Atezolizumab Immunotherapy in Patients With Advanced NSCLC

Carcinoma, Non-Small-Cell Lung Clinical Trial

Official title:

Phase II Trial of Induction Immunotherapy With Atezolizumab for Patients With Unresectable Stage IIIA and IIIB NSCLC Eligible for Chemoradiotherapy With Curative Intent.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03102242
• Other study ID #: AFT-16
• Status: Completed
• Phase: Phase 2
• Start date: November 1, 2017
• Est. completion date: October 1, 2022

Study information

• Verified date: April 2023
• Source: Alliance Foundation Trials, LLC.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Phase II trial of induction immunotherapy with atezolizumab for patients with unresectable stage IIIA and IIIB NSCLC eligible for chemoradiotherapy with curative intent.

Description:

This phase II pilot trial will combine neoadjuvant immunotherapy with Atezolizumab q 21 days for 12 weeks with standard chemoradiotherapy with curative intent for good PS patients with unresectable stage IIIA/B NSCLC. Because of the consequences of progression in this curative-intent population, restaging CT scans will be carried out after the first 2 cycles of neoadjuvant therapy. Non progressing patients will complete a total of one year of anti-PDL1 therapy with an interruption during chemoradiotherapy. Patients with evidence of progression at the first restaging evaluation will proceed immediately to chemoradiotherapy if still eligible for curative intent therapy.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 64
• Est. completion date: October 1, 2022
• Est. primary completion date: June 1, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

Inclusion Criteria:

• Newly diagnosed stage IIIA/B NSCLC, PS 0-1

• No active autoimmune disease or uncontrolled infection, normal bone marrow, renal, hepatic function, FEV1 > 1.2L, no significant underlying heart or lung disease

• Pathologically proven diagnosis of NSCLC

• Measurable Stage IIIA or IIIB disease

• Tissue available for PD-L1 testing and for correlative science testing

• Patients must be considered unresectable or inoperable. Patients with nodal recurrence after surgery for early-stage NSCLC are eligible if the following criteria are met:

• No prior chemotherapy or radiation for this lung cancer.

• Prior curative-intent surgery at least 3 months prior to the nodal recurrence.

• Stage III A or B disease with minimum diagnostic evaluation within 6 weeks to include:

• History/physical examination

• Contrast enhanced CT of the chest and upper abdomen

• MRI of the brain with contrast (or CT with contrast if MRI is medically contraindicated)

• PET/CT

• If pleural fluid is visible on CT scan thoracentesis to exclude malignancy should be obtained. Patients with effusions that are too small to tap are eligible.

• Patients must be at least 4 weeks from major surgery and must be fully recovered

• Age greater than or equal to 18 years.

• Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks or at least 4 unstained slides, with an associated pathology report, for central testing of tumor PD-L1 expression.

• If an archived tumor block exists, then either the block or at least 4 unstained slides from the block should be submitted. Tumor tissue should be of good quality based on total and viable tumor content, i.e. at least 50 viable tumor cells and intact tissue architecture. Fine needle aspiration, brushing,and lavage samples are not acceptable. If the block is tissue from a core-needle biopsy, then the block should contain tissue from at least three cores to be sufficient for evaluation.

• Patients who do not have existing (archived) tissue specimens meeting eligibility requirements may undergo a biopsy during the screening period. Acceptable samples include core needle biopsies for deep tumor tissue (minimum of three cores) or excisional, or forceps biopsies for endobronchial or nodal lesions. The tissue should be fixed in formalin and embedded on site and sent as a block.

• Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment (Cycle 1, Day 1):

• ANC = 1500 cells/µL

• WBC counts > 2500/µL

• Lymphocyte count = 300/µL

• Platelet count = 100,000/µL

• Hemoglobin = 10.0 g/dL

• Total bilirubin = 1.5 x upper limit of normal (ULN) with the following exception:

• Patients with known Gilbert disease who have serum bilirubin level = 3 x ULN may be enrolled.

• AST and ALT = 3.0 x ULN

• Alkaline phosphatase = 2.5 x ULN

• Serum creatinine = 1.5 x ULN or creatinine clearance = 50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation:

• (140 - age) x (weight in kg) x (0.85 if female)/ 72 x (serum creatinine in mg/dL)

• Measurable disease per RECIST v1.1 (see Appendix 3)

• For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use highly effective form(s) of contraception (i.e., one that results in a low failure rate [< 1% per year] when used consistently and correctly) and to continue its use for 90 days after the last dose of Atezolizumab.

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

• INR and aPTT = 1.5 x ULN • This applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation (such as low-molecular-weight heparin or warfarin) should be on a stable dose.

Exclusion Criteria:

• Active autoimmune disease

• Greater than minimal, exudative, or cytologically positive pleural effusions

• Involved contralateral hilar nodes

• 10% weight loss within the past month

• Known EGFR exon 19 or 21 mutation or ALK rearrangement

• Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years; non-invasive conditions such as carcinoma in situ of the breast, localized prostate cancer, carcinoma in situ of the oral cavity, or cervix are all permissible.

• Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable.

• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields.

