Phase 1/2 Study of Ensartinib and Durvalumab, in ALK-rearranged Non-small Cell Lung Cancer

Inclusion Criteria

• Histologic confirmation of metastatic NSCLC. Subjects must have had confirmed ALK rearrangement as assessed by immunohistochemistry. Subjects may have had prior therapy with ALK inhibitors (other than ensartinib) or been ALK inhibitor naïve. ALK inhibitor naïve subjects were informed of the availability of approved ALK inhibitors.
• Measurable disease according to RECIST 1.1, defined as ≥ 1 lesion that could be accurately measured in ≥ 1 dimension (longest diameter to be recorded for non-lymph node lesions, shortest diameter to be recorded for lymph node lesions). Each lesion must have been ≥ 10 mm when measured by computed tomography, magnetic resonance imaging, or caliper measurement by clinical examination or ≥ 20 mm when measured by chest x-ray.
• Willing to provide a fresh pre-treatment biopsy; however, if subject was ALK inhibitor naïve, either archival or pre-treatment biopsy was acceptable.
• Asymptomatic subjects with surgically treated brain metastases must have been ≥ 14 days post surgery at the time of first dosing, while clinically stable with no requirement for steroids. Asymptomatic subjects with radiation-treated brain metastases may have entered the study immediately after completion of the radiation (and been off steroids, if applicable). Symptomatic subjects (those experiencing headache, seizure etc.), must have been relieved from all symptoms of their central nervous system disease, and must have completed radiation and been off steroids prior to first dosing (anti seizure medicine permitted).
• Laboratory parameters for vital functions should have been in the normal range. Laboratory abnormalities that were not clinically significant were generally permitted, except for the following laboratory parameters, which must have been within the ranges specified, regardless of clinical significance:
• Hemoglobin: ≥ 9 g/dL
• Neutrophil count: ≥ 1.5 x 10^9/L
• Platelet count: ≥ 100,000/mm^3
• Serum creatinine: ≤ 1.5 x institutional upper limit of normal (ULN), OR creatinine clearance: ≥ 50 mL/min (by Cockcroft-Gault formula)
• Serum total bilirubin: ≤ 1.5 × ULN (except for subjects with Gilbert's syndrome who were allowed after consultation with their physician)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT): ≤ 2.5 x ULN
• Alkaline phosphatase: ≤ 2.5 x ULN
• Eastern Cooperative Oncology Group Performance Status ≤ 2.
• Age ≥ 18 years.
• Able and willing to provide valid written informed consent.
• Able and willing to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up.
• Body weight > 30 kg.

Exclusion criteria

• Treatment with an investigational agent within 4 weeks of starting treatment, and any prior drug-related toxicity (except alopecia) should have recovered to Grade 1 or less.
• Prior treatment with anti-PD-1, PD-L1 (including durvalumab), or cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), or ensartinib (X-396).
• Active, suspected or prior documented autoimmune disease (including but not restricted to inflammatory bowel disease, celiac disease, Wegner's granulomatosis, Hashimoto's thyroiditis, rheumatoid arthritis, systemic lupus, scleroderma and its variants, multiple sclerosis, myasthenia gravis). Vitiligo, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger were permitted.
• Subjects with clinically significant cardiovascular disease, including:
• New York Heart Association Class II or higher congestive heart failure.
• Myocardial infarction, unstable angina, cerebrovascular accident or transient ischemic attack within 6 months of start of study drug (Day -28).
• Clinically significant supraventricular or ventricular arrhythmia.
• QT interval corrected using Fridericia's formula (QTcF) ≥ 450 ms