendment) of each 28-days cycles (dose limiting toxicity/DLT period on cycle#1).
Results: A total of 50 patients (13M/37F; median age 54 years [range 18-76]; 23 in the dose escalation part, 27 in the expansion part) were enrolled with the following cancer types: Breast (n = 17), Cervix/Endometrium (n = 12), Liver (n = 4), H&N (n = 3), Ovary (n = 3), Stomach (n = 3), Kidney (n = 3), Colorectal (n = 2), Prostate/Testis (n = 2) and Bladder (n = 1). The most prevalent molecular alterations were mutations or amplifications on PI3K (64%) and AKT (6%) genes and PTEN gene or protein inactivation (42%). At the time of submission, results are available on safety and efficacy for the 23 patients in the escalation part during the first 4 cycles of therapy. Four out of 18 evaluable patients for DLT experienced a febrile neutropenia in addition to a grade 4 thrombopenia (1 patient at C1D22/DL#1), grade 3 cutaneous rash (1 patient at C1D22/DL#1.5), grade 3 increase in alkaline phosphatase (1 patient at C1D22/DL#2) and grade 3 alanine aminotransferase increased (1 patient at C1D15/DL#2). The most common non-DLT grade 3/4 AEs were decreased neutrophils (24%), lymphocytes (12%) and platelets (10%) counts, and increased alanine aminotransferase (18%). Other low grade adverse events (AEs) were anemia (40%), fatigue (38%), nausea (30%), transaminases increase (34%), neutrophils (32%) and platelets (32%) counts decrease. The MTD and recommended dose for the expansion part was DL#1.5 with LY2780301 at 500 mg QD and gemcitabine 750 mg/m2. No objective response was observed, but 10 patients remained on treatment beyond cycle#4 with stabilization, while 6 were in progressive disease and discontinued earlier.
Conclusions: LY2780301 QD with weekly gemcitabine is feasible and tolerable with reversible AEs. The final results including patients in the expansion part of the study will be presented.
Citation Format: ERIC ANGEVIN, PHILIPPE CASSIER, ANTOINE ITALIANO, ANTHONY GONCALVES, ANAS GAZZAH, CATHERINE TERRET, MAUD TOULMONDE, GWENAELLE GRAVIS, ANDREA VARGA, CEDRIC PARLAVECCHIO, JEAN-CHARLES SORIA, EMILIE LANOY, ANTOINE HOLLEBECQUE. A dose-escalating phase 1b study assessing the safety, tolerability and efficacy of LY2780301 (a p70S6K/Akt inhibitor) in combination with gemcitabine in molecularly-selected patients with advanced or metastatic cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A56.