Clinical trial NCT02898116 (phase 1/phase 2, status: completed)
Conditions: non-small cell lung cancer, carcinoma, nsclc
ICD codes: C78.00, C78.01, C78.02, D14.30, D14.31, D14.32, C34.2, C22.0, C22.1, C4A.9, C7B.1, D09.9, C4A.0, C4A.31
Drugs: ensartinib, durvalumab
SMILES: C[C@@H](OC1=CC(=NN=C1N)C(=O)NC1=CC=C(C=C1)C(=O)N1CCN(C)CC1)C1=C(Cl)C=CC(F)=C1Cl, [H][N]1([H])[C@@H]2CCCC[C@H]2[N]([H])([H])[Pt]11OC(=O)C(=O)O1
Eligibility criteria:

        Inclusion Criteria:

          1. 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.

          2. 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.

          3. Willing to provide a fresh pre-treatment biopsy; however, if subject was ALK inhibitor
             naïve, either archival or pre-treatment biopsy was acceptable.

          4. 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).

          5. 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

          6. Eastern Cooperative Oncology Group Performance Status ≤ 2.

          7. Age ≥ 18 years.

          8. Able and willing to provide valid written informed consent.

          9. 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.

         10. Body weight > 30 kg.

        Exclusion criteria:

          1. 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.

          2. Prior treatment with anti-PD-1, PD-L1 (including durvalumab), or cytotoxic
             T-lymphocyte-associated antigen-4 (CTLA-4), or ensartinib (X-396).

          3. 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.

          4. Subjects with clinically significant cardiovascular disease, including:

               1. New York Heart Association Class II or higher congestive heart failure.

               2. Myocardial infarction, unstable angina, cerebrovascular accident or transient
                  ischemic attack within 6 months of start of study drug (Day -28).

               3. Clinically significant supraventricular or ventricular arrhythmia.

               4. QT interval corrected using Fridericia's formula (QTcF) ≥ 450 ms (male) or QTcF ≥
                  470 ms (female).

               5. Clinically uncontrolled hypertension.

          5. History of pneumonitis or interstitial lung disease, or any unresolved immune-related
             adverse events following prior therapy.

          6. Major surgery within 4 weeks of starting treatment (or scheduled for surgery during
             the projected course of the study).

          7. Women of child bearing potential who were pregnant as evidenced by positive serum
             pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic
             gonadotropin) or nursing.

          8. Female subjects of childbearing potential who were sexually active with a
             non-sterilized male partner must have used at least one highly effective method of
             contraception (see table below) from the time of screening and must have agreed to
             continue using such precautions for 90 days after the final dose of investigational
             products. Non-sterilized male partners of a female subject must have used male condoms
             plus spermicide throughout this period. Cessation of birth control after this point
             should have been discussed with a responsible physician. Not engaging in sexual
             activity for the total duration of the trial and the drug washout period was an
             acceptable practice; however, periodic abstinence, the rhythm method, and the
             withdrawal method were not acceptable methods of birth control.

             Female subjects should have refrained from breastfeeding throughout the period
             described above.

             Females of childbearing potential were defined as those who were not surgically
             sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete
             hysterectomy) or post-menopausal.

             Females were considered post-menopausal if they had been amenorrheic for 12 months
             without an alternative medical cause. The following age-specific requirements applied:

               -  Females <50 years of age were considered post-menopausal if they had been
                  amenorrheic for 12 months or more following cessation of exogenous hormonal
                  treatments and if they had luteinizing hormone and follicle-stimulating hormone
                  levels in the post-menopausal range for the institution or underwent surgical
                  sterilization (bilateral oophorectomy or hysterectomy).

               -  Females ≥50 years of age were considered post-menopausal if they had been
                  amenorrheic for 12 months or more following cessation of all exogenous hormonal
                  treatments, had radiation-induced menopause with last menses >1 year prior to
                  study entry, had chemotherapy-induced menopause with last menses >1 year prior to
                  study entry, or underwent surgical sterilization (bilateral oophorectomy,
                  bilateral salpingectomy or hysterectomy).

             Non-sterilized male subjects who were sexually active with a female partner of
             childbearing potential must have used male condoms plus spermicide from screening
             through 90 days after receipt of the final dose of investigational products. Male
             subjects were to refrain from sperm donation throughout this period. Female partners
             (of childbearing potential) of a male subject must have used a highly effective method
             of contraception (see table below) throughout this period. Cessation of birth control
             after this point was to be discussed with a responsible physician. Not engaging in
             sexual activity for the total duration of the trial and the drug washout period was an
             acceptable practice; however, periodic abstinence, the rhythm method, and the
             withdrawal method were not acceptable methods of birth control.

             A highly effective method of contraception was defined as one that resulted in a low
             failure rate (i.e. less than 1% per year) when used consistently and correctly. Note
             that some contraception methods were not considered highly effective (e.g. male or
             female condom with or without spermicide; female cap, diaphragm, or sponge with or
             without spermicide; non-copper containing intrauterine device; progestogen-only oral
             hormonal contraceptive pills where inhibition of ovulation was not the primary mode of
             action [excluding Cerazette/desogestrel which was considered highly effective]; and
             triphasic combined oral contraceptive pills).

          9. Subjects who were immunosuppressed, including those with known immunodeficiency.

         10. Active infection including tuberculosis (clinical evaluation that included clinical
             history, physical examination and radiographic findings, and tuberculosis testing in
             line with local practice), hepatitis B (known positive hepatitis B virus surface
             antigen result), hepatitis C, or human immunodeficiency virus (positive 1/2
             antibodies). Subjects with a past or resolved hepatitis B virus infection (defined as
             the presence of hepatitis B core antibody and absence of hepatitis B virus surface
             antigen) were eligible. Subjects positive for hepatitis C antibody were eligible only
             if polymerase chain reaction was negative for hepatitis C virus ribonucleic acid.

         11. History of severe allergic reactions to any unknown allergens or components of the
             study drugs.

         12. Other serious illnesses (e.g., serious infections requiring antibiotics, bleeding
             disorders).

         13. Mental impairment that may have compromised compliance with the requirements of the
             study.

         14. Lack of availability for immunological and clinical follow-up assessment.

         15. Inability to swallow or retain oral medication, presence of active gastrointestinal
             disease or other condition that would have interfered significantly with the
             absorption, distribution, metabolism, or excretion of ensartinib.

         16. Any condition that, in the clinical judgment of the treating physician, was likely to
             prevent the subject from complying with any aspect of the protocol or that may have
             put the subject at unacceptable risk.

         17. History of allogeneic organ transplant.

         18. Subjects must not have donated blood while on study and for at least 90 days following
             the last durvalumab treatment.