Abstract C173: A first-in-human Phase I study of DS-3078a, an oral TORC1/2 inhibitor, in patients with advanced solid tumors: Preliminary results.
Authors: Capelan Marta , Kumar Prasana , Tolcher Anthony W. , Zivi Andrea , Desai Madhuri , Papadopoulos Kyriakos P. , Senaldi Giorgio , Patnaik Amita , Banerji Udai , Rasco Drew D. 
Published: August 2014

Abstract
Background: The phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is frequently deregulated in cancer due to mutations in PIK3CA and AKT, hyperactivation of upstream receptor kinases, and loss of function of PTEN. DS-3078a is a dual inhibitor of mTOR complex 1 (TORC1) and 2 (TORC2) that modulate the PI3K/AKT/mTOR pathway. This first-in-human study was conducted to determine the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of DS-3078a.
Methods: Dose escalation was performed using an accelerated titration method with single patient cohorts starting at 20 mg followed by a continuous reassessment method according to a Bayesian regression logistic model. DS-3078a was administered orally in a continuous once daily (QD) schedule in 28-day cycles. PK parameters including area under the curve (AUC) and maximum plasma concentration (Cmax) were assessed on cycle 1 days 1 and 8. PD analyses were performed on cycle 1 days 1 and 15 in platelet-rich plasma (PRP) for changes in phospho-AKT and, when available, in paired tumor biopsies for phospho-AKT and -S6.
Results: Seventeen patients (pts) with a median age of 61 years (range 38-72 years) were evaluable for dose limiting toxicities (DLT) according to NCI-CTCAE v 4.0. Mesothelioma (n=4) and neuroendocrine carcinoma (n=3) were the most common tumor types. Other tumor types included adenoid cystic, renal, ovarian, cervical, peritoneal, colorectal, and lung carcinoma, and unknown primary. Pts were treated at seven different dose levels of DS-3078a (20, 40, 80, 160, 320, 450, and 640 mg). MTD had been exceeded at 640 mg with DLT of grade 3 vomiting and grade 2 refractory nausea resulting in two pts not being able to complete 75% of the cycle 1 dose. The lower dose of 450 mg QD was well tolerated by 6 pts and 4 additional pts will be treated at this dose level to confirm MTD. The most common non-DLT drug-related toxicities at any cycle included grade ≤2 nausea (61%), vomiting (56%), diarrhea (50%), fatigue (33%), anorexia (28%), mucositis (28%), and hyperglycemia (17%). The mean Cmax and AUC value on day 1 at 450 mg QD was 542 ng/ml and 1898 ng.h/ml, respectively. Preliminary PD data showed up to 89% inhibition of Akt phosphorylation in platelets and up to 60% inhibition retained at 24 hours post-dose at ≥320 mg QD in some pts. The best response according to RECIST v1.1 was stable disease ≥6 months in 3 pts (ovarian, renal, and peritoneal carcinoma) with minor tumor response observed in a pt with renal carcinoma.
Conclusion: DS-3078a was well tolerated up to and pharmacodynamically active at 450 mg QD. A continuous twice daily dosing schedule has been opened to explore other schedules which may optimize the biological effects of DS-3078a. Clinical trial information NCT01588676.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C173.
Citation Format: Marta Capelan, Prasana Kumar, Anthony W. Tolcher, Andrea Zivi, Madhuri Desai, Kyriakos P. Papadopoulos, Giorgio Senaldi, Amita Patnaik, Udai Banerji, Drew D. Rasco. A first-in-human Phase I study of DS-3078a, an oral TORC1/2 inhibitor, in patients with advanced solid tumors: Preliminary results. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C173.