Study of Atezolizumab in Combination With Cabozantinib Versus Docetaxel in Patients With Metastatic Non-Small Cell Lung Cancer Previously Treated With an Anti-PD-L1/PD-1 Antibody and Platinum-Containing Chemotherapy
Condition: Carcinoma, Non-Small-Cell Lung
MeSH terms: Carcinoma, Non-Small-Cell Lung
Intervention: Cabozantinib; Atezolizumab; Docetaxel
Intervention description: Cabozantinib will be administered orally, once daily at a dose of 40 mg on Days 1-21 of each cycle.; Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-day cycle.; Docetaxel will be administered by IV infusion at a starting dose of 75mg/m2 on Day 1 of each 21-day cycle.
Intervention MeSH terms: Docetaxel; Atezolizumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 366.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a Phase III, multicenter, randomized, open-label study designed to evaluate the
      efficacy, safety, and pharmacokinetics of atezolizumab given in combination with cabozantinib
      compared with docetaxel monotherapy in patients with metastatic NSCLC, with no sensitizing
      EGFR mutation or ALK translocation, who have progressed following treatment with
      platinum-containing chemotherapy and anti-PD-L1/PD-1 antibody, administered concurrently or
      sequentially.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically or cytologically confirmed metastatic NSCLC

          -  Documented radiographic disease progression during or following treatment with
             platinum-containing chemotherapy and anti-PD-L1/PD-1 antibody, administered
             concurrently or sequentially for metastatic NSCLC

          -  Measurable disease per RECIST v1.1 outside CNS as assessed by investigator

          -  Known PD-L1 status or availability of tumor tissue for central PD-L1 testing

          -  ECOG Performance Status score of 0 or 1

          -  Recovery to baseline or Grade <=1 NCI CTCAE v5.0 from toxicities related to any prior
             treatments, unless adverse events are clinically nonsignificant and/or stable on
             supportive therapy in the opinion of the investigator

          -  Adequate hematologic and end-organ function

          -  Negative HIV test at screening

          -  Negative hepatitis B surface antigen (HBsAg) test at screening

          -  Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total
             HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening

          -  Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody
             test followed by a negative HCV RNA test at screening

          -  For women of childbearing potential: agreement to remain abstinent (refrain from
             heterosexual intercourse) or use contraception, and agreement to refrain from donating
             eggs,

          -  For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
             contraceptive methods, and agreement to refrain from donating sperm.

        Exclusion Criteria:

          -  Prior therapy with the following agents for NSCLC: Cabozantinib, Docetaxel,
             Combination of an anti-PD-L1/PD-1 antibody concurrently with a vascular endothelial
             growth factor (VEGF)R targeting tyrosine kinase inhibitor (TKI)

          -  Treatment with investigational therapy within 28 days prior to initiation of study
             treatment

          -  Documentation of known sensitizing mutation in the EGFR gene or ALK fusion oncogene

          -  Patients with known ROS1 rearrangements, BRAF V600E mutations, or other actionable
             oncogenes with approved therapies if available

          -  Symptomatic, untreated, or actively progressing CNS metastases

          -  History of leptomeningeal disease

          -  Uncontrolled tumor-related pain

          -  Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
             drainage procedures (more frequently than once monthly)

          -  Severe hepatic impairment

          -  Uncontrolled or symptomatic hypercalcemia

          -  Any other active malignancy at the time of initiation of study treatment or diagnosis
             of another malignancy within 3 years prior to initiation of study treatment that
             requires active treatment, except for locally curable cancers that have been
             apparently cured, such as basal or squamous cell skin cancer, incidental prostate
             cancer, or carcinoma in situ of the prostate, cervix, or breast

          -  Stroke, transient ischemic attack, myocardial infarction or other symptomatic ischemic
             events within 6 months of initiation of study treatment

          -  Significant vascular disease within 6 months of initiation of study treatment

          -  Significant cardiovascular disease within 3 months prior to initiation of study
             treatment, unstable arrhythmia, or unstable angina

          -  Active tuberculosis

          -  Severe infection within 4 weeks prior to initiation of study treatment, including, but
             not limited to, hospitalization for complications of infection, bacteremia, or severe
             pneumonia, or any active infection that, in the opinion on the investigator, could
             impact patient safety

          -  Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
             of study treatment

          -  Current treatment with anti-viral therapy for HBV

          -  Major surgical procedure, other than for diagnosis within 4 weeks prior to initiation
             of study treatment, or anticipation of need for a major surgical procedure during the
             study

          -  Pregnant or lactating females, or intention of becoming pregnant during the treatment
             with atezolizumab in combination with cabozantinib in the experimental arm or during
             the treatment with docetaxel in the control arm, or within 5 months after the final
             dose of atezolizumab and/or 4 months after the final dose of cabozantinib, whichever
             is later.

