Atezolizumab in Combination With Carboplatin Plus Pemetrexed in Chemotherapy-naïve Patients With Asymptomatic Brain Metastasis

Non-small Cell Lung Cancer Stage IV Clinical Trial

— ATEZO-BRAIN  

Official title:

Phase II Non-randomized Study of a Atezolizumab (MPDL3280A) in Combination With Carboplatin Plus Pemetrexed in Patients Who Are Chemotherapy-naïve and Have Stage IV Non-squamous Non-small Cell Lung Cancer Twith Asymptomatic Brain Metastasis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03526900
• Other study ID #: GECP 17/05_ATEZO-BRAIN
• Secondary ID: 2017-005154-11
• Status: Completed
• Phase: Phase 2
• Start date: July 7, 2018
• Est. completion date: September 15, 2022

Study information

• Verified date: January 2023
• Source: Spanish Lung Cancer Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a multicenter, national, nonrandomized, phase II trial in subjects with nonsquamous NSCLC patients that have untreated asymptomatic BM. A pre-screening period using brain MRI for patients diagnosed with advanced non-squamous NSCLC EGFR/ALK wild type and ECOG PS 0-1 will be crucial to identify patients with asyntomatic BM. Forty patients will be recruited.

Description:

Atezolizumab will be administered intravenously (iv) at a dose of 1200 mg over 60 minutes on day 1 of each cycle. The subsequent cycles of atezolizumab can be administered over 30 minutes, if there were no infusion-related toxicities. Pemetrexed will be administered at a dose of 500 mg/m2 iv over 15 minutes on day 1 of each cycle. In addition, folic acid, vitamin B12, and dexamethasone 4mg bid will be administered one day before and after pemetrexed treatment. Carboplatin will be administered at a dose with an area under the curve of 5 over 30 minutes on day 1 of each cycle approximately 30 minutes after the end of the pemetrexed infusion. After completing 4 to 6 cycles of carboplatin plus pemetrexed and atezolizumab, patients will continue with pemetrexed in combination with atezolizumab until unacceptable toxicity, disease progression, patient/physician decision or completion of 2 years of therapy.

Tumor measurements by CT scan (systemic response) and brain MRI (intracranial response) will be performed every 6 weeks until the 12th week and thereafter every 9 weeks until disease progression. In case of brain progression, rescue with brain radiotherapy should be considered. In case of exclusive brain progression, patients are allowed to receive brain radiotherapy (WBRT or SRS) and then continue with study therapy if the patients maintain clinical benefit and appropriate performance status (ECOG PS≤2).Immunotherapy should be started no later than 4 weeks after completing radiation therapy (brain radiotherapy 2 weeks + 4 weeks of recovery from potential acute toxicity). In case of systemic progression without brain progression, a novel line of systemic treatment should be considered. Patients experiencing systemic progression and/or brain progression will be followed and two post-progression visits will be performed at 30 and 90 days.

Response will be assessed independently in the brain and systemically: systemic response will be evaluated according to RECIST v1.1 and brain response according to the RANO response assessment criteria for BM (RANO-BM). Adverse events will be assessed throughout and assessed using the CTCAE version 4.03. EORTC quality of life questionnaire EORTC C30 and the submodules QLQ-LC13 and BN20 will be assessed in the ITT population at baseline, cycle 5 (week 12),cycle 9 (week 24), at end of study treatment (30 and 90 days) and/or at disease progression. Periodic evaluations of the trial data will be conducted by an independent DMC to ensure subject safety and to evaluate the efficacy at the interim analyses. Neurocognitive assessment including the standardized neuropsychological tests: Hopkins Verbal Learning Test (HVLT), Trail Making Test (TMT), Rey-Osterrieth complex figure test (ROCF) and Controlled Oral Word Association Test (COWA) will be assessed at baseline cycle 5 (week 12),cycle 9 (week 24), at end of study treatment (30 and 90 days) and/or at disease progression.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 43
• Est. completion date: September 15, 2022
• Est. primary completion date: March 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients aged 18 years or older.

• Signed written informed consent.

• ECOG Performance Status (PS) of 0 to 1.

• Subjects with histologically or cytologically confirmed stage IV non-squamous NSCLC who did not received any prior chemotherapy or brain radiotherapy. Patients with EGFR mutation or ALK fusion will be excluded.

