Abstract CT148: A phase Ib study evaluating the safety and pharmacokinetics of regorafenib in combination with cetuximab in patients with advanced solid tumors
Authors: Weekes Colin , Lockhart A Craig , Lenz Heinz-Josef , Lee James J. , Cleton Adriaan , Huang Funan , Sturm Isrid 
Published: July 2016

Background: Combining REGO, an oral multikinase inhibitor approved for the treatment of mCRC and advanced GIST, with i.v. CTX, an anti-EGFR monoclonal antibody, may overcome intrinsic and acquired resistance in both EGFR-sensitive and -resistant tumors. This phase 1b study was designed to evaluate the safety, pharmacokinetics (PK), maximum tolerated dose/recommended phase 2 dose (MTD/RP2D), and preliminary efficacy of REGO in combination with standard dose of CTX (initial 400 mg/m2 followed by 250 mg/m2 weekly).

Methods: This is an ongoing, open-label, dose-escalation (3+3 design) study in patients with locally advanced or metastatic solid tumors who progressed after standard therapy. The starting dose of REGO was 120 mg QD in a 28-day cycle (3 weeks on/1 week off; intermittent arm) plus CTX. If tolerable, REGO was escalated to 160 mg QD (intermittent arm) and a second arm of REGO 100 mg QD in a 28-day cycle (continuous arm) plus CTX was started. If not tolerable, the REGO dose was reduced to 80 mg QD (intermittent arm) and to 60 mg QD (continuous arm) plus CTX. Dose-limiting toxicities (DLTs) were evaluated in Cycle 1. Antitumor activity was assessed according to RECIST v1.1 as secondary endpoint. Blood samples were collected for PK analysis. RP2D will be confirmed by expanding the MTD cohort to 12 evaluable patients.

Results: As of 5 February 2016, 32 patients received study treatment (21 intermittently and 11 continuously). In the intermittent arm, 8 patients received REGO 120 mg and 13 received REGO 160 mg. One DLT was reported in 6 evaluable patients at each dose level (Grade 3 hand-foot skin reaction; recurrent Grade 3 ALT/AST increase). The MTD was declared at REGO 160 mg QD (intermittently) plus standard dose of CTX. In the continuous arm, 4 out of 6 treated patients were evaluable at REGO 100 mg plus CTX and reported 2 DLTs (1 Grade 3 hoarseness, 1 fatal liver failure). The REGO dose was de-escalated to 60 mg and 3 out of 5 treated patients were evaluable without DLTs. This arm was terminated as higher REGO dose was tolerable in the intermittent arm. The most common adverse events (AEs), regardless of relationship to study drug, were fatigue (62.5%), hypophosphatemia (53.1%), decreased appetite (43.7%), ALT/AST increased (40.6%), and hyponatremia (37.5%). The most common Grade ?3 REGO-related AEs were hypophosphatemia (28.1%) and fatigue (9.4%). Only 1 AE of thrombocytopenia (Grade 2) was reported which was related to REGO and CTX. Preliminary PK data indicate that REGO in combination with CTX has similar exposure to that of REGO alone, as reflected by only a 1.17-fold increase in REGO geometric mean AUC(0-tlast). One patient (120 mg REGO) with adenoid cystic carcinoma with lung metastasis had a confirmed partial response (PR; 41.6% decrease in sum of longest diameter) lasted &gt;12 months. Additionally, 3 unconfirmed PRs (anal squamous cancer, HCC, and SCLC) and 7 stable diseases were reported.

Conclusions: REGO at 160 mg QD (3 weeks on/1 week off) in combination with standard dose of CTX was well tolerated, whereas the REGO continuous arm met the predefined dose reduction criteria and was tolerated only at 60 mg. Toxicity was in line with known REGO and CTX safety profiles. No clinically significant drug interactions were observed. Additional data, especially for RP2D and efficacy, will be evaluated after completion of an expansion cohort.

Citation Format: Colin Weekes, A Craig Lockhart, Heinz-Josef Lenz, James J. Lee, Adriaan Cleton, Funan Huang, Isrid Sturm. A phase Ib study evaluating the safety and pharmacokinetics of regorafenib in combination with cetuximab in patients with advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT148.