Carboplatin, Pemetrexed, and Atezolizumab in Patients With Non-squamous Non-small Cell Lung Cancer (NSCLC) and Untreated Brain Metastases

Study Overview
=================
Brief Summary
-----------------
This clinical trial is aimed at the evaluation of the safety and clinical activity of tiragolumab in combination with carboplatin, pemetrexed and atezolizumab in the first line treatment of metastatic non-squamous NSCLC patients with asymptomatic untreated brain metastases.

Detailed Description
-----------------
This is a phase II clinical trial aimed at the evaluation of the safety and clinical activity of tiragolumab in combination with carboplatin, pemetrexed and atezolizumab in the first line treatment of metastatic non-squamous NSCLC patients with asymptomatic untreated brain metastases. Patients with at least one untreated evaluable brain metastasis of 5 mm or more will be enrolled. Lesions previously treated with SRS may not be used as target lesions. Patients will be required to undergo an on-treatment brain MRI at three weeks for safety purposes. Additional restaging will occur at nine-week intervals. PD-L1 tumor proportion score (TPS) will be determined utilizing an FDA-approved test by local testing.

Official Title
-----------------
A Phase II Clinical Trial of Tiragolumab in Combination With Carboplatin, Pemetrexed, and Atezolizumab in Patients With Non-squamous Non-small Cell Lung Cancer (NSCLC) and Untreated Brain Metastases

