Targ Oncol DOI 10.1007/s11523-017-0482-9 ORIGINAL RESEARCH ARTICLE A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies Trisha M. Wise-Draper1 & Ganesh Moorthy2 & Mohamad A. Salkeni1,3 & Nagla Abdel Karim1 & Hala Elnakat Thomas1 & Carol A. Mercer1 & M. Shalaan Beg1,4 & Sue O’Gara1 & Olugbenga Olowokure1 & Hassana Fathallah1 & Sara C. Kozma1,5 & George Thomas1,5 & Olivier Rixe1,6 & Pankaj Desai2,7 & John C. Morris1,8 # The Author(s) 2017. This article is published with open access at Springerlink.com Abstract Results Common toxicities observed included fatigue, diar- Background The combination of everolimus and the rhea, nausea, mucositis, and elevated liver enzymes. No con- imidazoquinoline derivative, BEZ235 (dactolisib), a dual firmed responses were observed. BEZ235 pharmacokinetics PI3K/mTOR inhibitor, demonstrated synergy in a preclinical exhibited dose-proportional increases in Cmax and AUC0-24 model. over the three doses, with high inter-individual variability. Objective To establish clinical feasibility, a phase Ib dose- Non-compartmental and population pharmacokinetic-based escalation trial investigating safety and pharmacokinetics of simulations indicated significant increases in everolimus this combination in patients with advanced tumors was Cmax and AUC0-24 on day 28 and decreased clearance to performed. 13.41 L/hr. Patients and Methods BEZ235 was orally administered daily Conclusions The combination of BEZ235 and everolimus in escalating doses of 200, 400, and 800 mg along with evero- demonstrated limited efficacy and tolerance. BEZ235 system- limus at 2.5 mg daily in 28-day cycles. Nineteen patients were ic exposure increased in a dose-proportional manner while enrolled. Adverse events and tumor responses were evaluated oral bioavailability was quite low, which may be related to using CTCAE v4.0 and RECIST 1.1, respectively. gastrointestinal-specific toxicity. The changes in steady-state Pharmacokinetic analyses were performed. pharmacokinetics of everolimus with BEZ235 highlight po- Trisha M. Wise-Draper and Ganesh Moorthy are co-first authors Electronic supplementary material The online version of this article (doi:10.1007/s11523-017-0482-9) contains supplementary material, which is available to authorized users. * Pankaj Desai 5 Institut Català d’Oncologia i Institut d’Investigació Biomèdica de [email protected] Bellvitge, Laboratory of Cancer Metabolism, Hospital Duran i Reynals, 08908 Barcelona, Spain * John C. Morris [email protected] 6 Division of Hematology-Oncology, Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87106, 1 Division of Hematology-Oncology, Department of Internal USA Medicine, University of Cincinnati, Cincinnati, OH 45267, USA 2 Division of Pharmaceutical Sciences, University of Cincinnati, 7 The James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA 3225 Eden Avenue, Cincinnati, OH 45267-0004, USA 3 Division of Hematology-Oncology, Department of Medicine, West Virginia University Cancer Institute, Morgantown, WV 26506, USA 8 Division of Hematology-Oncology, University of Cincinnati, Vontz 4 Division of Hematology-Oncology, University of Texas Center for Molecular Studies, 3125 Eden Avenue, ML 0562, Southwestern, Dallas, TX 75390, USA Cincinnati, OH 45267-0562, USA Targ Oncol tential drug–drug interactions when these two drugs are ad- carcinoma (HCC) in mice [13]. Microarray gene expression ministered together. analyses revealed that a number of genes in tumors treated Clinicaltrials.gov: NCT01508104 with the drug combination, but not as single agents, reverted to expression levels found in normal liver. Furthermore, the Key Points expression of autophagy genes was decreased in tumors com- pared to normal liver [13]. These findings formed the basis for BEZ235 in combination with everolimus demonstrated this phase I study to evaluate the safety and efficacy of this combination in patients with advanced cancer. superior survival in a preclinical model but limited Everolimus is primarily metabolized by CYP3A4 [14, 15] clinical efficacy. and is also a substrate for efflux transporter P-glycoprotein (P- BEZ235 in combination with everolimus was poorly gp) [16]. A number of clinical trials investigating drug–drug tolerated at administered doses in this phase I study. interactions have established everolimus to be a sensitive probe for alterations in CYP3A4/ P-gp activity [17]. BEZ235 resulted in increases in everolimus steady Therefore, we chose a starting dose of 2.5 mg of everolimus state pharmacokinetics when administered together. (rather than standard dosing of 10 mg) to account for this interaction. We report a detailed description of the combina- tion pharmacokinetics (PK) of BEZ235 and its potential im- pact on everolimus. 