Abstract CT029: Pharmacokinetic (PK), safety, and tolerability profile of DCC-2618 in a phase I trial supports 150mg QD selected for a pivotal phase III trial in gastrointestinal stromal tumor (GIST)
Authors: Janku Filip , Heinrich Michael , Razak Albiruni , Gordon Michael , Chi Ping , Ganjoo Kristen , Mehren Margaret von , Somaiah Neeta , Lee Jongtae , Kuida Keisuke , Soto Rodrigo Ruiz , Rosen Oliver , George Suzanne 
Published: August 2018

Abstract
Background: DCC-2618, a pan-KIT and PDGFRα kinase switch control inhibitor, is being studied in a pivotal, randomized phase 3 trial, INVICTUS (NCT03353753), based on encouraging disease control observed in a phase 1 trial (NCT02571036) in heavily pretreated GIST patients (pts). In the phase 1 trial, escalating doses of DCC-2618 up to 400 mg per day did not result in a DLT or MTD dose level. The RP2D of 150 mg QD was selected based on PK, efficacy and safety observed across the dose escalation cohorts before enrolling pts into expansion cohorts.
Methods: Dose escalation in the phase 1 study is complete, and this study is now enrolling pts into 6 expansion cohorts, including 3 GIST cohorts. DCC-2618 was administered in 28-day cycles at daily oral doses of 20 to 200 mg BID or 100 to 250 mg QD in pts with advanced solid tumors, including GIST. The safety and tolerability of DCC-2618 will be reviewed as a function of exposure to study drug. We report PK results from all dose-escalation cohorts and the expansion phase. The impact of dose modifications including intra-patient dose escalation was assessed based on PK.
Results: As of Jan 18, 2018, a total of 168 patients had been treated including 141 GIST patients. The most common treatment-emergent adverse effects (TEAE; all grades, ≥10% of patients) for the overall population across all dose levels included fatigue, myalgia, lipase increase (↑), alopecia, constipation, decreased appetite, nausea, hand-foot-syndrome, anaemia, diarrhea, dyspnea, abdominal pain, weight decrease, arthralgia, and hypertension (HTN). The most common TEAEs for the RP2D of 150 mg QD, based on 106 pts, included fatigue, myalgia, lipase ↑, alopecia, constipation and hand-foot-syndrome. G3 or G4 TEAE, regardless of attribution, occurring in ≥2% pts across all dose levels included included lipase ↑, anemia and HTN. 7.2% of patients underwent dose reductions. All patients who could have received at least 1 cycle prior to Dec 1, 2017 were included for further analysis (127 total, 114 GIST). Among these 114 GIST patients, 83 (73%) remain active on treatment, and 27, 14, 9 and 6 patients have been on DCC-2618 for more than 6, 9, 12, or 15 mo, respectively (15 pts were treated beyond progression per RECIST; a total of 21 were allowed to dose escalate while on study). The median follow up is 3.7 months with a range from 1 to 20 months. Population PK modeling using data from 67 patients demonstrated that combined exposures of DCC-2618 and its active metabolite, DP-5439, increase dose-proportionally. Dosing with a high fat meal increased exposure only slightly. The impact of dose escalation on plasma exposure will be shown.
Conclusions: The PK, safety and tolerability data presented together with efficacy data from the phase 1 trial demonstrate a favorable profile and broad therapeutic window for DCC-2618 and support the selection of 150 mg QD as the RP2D for the ongoing pivotal phase 3 INVICTUS study of DCC-2618 in pts with &gt;4th-line GIST.
Citation Format: Filip Janku, Michael Heinrich, Albiruni Razak, Michael Gordon, Ping Chi, Kristen Ganjoo, Margaret von Mehren, Neeta Somaiah, Jongtae Lee, Keisuke Kuida, Rodrigo Ruiz Soto, Oliver Rosen, Suzanne George. Pharmacokinetic (PK), safety, and tolerability profile of DCC-2618 in a phase I trial supports 150mg QD selected for a pivotal phase III trial in gastrointestinal stromal tumor (GIST) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT029.