Checkpoint Kinase 1 (CHK1) is a multifunctional protein kinase and regulator of DNA damage response. LY2606368, an ATP-competitive inhibitor of CHK1, has been tested in Phase I studies as a monotherapy and in combination with cytotoxic and targeted agents. Objective responses have been observed following LY2606368 monotherapy in patients with squamous cell tumors, including head and neck cancer (HNSCC). Transient Grade 4 neutropenia (typically
This study is a two-part multicenter, parallel, non-randomized, open-label Phase 1b trial (NCT02555644) in patients with newly diagnosed locally advanced untreated HNSCC. The primary objective is to determine the recommended Phase 2 dose (RP2D) of LY2606368 in combination with either cisplatin and radiation therapy (RT) (Part A) or cetuximab and RT (Part B). Secondary objectives include an evaluation of pharmacokinetics, safety/toxicity, and preliminary efficacy. Key inclusion criteria include: patients ≥18 yrs with newly diagnosed stage III, IVA, or IVB HNSCC of oropharynx, hypopharynx, or larynx; Key exclusion criteria include: received prior systemic therapy for the study cancer, radiation therapy to head and neck region, or curative-intent surgery in head and neck region; evidence of distant metastatic disease; serious heart condition, such as congestive heart failure, unstable angina pectoris, or heart attack within the last three months; and family history of long corrected QT interval (QTc) syndrome. Part A patients will receive 40 mg/m2 cisplatin weekly for 7 weeks, while patients in Part B will receive cetuximab weekly at an initial dose of 400 mg/m2 followed by 250 mg/m2 for 7 weeks. All patients will receive ∼70 Gy RT delivered as 5 fractions/week over 7 weeks and LY2606368 as a 1 hour infusion every 2 weeks. Dose escalation of LY2606368 will be performed using modified Time-to-Event Continual Reassessment Method (TITE-CRM). Following escalation and the determination of the RP2D for each arm, expansion cohorts of approximately 15 patients will be enrolled to confirm the dose.
Clinical trial identification
Legal entity responsible for the study
Eli Lilly and Company
Eli Lilly and Company
E. Yang: Research support from Eli Lilly and serve on advisory board for Nanostring Technologies. W. Zhang, A. Fink, A.B. Lin: Employee of Eli Lilly and Company and a minor stockholder. A.B. Lin: I and my husband are employees of Eli Lilly and Company and a minor stockholder. E. Deutsch: Grant for preclinical research through Gustave Roussy cancer campus. All other authors have declared no conflicts of interest.