1 Introduction 2 Methods The development of molecularly targeted agents (MTA), small molecules or antibodies directed against specific onco- 2.1 Eligibility Criteria genic targets has transformed cancer therapy, leading to im- proved disease control and extended survival. However, only For this IRB-approved study, BEZ235 was supplied by afewMTAs,suchasimatinibhavebeensuccessfulassingle Novartis Oncology (East Hanover, NJ, USA). Patients agents, likely because many tumors develop alternate signal- ≥18 years with cytologically or histologically confirmed ad- ing pathways or harbor additional genetic alterations, and, vanced or metastatic solid cancers that had exhausted standard hence, are not driven by a single mutation [1]. Therefore, therapies were eligible for enrollment. At least one measurable heterogeneous tumors presumably require inhibition of multi- lesion defined by RECIST 1.1 was required [18]. Key inclu- ple key signaling regulators, warranting combination therapy. sion criteria were Eastern Cooperative Oncology Group per- The phosphatidylinositol 3-kinase/AKT/mammalian target of formance status (ECOG PS) ≤2, ability to understand and sign rapamycin (PI3K/AKT/mTOR) pathway has emerged as a informed consent, and adequate bone marrow and organ func- central pathway in cell survival, proliferation, and angiogene- tion [19]. Key exclusion criteria included prior anticancer ther- sis that is frequently dysregulated in cancer and its activation apy within 4 weeks prior to enrollment, poorly controlled hasbeenassociatedwithpooroutcomes[2]. The mTOR in- diabetes, chronic immunosuppression, other serious disease hibitor, everolimus (RAD001), is FDA-approved for the treat- that may impact survival, abnormal gastrointestinal function ment of renal cell carcinoma, subependymal giant cell astro- resulting in poor BEZ235 absorption, or required treatment cytoma, pancreatic neuroendocrine tumors, and advanced with other drugs that are known to modulate isoenzyme breast cancer [3–5]. However, obtaining optimal clinical re- CYP3A4. sponses with single-agent everolimus is challenging, perhaps due to loss of a negative feedback mechanism that results in 2.2 Study Design and Dose Escalation Scheme activation of PI3K and its downstream effectors, or due to incomplete inhibition of mTORC1 substrates such as 4E- The study was an open-label, single-center, dose-escalation BP1 [6, 7]. BEZ235 is a dual PI3K/mTOR inhibitor that binds trial assessing the safety and tolerability of the combination to the ATP-binding pocket of these enzymes, thereby of BEZ235 and everolimus (NCT01508104). The primary inhibiting PI3K along with mTOR complexes, TORC1, and objectives of the study were to determine the maximum toler- TORC2 [8]. Preclinical studies in mouse transgenic and xeno- ated dose (MTD) and dose-limiting toxicities (DLT) in pa- graft tumor models have shown that BEZ235 effectively in- tients with solid tumors. The secondary objective was to char- hibits growth of tumors, including glioblastoma, breast, lung, acterize the PK of BEZ235 and everolimus in combination. pancreatic, and prostate cancer [9–12]. Nineteen patients were enrolled from 1/12/12 to 9/30/13 We previously reported that the combination of BEZ235 (Table 1). Patients were treated in 28-day cycles that included and everolimus slowed progression of hepatocellular once daily oral administration of everolimus and BEZ235. Targ Oncol Table 1 Patient demographics Demographic or patient BEZ235 200 mg/ BEZ235 400 mg/ BEZ235 800 mg/ Total characteristic d + 2.5 mg/d d + 2.5 mg/d d + 2.5 mg/d (N = 19) Everolimus Everolimus Everolimus (N = 4) (N = 7) (N = 8) Age (median, years) 59 57 52 56 (range 36–64) (range 54–73) (range 38–62) Male 3 3 6 12 Female 1 4 2 7 ECOG PS = 0 0 2 1 3 ECOG PS = 1 4 5 6 15 ECOG PS = 2 0 0 1 1 White 3 6 6 15 Black 1 1 1 3 Hispanic 0 0 1 1 # Prior treatments 3.5 3 3.5 3 (range 2–5) (range 2–9) (range 1–5) (range 1–9) Days of treatment received 56 19 15 24 (range 18–56) (range 6–56) (range 5–46) (range 5–56) Tumor types NSCLC 1 1 0 2 Brain tumor 1 1 1 3 Colon carcinoma 1 1 1 3 HCC 1 0 0 1 Pancreatic Ca 0 1 0 1 Esophageal Ca 0 1 1 2 Laryngeal ca 0101 (adenoid cystic) Appendix ca 0 1 0 1 HNSCC 0 0 1 1 Prostate ca 0 0 1 1 Ovarian ca 0 0 1 1 Rectal NET 0 0 1 1 Endometrial Ca 0 0 1 1 The starting dose of everolimus was 2.5 mg and 200 mg for >7 days, grade 4 thrombocytopenia or grade 3 with bleeding, BEZ235. BEZ235 was escalated to 400 mg and 800 mg in grade 3 or 4 non-hematologic toxicity, treatment delay cohorts 2 and 3, respectively. Patients self-administered and ≥2 weeks due to unresolved toxicity, or any other non- reported daily everolimus and BEZ235 dosing on a patient hematologic toxicity grade 2 or higher that the investigator calendar. Patients were treated until either unacceptable toxic- and medical monitor felt was dose-limiting. If a patient devel- ity was reached or until disease progression. oped a DLT, then three more patients were entered at that dose Safety was evaluated by monitoring adverse events, hema- level. The MTD was the dose in which ≤1 patient developed a tology, blood chemistry profiles, and regular physical exams. DLT. Adverse events were graded using CTCAE v4.1.