Clinical trial NCT04471428: 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
Official title: A Phase III, Multicenter, Randomized, Open-Label, Controlled Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Atezolizumab Given in Combination With Cabozantinib Versus Docetaxel Monotherapy in Patients With Metastatic Non-Small Lung Cancer Previously Treated With an Anti-PD-L1/PD-1 Antibody and Platinum-Containing Chemotherapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Carcinoma, Non-Small-Cell Lung
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
Collaborators: name: Exelixis
First posted: 2020-07-15
Enrollment: 366
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: Up to approximately 24 months
Secondary outcomes:
measure: Progression-Free Survival (PFS) as Determined by Investigator
timeFrame: Up to approximately 24 months
measure: Confirmed Objective Response Rate (ORR) as Determined by Investigator
timeFrame: Up to approximately 24 months
measure: Duration of Response (DOR) as Determined by Investigator
timeFrame: Up to approximately 24 months
measure: Time to Confirmed Deterioration in Patient-Reported Physical Functioning (PF)
timeFrame: Up to approximately 24 months
measure: Time to Confirmed Deterioration in Patient-Reported Global Health Status (GHS)
timeFrame: Up to approximately 24 months
measure: PFS Rates Assessed by Investigator
timeFrame: 6 months and 1 year
measure: OS Rates
timeFrame: 1 and 2 years
measure: Percentage of Participants With Adverse Events
timeFrame: From signing the informed consent form up to the study completion date (approximately 41 months)
measure: Minimum Serum Concentration (Cmin) of Atezolizumab
timeFrame: Predose on Day 1 of Cycles 2, 3, 4, 8, 12 and 16 (each cycle is 21 days)
measure: Maximum Serum Concentration (Cmax) of Atezolizumab
timeFrame: Postdose on Day 1 of Cycle 1 (each cycle is 21 days)
measure: Minimum Plasma Concentration (Cmin) of Cabozantinib
timeFrame: Predose on Day 1 of Cycles 1, 2, 3, 4, and 5 (each cycle is 21 days)
measure: Maximum Plasma Concentration (Cmax) of Cabozantinib
timeFrame: Predose on Day 1 of Cycles 1, 2, 3, 4, and 5 (each cycle is 21 days)
measure: Number of Participants With Anti-Drug Antibodies (ADAs) to Atezolizumab
timeFrame: Predose on Day 1 of Cycles 1,2,3,4,8,12 and 16 (each cycle is 21 days) and at post-treatment follow-up visit (≤ 30 days after final dose)
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: San Diego
country: United States
facility: Kaiser Permanente - San Diego
state: California
city: Santa Barbara
country: United States
facility: Sansum Clinic
state: California
city: Denver
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Bethesda
country: United States
facility: Regional Cancer Care Associates
state: Maryland
city: Saint Paul
country: United States
facility: Minnesota Oncology Hematology
state: Minnesota
city: Broomall
country: United States
facility: Consultants in Medical Oncology and Hematology
state: Pennsylvania
city: Charleston
country: United States
facility: Charleston Oncology, P .A
state: South Carolina
city: Dallas
country: United States
facility: Texas Oncology - Baylor Charles A. Sammons Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute at The University of Utah
state: Utah
city: Blacksburg
country: United States
facility: Oncology and Hematology Associates of Southwest Virginia, Inc.,-Blacksburg
state: Virginia
city: St. Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Townsville
country: Australia
facility: Townsville Hospital
state: Queensland
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Heidelberg
country: Australia
facility: Austin Hospital Olivia Newton John Cancer Centre
state: Victoria
city: Nedlands
country: Australia
facility: Affinity Oncology
state: Western Australia
city: Graz
country: Austria
facility: Lkh-Univ. Klinikum Graz
city: Linz
country: Austria
facility: Ordensklinikum Linz Elisabethinen
city: Rankweil
country: Austria
facility: Lhk Feldkirch
city: Salzburg
country: Austria
facility: Lkh Salzburg - Univ. Klinikum Salzburg
city: Wien
country: Austria
facility: Medizinische Universität Wien
city: Anderlecht
country: Belgium
facility: Institut Jules Bordet
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires St-Luc
city: Namur
country: Belgium
facility: Clinique Ste-Elisabeth
city: Angers
country: France
facility: CHU Angers,Service de Pneumologie
city: Grenoble
country: France
facility: CHU de Grenoble
city: Limoges
country: France
facility: Hopital Dupuytren
city: Marseille
country: France
facility: Hôpital Saint Joseph
city: Montpellier
country: France
facility: Centre Regional de Lutte contre le Cancer Val d Aurelle - Paul Lamarque