          -  Ongoing Grade >= 2 sensory or motor neuropathy

          -  Active or history of autoimmune disease or immune deficiency, including, but not
             limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
             antibody syndrome, granulomatosis with polyangiitis, Sjögren syndrome, Guillain-Barré
             syndrome, or multiple sclerosis with the following exceptions: Patients with a history
             of autoimmune-mediated hypothyroidism who are on thyroid replacement hormone are
             eligible for the study. Patients with controlled Type 1 diabetes mellitus are eligible
             for the study. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo
             with dermatologic manifestations only are eligible for the study provided all of
             following conditions are met: Rash must cover < 10% of body surface area.

          -  Pharmacologically uncompensated, symptomatic hypothyroidism

          -  History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced
             pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening
             chest computed tomography (CT) scan

          -  Prior allogeneic stem cell or solid organ transplantation

          -  Administration of a live, attenuated vaccine within 4 weeks prior to initiation of
             study treatment or anticipation of need for such a vaccine during atezolizumab
             treatment or within 5 months after the final dose of atezolizumab

          -  Treatment with systemic immunostimulatory agents (including, but not limited to,
             interferon and interleukin 2) within 4 weeks or 5 drug-elimination half-lives
             (whichever is longer) prior to initiation of study treatment

          -  Treatment with systemic immunosuppressive medication within 2 weeks prior to
             initiation of study treatment, or anticipation of need for systemic immunosuppressive
             medication during study treatment, with the following exceptions: Patients who
             received acute, low-dose systemic immunosuppressant medication or a one-time pulse
             dose of systemic immunosuppressant medication are eligible for the study after Medical
             Monitor confirmation has been obtained. Patients who received mineralocorticoids,
             inhaled or low-dose systemic corticosteroids for COPD or asthma, or low-dose
             corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for
             the study.

          -  History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
             or fusion proteins

          -  Known hypersensitivity to Chinese hamster ovary cell products or to any component of
             the atezolizumab formulation

          -  Known allergy or hypersensitivity to any component of the cabozantinib formulation

          -  History of severe hypersensitivity to docetaxel or to other drugs formulated with
             polysorbate 80

          -  Concomitant anticoagulation with coumarin agents, direct thrombin inhibitor
             dabigatran, direct factor Xa inhibitor betrixaban, or platelet inhibitors

          -  History of risk factors for torsades de pointes

          -  Corrected QT interval corrected through use of Fridericia's formula (QTcF) > 480 ms
             per ECG within 14 days before initiation of study treatment

          -  Uncontrolled hypertension defined as systolic blood pressure > 150 mm Hg or diastolic
             BP > 90 mm Hg despite optimal antihypertensive treatment

          -  Tumors invading the GI-tract, active peptic ulcer disease, acute pancreatitis, acute
             obstruction of the pancreatic or biliary duct, appendicitis, cholangitis,
             cholecystitis, diverticulitis, gastric outlet obstruction, or inflammatory bowel
             disease

          -  Abdominal fistula, bowel obstruction, GI perforation, or intra-abdominal abscess
             within 6 months before initiation of study treatment

          -  Known cavitating pulmonary lesion(s) or known endobronchial disease manifestation

          -  Lesions invading major pulmonary blood vessels

          -  Clinically significant hematuria, hematemesis, hemoptysis of > 0.5 teaspoon (2.5 mL)
             of red blood, coagulopathy, or other history of significant bleeding within 3 months
             before initiation of study treatment

          -  Serious non-healing wound/ulcer/bone fracture

          -  Malabsorption syndrome

          -  Patients with rare hereditary problems of galactose intolerance, the Lapp lactase
             deficiency, or glucose-galactose malabsorption are also excluded.

          -  Requirement for hemodialysis or peritoneal dialysis

          -  Inability to swallow tablets