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

Phase 2

Completed

Conditions: Non-small Cell Lung Cancer Stage IV

Interventions: Drug: Atezolizumab

Registration Number: NCT03526900

Lead Sponsor: Spanish Lung Cancer Group

Brief 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.

Detailed 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 & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 40

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Atezolizumab	Atezolizumab	Induction phase: atezolizumab will be given intravenously (iv) at a dose of 1200 mg for 60 minutes on day 1 of each cycle. Subsequent atezolizumab cycles may be administered for 30 minutes, if there were no perfusion-related toxicity. Pemetrexed will be administered at a dose of 500 mg/m2 IV for 15 minutes on day 1 of each cycle. In addition, folic acid, vitamin B12, and dexamethasone 4 mg will be given the day before and the day after treatment with pemetrexed. Carboplatin will be given at a dose with an area under the 5 curve for 30 minutes on day 1 of each cycle, approximately 30 minutes after the pemetrexed infusion is complete. After completing 4 to 6 cycles of Carboplatino plus pemetrexed and atezolizumab, patients will continue with pemetrexed in combination with atezolizumab (maintenance phase) until they have an unacceptable toxicity, progression of the disease, decision of the patient/physician or have Completed 2 years of treatment.

Primary Outcome Measures

Name	Time	Method
Efficacy of Atezolizumab + CBDCA + Pemetrexed by Evaluating PFS Rate	12 weeks after enrollment	Percentage of subjects without disease progression (intracranial or systemic) at 12 weeks after enrollment. Determined by the investigator according to RANO and RECIST v1.1 criteria for brain and systemic disease respectively. Response Evaluation Criteria In Solid Tumors (RECIST v1.1) for target lesions and assessed by MRI:Complete Response(CR),Disappearance of all target lesions; Partial Response (PR) ≥30% decrease in the sum of the longest diameter of target lesions; Progressive disease (PD) ≥20% increase in the sum of diameters of target lesions. Reponse Evaluation criteria in brain metastasis (RANO) for target lesions assessed by MRI: Complete Response (CR) Disappearance of all CNS target lesions without use of corticosteroids, Partial response (PR) ≥30% decrease in the sum longest diameter of CNS target lesions;Progessive disease (PD) ≥20% increase in the sum longest diameter of CNS target lesions

Secondary Outcome Measures

Name	Time	Method
Efficacy of Atezolizumab + CBDCA + Pemetrexed by Measuring Objective Response.	Two consecutive evaluations 6 weeks apart	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. Response Evaluation Criteria In Solid Tumors (RECIST v1.1) for target lesions and assessed by MRI: Complete Response(CR), Disappearance of all target lesions; Partial Response (PR) ≥30% decrease in the sum of the longest diameter of target lesions; Progressive disease (PD) ≥20% increase in the sum of diameters of target lesions. Reponse Evaluation criteria in brain metastasis (RANO) for target lesions assessed by MRI: Complete Response (CR), Disappearance of all CNS target lesions without use of corticosteroids, Partial response (PR) ≥30% decrease in the sum longest diameter of CNS target lesions; Progessive disease (PD) ≥20% increase in the sum longest diameter of CNS target lesions or the appearance of new lesions

Trial Locations

Locations (15): Hospital Universitari Germans Tries i Pujol
🇪🇸
Badalona, Barcelona, Spain
Hospital Universitari de Bellvitge
🇪🇸
L'Hospitalet de Llobregat, Barcelona, Spain
Hospital Insular de Gran Canaria
🇪🇸
Las Palmas de Gran Canaria, Las Palmas, Spain
Complexo Hospitalario Universitario de Vigo
🇪🇸
Vigo, Pontevedra, Spain
Hospital General Universitario de Elche
🇪🇸
Elche, Alicante, Spain
Hospital La Fe
🇪🇸
Valencia, Spain
H. La Paz
🇪🇸
Madrid, Spain
Hospital Clínico Universitario de Valladolid
🇪🇸
Valladolid, Spain
Hospital de Santa Creu i Sant Pau
🇪🇸
Barcelona, Spain
Hospital Dr. Josep Trueta
🇪🇸
Girona, Spain
Complejo Hospitalario de la Coruña
🇪🇸
La Coruña, Coruña, Spain
Hospital Fundación Jiménez Díaz
🇪🇸
Madrid, Spain
Hospital General de Alicante
🇪🇸
Alicante, Spain
Hospital General Universitario de Valencia
🇪🇸
Valencia, Spain
H.U.Vall D´Hebrón
🇪🇸
Barcelona, Spain