city: Paris
country: France
facility: Hopital Tenon
city: Bad Berka
country: Germany
facility: Zentralklinik Bad Berka GmbH
city: Essen
country: Germany
facility: KEM/Evang. Kliniken Essen Mitte gGmbH
city: Gießen
country: Germany
facility: Universitaetsklinikum Giessen und Marburg GmbH
city: Hannover
country: Germany
facility: KRH Klinikum Siloah-Oststadt-Heidehaus
city: Köln
country: Germany
facility: Klinikum Koeln-Merheim
city: Marburg
country: Germany
facility: Universitaetsklinikum Giessen und Marburg
city: Paderborn
country: Germany
facility: Brüderkrankenhaus St. Josef Paderborn
city: Athens
country: Greece
facility: Uoa Sotiria Hospital
city: Heraklion
country: Greece
facility: Univ General Hosp Heraklion
city: Napoli
country: Italy
facility: AORN Ospedali dei Colli Ospedale Monaldi
state: Campania
city: Parma
country: Italy
facility: Azienda Ospedaliero Universitaria di Parma
state: Emilia-Romagna
city: Ravenna
country: Italy
facility: Ospedale Provinciale Santa Maria Delle Croci
state: Emilia-Romagna
city: Aviano
country: Italy
facility: Irccs Centro Di Riferimento Oncologico (CRO)
state: Friuli-Venezia Giulia
city: Roma
country: Italy
facility: Azienda Ospedaliera San Camillo Forlanini
state: Lazio
city: Roma
country: Italy
facility: Policlinico Umberto I, Oncologia B
state: Lazio
city: Genova
country: Italy
facility: IRCCS AOU San Martino - IST
state: Liguria
city: Brescia
country: Italy
facility: ASST Spedali Civili di Brescia
state: Lombardia
city: Milan
country: Italy
facility: Instituto Europeo di Oncologia
state: Lombardia
city: Lecce
country: Italy
facility: Ospedale Vito Fazzi
state: Puglia
city: Florence
country: Italy
facility: A.O.U Careggi
state: Toscana
city: Hyogo
country: Japan
facility: Hyogo Cancer Center
city: Miyagi
country: Japan
facility: Sendai Kousei Hospital
city: Osaka
country: Japan
facility: Osaka International Cancer Institute
city: Tokyo
country: Japan
facility: National Cancer Center Hospital
city: Tokyo
country: Japan
facility: The Cancer Institute Hospital of JFCR
city: Goyang-si
country: Korea, Republic of
facility: National Cancer Center
city: Gyeonggi-do
country: Korea, Republic of
facility: St. Vincent's Hospital
city: Gyeonggi-do
country: Korea, Republic of
facility: Ajou University Medical Center
city: Gyeongsangnam-do
country: Korea, Republic of
facility: Samsung Changwon Hospital
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul St Mary's Hospital
city: Ulsan
country: Korea, Republic of
facility: Ulsan University Hosiptal
city: Bytom
country: Poland
facility: SP ZOZ Wojewódzki Szpital Specjalistyczny nr 4
city: Gliwice
country: Poland
facility: Narodowy Inst.Onkol.im.Sklodowskiej-Curie Panstw.Inst.Bad Gliwice
city: Koszalin
country: Poland
facility: Szpital Wojewódzki im. Miko?aja Kopernika
city: Porto
country: Portugal
facility: Centro Hospitalar do Porto ? Hospital de Santo António
city: Porto
country: Portugal
facility: Hospital CUF Porto
city: Porto
country: Portugal
facility: IPO do Porto
city: Vila Nova De Gaia
country: Portugal
facility: CHVNG/E_Unidade 1
city: Yaroslavl
country: Russian Federation
facility: Regional Clinical Oncology Hospital
state: Jaroslavl
city: Moscow
country: Russian Federation
facility: MEDSI Clinical Hospital on Pyatnitsky Highway
state: Moskovskaja Oblast
city: Saint-Petersburg
country: Russian Federation
facility: S-Pb clinical scientific practical center of specialized kinds of medical care (oncological)
state: Sankt Petersburg
city: St. Petersburg
country: Russian Federation
facility: GBUZ Leningradskaya state clinical hospital
state: Sankt Petersburg
city: Barcelona
country: Spain
facility: Vall d?Hebron Institute of Oncology (VHIO), Barcelona
city: La Coruna
country: Spain
facility: Complejo Hospitalario Universitario A Coruña (CHUAC)
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Sevilla
country: Spain
facility: Hospital Univ. Nuestra Señora de Valme
city: Cambridge
country: United Kingdom
facility: Addenbrookes Hospital
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: London
country: United Kingdom
facility: Barts & London School of Med
city: London
country: United Kingdom
facility: University College London Hospital
city: London
country: United Kingdom
facility: Chelsea & Westminster Hospital
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Xing P, Wang M, Zhao J, Zhong W, Chi Y, Xu Z, Li J. Study protocol: A single-arm, multicenter, phase II trial of camrelizumab plus apatinib for advanced nonsquamous NSCLC previously treated with first-line immunotherapy. Thorac Cancer. 2021 Oct;12(20):2825-2828. doi: 10.1111/1759-7714.14113. Epub 2021 Aug 18.