Conditions
-----------------
Non-small Cell Lung Cancer

Intervention / Treatment
-----------------
* Drug: Tiragolumab
* Drug: Atezolizumab
* Drug: Pemetrexed
* Drug: Carboplatin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have histologically or cytologically confirmed non-squamous NSCLC. Patients must have asymptomatic brain metastases with at least one untreated evaluable (per RANO-BM) brain metastasis of 5 mm or more. A growing lesion previously treated with whole brain radiotherapy is acceptable given the lower incidence of radiation necrosis. Lesions previously treated with SRS may not be used as target lesions. o Patients are not required to have measurable disease outside the CNS per RECIST 1.1. Prior chemotherapy, immunotherapy or radiation given with curative intent in early stage or locoregionally advanced NSCLC is permitted, if completed more than 12 months prior to initiation of study treatment. Prior radiation with palliative intent in the metastatic setting to non-CNS lesions is permitted (no wash-out period). Age ≥18 years. ECOG performance status ≤ 1. Life expectancy ≥12 weeks. Patients must have normal organ and marrow function as defined below: Absolute neutrophil count ≥1,500/mcL Platelets ≥100,000/mcL Total bilirubin ≤ institutional upper limit of normal (ULN) AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN Creatinine Clearance (CrCl) ≥45 mL/min/1.73 m2 No known history of HIV, with the following exception: patients who are HIV positive are eligible provided they are stable on anti-retroviral therapy, have a CD4 count ≥ 200/µL, and have an undetectable viral load. Negative hepatitis B surface antigen (HBsAg) test at screening. If positive, an HBV DNA test must also be performed to determine if the patient has an HBV infection, which would render the patient ineligible. Patients receiving treatment with anti-viral therapy for HBV are excluded. Negative hepatitis C antibody. If positive, an HCV RNA test must also be performed to determine if the patient has an HCV infection, which would render the patient ineligible. Availability of a representative tumor specimen for exploratory biomarker research. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception: Women must remain abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 90 days after the final dose of tiragolumab, 5 months after the final dose of atezolizumab, and 6 months after the final dose of paclitaxel, pemetrexed, gemcitabine, carboplatin, or cisplatin. A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). Per this definition, a woman with a tubal ligation is considered to be of childbearing potential. The definition of childbearing potential may be adapted for alignment with local guidelines or regulations. Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form. Women who would like to become pregnant after study treatment discontinuation should seek advice on oocyte cryopreservation prior to initiation of study treatment because of the possibility of irreversible infertility due to treatment with cisplatin and carboplatin. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below: With a female partner of childbearing potential, men who are not surgically sterile must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period, for 90 days after the final dose of tiragolumab, and for 6 months after the final dose of paclitaxel, pemetrexed, gemcitabine, carboplatin or cisplatin. Men must refrain from donating sperm during this same period. With a pregnant female partner, men must remain abstinent or use a condom during the treatment period for 90 days after the final dose of tiragolumab, and for 6 months after the final dose of paclitaxel, pemetrexed, gemcitabine, carboplatin, or cisplatin to avoid exposing the embryo. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form. Men who would like to father a child after study treatment initiation should be advised regarding the conservation of sperm prior to treatment because of the possibility of irreversible infertility resulting from chemotherapies used in this study. Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Symptoms related to brain metastases requiring CNS radiation ≤ 2 weeks of treatment initiation are exclusionary. Steroids greater than prednisone 10 mg/d or equivalent, or anti-epileptic therapy ≤ 2 weeks of treatment initiation are exclusionary. Prior systemic therapy for metastatic disease is not allowed. Patients whose tumors harbor oncogenic drivers with an approved 1st line therapy (e.g. EGFR, ALK, and ROS1 alterations) are excluded. Patients who are receiving any other investigational agents. 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, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions: Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met: Rash must cover < 10% of body surface area Disease is well controlled at baseline and requires only topical corticosteroids No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis or fibrosis in a radiation field is permitted. History of leptomeningeal disease. Active tuberculosis. Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina. 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. History of malignancy other than NSCLC within 2 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate ≥ 90%). Severe infection within 2 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia. Prior allogeneic stem cell or solid organ transplantation. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications. Treatment with 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 immunosuppressive medication (including, but not limited to, corticosteroids in excess of prednisone 10 mg/d or equivalent, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-α agents) 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 (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study. Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic History of allergic reactions attributed to compounds of similar chemical or biologic composition to atezolizumab or other agents used in 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 or tiragolumab formulation. Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment, within 90 days after the final dose of tiragolumab, 5 months after the final dose of atezolizumab, or 6 months after the final dose of pemetrexed, gemcitabine, paclitaxel, carboplatin, or cisplatin o Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Treatment Arm<br>Tiragolumab in combination with atezolizumab, pemetrexed, and carboplatin. | Drug: Tiragolumab<br>* Tiragolumab (an investigational novel immune checkpoint inhibitor): 600 mg IV for induction treatment administered on Day 1 of each 21-day cycle for 4 cycles. Maintenance therapy will continue with tiragolumab on Day 1 of each 21-day cycle.<br>* Other names: RO7092284;Drug: Atezolizumab<br>* Atezolizumab (monoclonal antibody): 1200 mg IV administered on Day 1 of each 21-day cycle.<br>* Other names: RO5541267;Drug: Pemetrexed<br>* Pemetrexed (antifolate antineoplastic agent chemotherapy): 500 mg/m2 administered IV on Day 1 of each 21-day cycle.<br>* Other names: Pemfexy;Drug: Carboplatin<br>* Carboplatin AUC 5 (alkylating agent chemotherapy): injection administered on Day 1 of each 21-day cycle.<br>* Other names: Paraplatin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Initiation of Salvage Radiation Therapy to Central Nervous System (CNS) | The proportion of patients that require salvage radiation therapy to the CNS (within 18 weeks from study initiation). Salvage radiation therapy is radiation treatment given for suspected recurrent malignant disease. | Up to 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events Related to Treatment | Adverse Events and Serious Adverse Events per Common Terminology Criteria for Adverse Events CTCAE v5.0, at least possibly related to trial treatment. | Up to 26 months | 
| Brain Metastasis Response Rate (BMRR) | Proportion of patients with brain metastases that experience a Complete or Partial Response per RANO-BM. RANO Criteria: Complete Response (CR):disappearance of all enhancing disease (measurable and non-measurable), sustained for at least 4 weeks, stable or improved non-enhancing FLAIR/T2W lesions, no new lesions; clinical features - no corticosteroids (physiological replacement doses allowed) clinically stable or improved. Partial Response (PR): 50% or more decrease of all measurable enhancing lesions sustained for at least 4 weeks no progression of non-measurable disease stable or improved non-enhancing FLAIR/T2W lesions no new lesions; clinical features stable or reduced corticosteroids (compared to baseline) clinically stable or improved. | Up to 26 months | 
| Objective Response Rate (ORR) | The proportion of participants experiencing Complete or Partial Response assessed using RECIST v1.1. Per RECIST v1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) with reduction in short axis to <10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | Up to 26 months | 
| Progression-free Survival (PFS) | The length of time during and after treatment that a patient lives with disease but without disease progression. Per RECISIT v1.1: Progressive Disease (PD):≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression. | Up to 5 years | 
| Overall Survival (OS) | The length of time from start of treatment that patients remain still alive. | Up to 5 years | 
| Progression-free Survival after initiation of salvage XRT (PFS2) | The length of time during and after treatment and after after initiation of salvage radiation therapy (XRT) that a patient lives with disease but without disease progression. Per RECISIT v1.1: Progressive Disease (PD):≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression. | Up to 5 years | 
| PD-L1 Tumor Proportion Score (TPS) | Tumor Proportion Score (TPS) indicates protein expression by measuring the percentage of viable tumor cells showing partial or complete membrane staining at any intensity. The specimen is considered to have PD-L1 expression if TPS ≥ 1% and high PD-L1 expression if TPS ≥ 50%. | Up to 26 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PD-L1 tumor proportion score (TPS), salvage radiation therapy, brain metastases