• Patients who received prior neo-adjuvant, adjuvant chemotherapy or chemoradiotherapy with curative intent for non-metastatic disease must have experienced a treatment-free interval of at least 6 months since the last dose of chemotherapy and/or radiotherapy.

• Asymptomatic or oligosymptomatic(considered to have alterations in the neurological examination, whether or not they are noted in the anamnesis, that do not prevent appropriate functioning according to the patients' basal state, or that disappear with medical treatment (corticosteroids, analgesics, anticonvulsants) untreated brain metastases.

• Steroids treatment (dexamethasone) is allowed and patients that remained oligosymptomatic or asymptomatic for 2 weeks on steroids will be eligible when they were receiving = 4mg dexamethasone once a day.

• Systemic measurable disease by computed tomography (CT) per response evaluation criteria in solid tumors version (RECIST) 1.1 criteria AND brain measurable disease by magnetic resonance imaging (MRI) per RANO-BM criteria.

• Availability of a formalin-fixed paraffin-embedded block (cell blocks will be accepted if tumor biopsy is not available) containing tumor tissue or 10 unstained slides.

• Adequate hematopoietic, hepatic and renal function:

ANC = 1,500 cells/µL o Lymphocyte count = 500 cells/µL o Platelet count = 100,000 cells µL o Hemoglobin = 9.0 g/dL (transfusion are is allowed) o INR or aPTT = 1.5 x upper limit of normal (ULN); patients receiving therapeutic anticoagulation should be on a stable dose o ALT, AST and/or alkaline phosphatase = 2.5 x ULN, with the following exceptions: -patients with known liver metastasis: ALT and/or AST = 5 x ULN -patients with known bone metastasis: alkaline phosphatase = 5 x ULN o Serum bilirubin = 1.5 x ULN; patients with known Gilbert disease who have serum bilirubin = 3 x ULN may be recruited) o Calculated creatinine clearance (CRCL) = 45 mL/min (based on the standard Cockcroft and Gault formula).

• For women of childbearing potential: agreement to remain abstinent or use contraceptive non-hormonal methods with a failure rate of 1% per year during the treatment period and for 3 months after the last dose of study treatment. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of non-hormonal contraceptive methods with a failure rate of 1% per year include bilateral tubal ligation, male sterilization and copper intrauterine devices.

• For men: agreement to remain abstinent or use a condom, and agreement to refrain from donating sperm. With female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for 3 months after the last dose of study treatment to avoid exposing the embryo. Men must refrain from donating sperm during this same period.

Exclusion Criteria:

• History of other malignancy within 3 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer

• Patients harboring an EGFR mutation or an ALK fusion will be excluded

• Leptomeningeal carcinomatosis or metastases in the brain stem, mid-brain, pons, medulla or lesions causing obstructive hydrocephalus

• Patients with neurological symptoms, including those receiving > 4mg of dexamethasone will not be eligible for this study

• Spinal or hemorrhagic metastases will be excluded

• Prior surgical resection of brain or spinal lesions in the prior 14 days

• Previous systemic treatment or neo-adjuvant or adjuvant chemotherapy less than 6 months before enrollment

• Clinical significant comorbidities that impaired administration of platinum-based chemotherapy

• History of autoimmune disease, including but not limited to myasthenia gravis, myosistis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis or glomerulonephritis

• Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid-replacement hormone are eligible for this study

• Patients with controlled Type 1 diabetes mellitus on a stable dose of insulin are eligible for this study

• Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic manifestations only (e.g. patients with psoriasic arthritis would be excluded) are permitted provided that they meet the following conditions: rash covers less than 10% of body surface area, disease is well controlled at baseline and only requires lowpotency topical steroids, no acute exacerbations during the last 12 months

• History of idiopathic pulmonary fibrosis, drug-induced pneumonitis or active radiation pneumonitis out of the radiation field

• Previous treatment with immune checkpoint inhibitors or CD137 and OX-40 agonists

• Treatment with investigational therapy within 28 days prior to initiation of study drug - Positive for hepatitis C virus (HCV) antibody or for hepatitis B surface antigen (HBsAg) at screening. Patients with past or resolved hepatitis B virus (HBV) infection (HBcAb positive with absence of HBsAg) would be eligible whether they are negative for HBV DNA. Patients positive for HCV antibody would be eligible whether they are negative for HCV RNA

• Active tuberculosis or HIV infection

• Illicit drug or alcohol abuse within 12 months prior to screening, in the investigator's judgment.

• Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study.

Related Conditions & MeSH terms

• Brain Neoplasms
• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non-small Cell Lung Cancer Stage IV

Intervention

Drug:
• Atezolizumab
Induction (four or six 21-day cycles) : Atezolizumab 1200 mg / iv + carboplatin 5 AUCs + pemetrexed 500 mg/m2 Maintenance (21-day cycles): atezolizumab 1200 mg/iv + pemetrexed 500 mg/m2.

Locations

Country	Name	City	State
Spain	Hospital General de Alicante	Alicante
Spain	Hospital Universitari Germans Tries i Pujol	Badalona	Barcelona
Spain	H.U.Vall D´Hebrón	Barcelona
Spain	Hospital de Santa Creu i Sant Pau	Barcelona
Spain	Hospital General Universitario de Elche	Elche	Alicante
Spain	Hospital Dr. Josep Trueta	Girona
Spain	Hospital Universitari de Bellvitge	L'Hospitalet de Llobregat	Barcelona
Spain	Complejo Hospitalario de la Coruña	La Coruña	Coruña
Spain	Hospital Insular de Gran Canaria	Las Palmas de Gran Canaria	Las Palmas
Spain	H. La Paz	Madrid
Spain	Hospital Fundación Jiménez Díaz	Madrid
Spain	Hospital General Universitario de Valencia	Valencia
Spain	Hospital La Fe	Valencia
Spain	Hospital Clínico Universitario de Valladolid	Valladolid
Spain	Complexo Hospitalario Universitario de Vigo	Vigo	Pontevedra

Sponsors (1)

Lead Sponsor	Collaborator
Spanish Lung Cancer Group

Country where clinical trial is conducted

Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	The Neurologic Assessment in Neuro-Oncology (NANO) scale: a tool to assess neurologic function for integration intro the Response Assessment.	The NANO scale (Neuro-Oncology Scale) is and objective clinician-reported outcome of neurologic function with high inter-observer agreement quantifiable evaluation of 9 relevant neurologic domains.The NANO scale evaluates 9 major domains of neurologic function that are most relevant to patients with supratentorial, infratentorial, and brainstem tumors, including gait, strength, upper extremity ataxia, sensation, visual fields, facial strength, language, level of consciousness, and behavior. Each domain is subdivided into 3 or 4 levels of function with scores based on discrete quantifiable measures. Thus, levels of function for each domain range from 0 to 2 or 0 to 3. A score of 0 indicates normal function, while the highest score indicates the most severe level of deficit for that domain.	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months.
Other	Number of patients who have neurological deterioration.	To record the number of patients requiring an increase steroid dose for > 96h to control neurologic symptoms.	From the date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months.
Other	Median time to brain radiotherapy (WBRT or SRS)	Register the median time to needed brain radiotherapy (WBRT or SRS).	From date of randomization until the date of first needed salvage therapy, assessed up to 48 months.
Other	Quality of life measured with Health-related Quality of Life questionnaires (EORTC QLQ-BN20).	QLQ tests allow to capture the patient's' own perception about their physical, mental, and social functions, as well as other related symptoms frequently suffered by cancer patients specially in patients with brain cancer (EORTC QLQ-BN20).	From the date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 48 months.
Primary	Efficacy of atezolizumab + CBDCA + pemetrexed by evaluating PFS	To evaluate the efficacy of Atezolizumab in terms of rate of progression free survival after enrollment defined as the sate of patients free of disease progressionor death from any cause wichever occurs first at 12 weeks as determined by the investigator according to RANO and RECIST v1.1 criteria for brain and Systemix disease respectively.	12 weeks after enrollment
Secondary	Efficacy of atezolizumab + CBDCA + pemetrexed by measuring objective response.	Objective response defined as a complete response or partial response on two consecutive evaluations 6 weeks apart, as determined by the investigator according to RANO and RECIST v1.1 criteria for brain and systemic disease respectively.	Two consecutive evaluations 6 weeks apart

External Links

•   Grupo Español de Cáncer de Pulmón website