Atezolizumab Plus Induction Chemotherapy Plus CT-radiotherapy. (APOLO)

A Phase II Trial of Atezolizumab Plus Induction Chemotherapy (CT) Plus Chemo-radiotherapy and Atezolizumab Maintenance Therapy in Non-resectable Stage IIIA-IIIB Non-small Cell Lung Cancer (NSCLC) Patients

Open-label, non-randomized, phase II multi-centre controlled clinical trial.

51 non-resectable stage IIIA-IIIB non-small cell lung cancer patients will be enrolled in this trial to evaluate the efficacy of the treatment (Atezolizumab + Induction chemotherapy (CT) + CT-Radiotherapy) in terms of the Progression Free Survival at 12 months

This is an open-label, non-randomized, phase II multi-centre controlled clinical trial.The total sample size is 51 patients. The population to be included are non-resectable stage IIIA-IIIB non-small cell lung cancer patients.

Patients randomised will receive induction treatment (Atezolizumab 1200mg+ Carboplatin AUC5+Paclitaxel 200 mg/m2 for 3 cycles) and concurrent chemotherapy (CT) -radiotherapy treatment for 3 cycles. At the end of concurrent treatment Atezolizumab 1200mg maintenance treatment will start and will be administered for 12 months (16 cycles).

The primary objective is to assess the efficacy of the treatment (Atezolizumab + Induction chemotherapy (CT) + CT-Radiotherapy) in terms of the Progression Free Survival (PFS) at 12 months according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.

PFS are defined as the time from inclusion until objective tumor progression or death.

Patient accrual is expected to be completed within 2 years, treatment is planned to extend during 1.5 years and the patients will be followed up for 2 years. The study will end once survival follow-up has concluded.

Inclusion Criteria:

• Male or female, aged ≥ 18 years old and ≤ 75 years.
• ECOG Scale (Eastern Cooperative Oncology Group) of performance status of 0 or 1.
• Histologically or cytologically confirmed, non-resectable Stage IIIA-IIIB NSCLC according to the 8th version of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology.
• PET-CT (Positron Emission Tomography -Computed tomography) and brain computed tomography or Magnetic resonance imaging (MRI) at baseline to confirm the absence of distant disease.
• Mediastinal involvement could be considered without histological confirmation when no margin can be distinguished in the lymph node mass.
• No prior treatment with anti-neoplastic drugs or thoracic radiotherapy for Stage IIIA-IIIB NSCLC.
• Patients who have received prior neo-adjuvant, adjuvant chemotherapy with curative intent for non-metastatic disease must have experienced a treatment-free interval of at least 6 months from enrollment since the last chemotherapy.
• Presence of at least one measurable disease by CT-SCAN, as defined by RECIST v1.1.
• Adequate hematologic and organ function defined by the following laboratory results obtained within 14 days prior to enrollment:
• Neutrophils ≥ 1500 cells/μL without granulocyte colony-stimulating factor support.
• Lymphocyte count ≥ 500/μL.
• Platelet count ≥ 100,000/μL without transfusion.
• Haemoglobin ≥ 10.0 g/dL. Patients may be transfused to meet this criterion.
• INR or aPTT ≤ 1.5 × upper limit of normal (ULN). This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose.
• AST, ALT, and alkaline phosphatase ≤ 2.5 × ULN, with the following exceptions:
• Serum bilirubin ≤ 1.5 × ULN. Patients with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may be enrolled.
• Serum creatinine ≤ 1.5 × ULN or creatinine clearance of ≥60ml/min (based on the Cockcroft Gault formula).
• All patients are notified of the investigational nature of this study and signed a written informed consent in accordance with institutional and national guidelines, including the Declaration of Helsinki prior to any trial-related intervention.
• Adequate lung function: Forced Expiratory Volumen in 1 second (FEV1) >50% of normal volume and Diffusion Capacity of the Lungs for Carbon Monoxide (DLCO) >40% of normal value.
• No more than 35% of the total volume of the two lungs should receive more than 20 Gy (V20) or no more than 7cm maximum diameter.
• For female patients of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception that results in a low failure rate (< 1% per year) when used consistently and correctly, and to continue its use for 6 months after the last dose of trial treatment. Such methods include: combined (oestrogen and progesterone containing) hormonal contraception, progestogen-only hormonal contraception associated with inhibition of ovulation together with another additional barrier method always containing a spermicide, intrauterine device (IUD): intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised partner (on the understanding that this is the only one partner during the whole study duration), and sexual abstinence.
• For male patients with female partners of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception that results in a low failure rate [< 1% per year] when used consistently and correctly, and to continue its use for 6 months after the last dose of trial treatment. Male patients should not donate sperm during this study and for at least 6 months after the last dose of trial treatment.
• Oral contraception should always be combined with an additional contraceptive method because of a potential interaction with the study drugs. The same rules are valid for male patients involved in this clinical study if they have a partner of childbirth potential. Male patients must always use a condom.
• Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 8 days prior to initiation of study drug.

Exclusion Criteria:

• Patients with known sensitizing mutation or an amplification in the epidermal growth factor receptor (EGFR) gene, ALK fusion oncogene.
• Known STK-11 ligand alterations, MDM2 amplifications or ROS1 translocations.
• Weight loss >10% within the previous 3 months.
• Malignant pleural effusion or pericardial effusion: both will be considered as suggestive of metastatic disease. Also excluded those with negative cytology but being exudates.
• Patients with non-visible by thoracic X-Ray pleural effusion or too small to be safely punctioned could be included.
• Malignancies other than NSCLC within 3 years prior to enrollment, with the exception of those with a negligible risk of metastasis or death (e.g., expected 3-year OS > 90%) treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous-cell skin cancer, localized prostate cancer treated with radiotherapy or surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent).
• Women who are pregnant, lactating, or intending to become pregnant during the study.
• Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the Atezolizumab formulation.
• History of autoimmune disease.
• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.
• Positive test for human immunodeficiency viruses (HIV). All patients will be tested for HIV prior to inclusion into the study; patients who test positive for HIV will be excluded from the clinical study.
• Patients with active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C.
• Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are eligible only if they are negative for HBV DNA (vaccinated patients are excluded).
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV RNA.
• Active tuberculosis.
• Symptomatic neuropathy (sensory) grade > 1 according to the NCI Common Toxicity Criteria for Adverse Events v5.0
• Severe infections within 4 weeks prior to be included in the study, including but not limited to hospitalization for complications of infection, bacteraemia, or severe pneumonia.
• Received therapeutic oral or IV antibiotics within 2 weeks prior to be included in the study.
• Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or to prevent chronic obstructive pulmonary disease exacerbation) are eligible.
• Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction, or cerebrovascular accident within 3 months prior to inclusion, unstable arrhythmias, or unstable angina.
• Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate.
• Patients with a superior vena cava syndrome.
• Major surgical procedure other than for diagnosis within 28 days prior to inclusion or anticipation of need for a major surgical procedure during the course of the study.
• Prior allogeneic bone marrow transplantation or solid organ transplant.
• Administration of a live, attenuated vaccine within 4 weeks before inclusion or anticipation that such a live attenuated vaccine will be required during the study.
• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patient at high risk from treatment complications.
• Patients with illnesses or conditions that interfere with their capacity to understand follow and/or comply with study procedures.
• Treatment with any other investigational agent with therapeutic intent within 28 days prior to initiation of study treatment.
• Treatment with systemic immunosuppressive medications (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to inclusion.