Goey, Andrew K.L.

AbstractIn this phase I, dose‐escalation study, we sought to determine the maximum tolerated dose (MTD) of the anaplastic lymphoma kinase/c‐ROS oncogene 1 receptor (ALK/ROS1) inhibitor ceritinib in combination with gemcitabine‐based chemotherapy in patients with advanced solid tumors. Secondary objectives were characterization of the safety profile, pharmacokinetics and preliminary efficacy of these combinations, and identification of potential biomarkers of efficacy. Ceritinib was combined with gemcitabine (Arm 1), gemcitabine/nab‐paclitaxel (Arm 2) or gemcitabine/cisplatin (Arm 3). Drug concentrations in plasma were measured by tandem mass spectrometric detection (LC‐MS/MS). We analyzed archival tumor tissue for ALK, ROS1, hepatocyte growth factor receptor (c‐MET) and c‐Jun N‐terminal kinase (JNK) expression by immunohistochemistry. Arm 2 closed early secondary to toxicity. Twenty‐one patients were evaluable for dose‐limiting toxicity (DLT). There was one DLT in Arm 1 (grade 3 ALT increase) and three DLTs in Arm 3 (grade 3 acute renal failure, grade 3 thrombocytopenia, grade 3 dyspnea). The MTD of ceritinib was determined to be 600 mg (Arm 1) and 450 mg orally daily (Arm 3). Main toxicities were hematologic, constitutional and gastrointestinal as expected by the chemotherapy backbone. The apparent clearance for ceritinib decreased substantially after repeated dosing; cisplatin did not significantly affect the pharmacokinetics of ceritinib. The overall response rate was 20%; the median progression‐free survival was 4.8 months. Three out of five response‐evaluable cholangiocarcinoma patients had clinical benefit. Increased expression of c‐MET was associated with a lack of clinical benefit. Ceritinib in combination with gemcitabine and gemcitabine/cisplatin has a manageable toxicity profile. Further development of this strategy in tumors with ALK or ROS1 fusions is warranted.

Abstract Introduction: Cer is an oral ALK/ROS1 inhibitor. Aberrancies in ALK and ROS1 have been observed in many cancer types and ALK inhibition has synergistic effects with chemotherapy in ALK or ROS1 rearranged tumors in preclinical models. We launched a Phase I study of Cer in combination with Gem-based chemotherapy in advanced solid tumors. Herein we present initial results of this study. Methods: Phase I, dose-escalation study of Cer in combination with A1: Gem 1000 mg IV D1/8/15 q28 days; A2: Gem 1000 mg IV + nanoparticle albumin-bound Paclitaxel 125 mg IV both D1/8/15 q28 days; A3: Gem 1000 mg IV + Cisplatin 60 mg IV D1/8 q21 days in pts with advanced, solid malignancies until disease progression, intolerable toxicity or withdrawal. A 3 + 3 dose-escalation design was used starting at Cer 450 mg once daily (DL1) in all arms; DL2 was 600 mg once daily. Primary objective was to determine the maximum tolerated dose (MTD) of Cer. Key inclusion criteria: diagnosis of advanced solid malignancy for which Gem-based treatment was appropriate, >18 years old, ECOG PS 0/1, adequate bone marrow/renal/liver function. Key exclusion criteria: interstitial lung fibrosis/disease, recent acute coronary event, CHF NYHA III/IV, corrected QTc > 450 ms. Pts in A3 could have up to 2 prior lines of therapy. Prior use of ALK inhibitors allowed. Plasma was collected for PK on C1D1, C2D1, and C1D15. Archival tumor tissue was tested for ALK/ROS1/JNK/MET by IHC. Results: Thirty-eight patients were enrolled with 21 evaluable for dose-limiting toxicity (DLT) in A1 and A3. A2 (n=4) closed to accrual for toxicity. Median age was 61 years. Seven pts (41%) had cholangiocarcinoma. A1 had one DLT (G3 ALT increase) in DL2; MTD was 600 mg. A3 had one DLT in DL1 (G3 acute renal failure) and two DLTs in DL2 (G3 thrombocytopenia and G3 dyspnea); MTD was 450 mg. G3-5 AEs in all pts: anemia (A1: 3/19, A3: 2/15), nausea (A1: 1/19, A3: 2/15), emesis (A1: 1/19, A3: 1/15), neutropenia (A1: 2/19, A3: 8/15), thrombocytopenia (A1: 1/19, A3: 4/15), hyperbilirubinemia (A3: 3/15), pneumonia (A1: 2/19), acute renal failure (A3: 1/15), fatigue (A3: 2/15). Fifteen patients were evaluable for response; the overall response rate was 20% with two PR (pt with head and neck carcinoma in A1 and pt with carcinoma of unknown primary in A3) - and one CR in a pt with cholangiocarcinoma (A3) lasting 10.3 months. Overall, disease control rate was 47%. Of 5 evaluable pts with cholangiocarcinoma 3 had clinical benefit. Median PFS 3.4 mo (A1)/4.8 mo (A3) and OS 13.7 mo (A1)/29.1 mo (A3). PK and IHC data will be presented at the conference. Conclusions: The MTD of Cer is 600 mg in combination with Gem and 450 mg in combination with Gem/Cisplatin. Further evaluation of Cer plus Gem-based chemotherapy is planned in ALK/ROS1 positive cholangiocarcinomas. Citation Format: Christos Fountzilas, Alex Adjei, Mateusz Opyrchal, Rachel Evans, Kristopher Attwood, Andrew Goey, John Wilton, Wen Wee Ma, Renuka Iyer. Ceritinib (Cer) in combination with gemcitabine (Gem)-based chemotherapy in patients (pts) with advanced solid tumors, a phase I study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT139.