• Prior severe infusion reaction to a monoclonal antibody

• Severe, active co-morbidity, defined as follows:

• Significant history of uncontrolled cardiac disease; i.e., uncontrolled hypertension, unstable angina, myocardial infarction within the last 6 months, uncontrolled congestive heart failure, and cardiomyopathy with decreased ejection fraction.

• Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration or within 2 weeks of cycle 1 day 1.

• Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before registration

• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

• Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; note, HIV testing is required for entry into this protocol due to the immunologic basis for induction treatment.

• Pregnancy, lactation, or inability or unwillingness to use medically acceptable forms of contraception if pregnancy is a risk.

• Any history of allergic reaction to paclitaxel or other taxanes, or to carboplatin;

• Uncontrolled neuropathy grade 2 or greater regardless of cause.

• Any approved anticancer therapy, including chemotherapy, hormonal therapy, or radiotherapy, within 3 weeks prior to initiation of study treatment; however, the following are allowed:

i. Hormone-replacement therapy or oral contraceptives ii. Herbal therapy > 1 week prior to Cycle 1, Day 1 (herbal therapy intended as anticancer therapy must be discontinued at least 1 week prior to Cycle 1, Day 1)

• Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease

• Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible.

• Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.

• Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies

• Inability to comply with study and follow-up procedures

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

• Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible.

• Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible.

• Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:

• Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations

• Rash must cover less than 10% of body surface area (BSA)

• Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alcometasone dipropionate 0.05%)

• No acute exacerbations of underlying condition within the last 6 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids)

• History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan

• 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 render the patient at high risk from treatment complications

• Active tuberculosis

• Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of need for a major surgical procedure during the course of the study

• Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or anticipation that such a live, attenuated vaccine will be required during the study

• Influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to Cycle 1, Day 1 or at any time during the study.

• Malignancies other than the disease under study within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death and with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ treated surgically with curative intent) or undergoing active surveillance per standard-of-care management (e.g., chronic lymphocytic leukemia Rai Stage 0, prostate cancer with Gleason score = 6, and prostate-specific antigen [PSA] = 10 mg/mL, etc.)

Medication-Related Exclusion Criteria:

• Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway targeting agents

• Treatment with systemic immunostimulatory agents (including but not limited to interferon [IFN]

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung

Intervention

Drug:
• Atezolizumab
Single arm phase II trial of induction immunotherapy with anti-PD-L1 for patients with unresectable stage III NSCLC and PS 0-1.

Locations

Country	Name	City	State
United States	Saint Joseph Mercy Hospital	Ann Arbor	Michigan
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	EMMC Cancer Care	Brewer	Maine
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	The University of Chicago Medical Center	Chicago	Illinois
United States	Ohio State University James Cancer Center	Columbus	Ohio
United States	Prisma Health Greenville Memorial Hospital	Greenville	South Carolina
United States	UCSD Moores Cancer Center	La Jolla	California
United States	Metro MN Community Oncology Research Consortium	Minneapolis	Minnesota
United States	Mayo Clinic Hospital	Phoenix	Arizona
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	SUNY Upstate Medical University	Syracuse	New York
United States	Lankenau Medical Center	Wynnewood	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Alliance Foundation Trials, LLC.

Country where clinical trial is conducted

United States, 

References & Publications (7)

Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Aren Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. doi: 10.1056/NEJMoa1504627. Epub 2015 May 31. — View Citation

Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026. — View Citation

Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, Hicks M, Puzanov I, Alexander MR, Bloomer TL, Becker JR, Slosky DA, Phillips EJ, Pilkinton MA, Craig-Owens L, Kola N, Plautz G, Reshef DS, Deutsch JS, Deering RP, Olenchock BA, Lichtman AH, Roden DM, Seidman CE, Koralnik IJ, Seidman JG, Hoffman RD, Taube JM, Diaz LA Jr, Anders RA, Sosman JA, Moslehi JJ. Fulminant Myocarditis with Combination Immune Checkpoint Blockade. N Engl J Med. 2016 Nov 3;375(18):1749-1755. doi: 10.1056/NEJMoa1609214. — View Citation

Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements. Clin Cancer Res. 2013 Jul 15;19(14):3936-43. doi: 10.1158/1078-0432.CCR-13-0895. Epub 2013 Jun 6. — View Citation

Reck M, Paz-Ares L. Immunologic checkpoint blockade in lung cancer. Semin Oncol. 2015 Jun;42(3):402-17. doi: 10.1053/j.seminoncol.2015.02.013. Epub 2015 Feb 19. — View Citation

Rizvi NA, Mazieres J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, Horn L, Lena H, Minenza E, Mennecier B, Otterson GA, Campos LT, Gandara DR, Levy BP, Nair SG, Zalcman G, Wolf J, Souquet PJ, Baldini E, Cappuzzo F, Chouaid C, Dowlati A, Sanborn R, Lopez-Chavez A, Grohe C, Huber RM, Harbison CT, Baudelet C, Lestini BJ, Ramalingam SS. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015 Mar;16(3):257-65. doi: 10.1016/S1470-2045(15)70054-9. Epub 2015 Feb 20. — View Citation

Tecentriq Package Insert, 06May 2016 http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/761034s000lbl.pdf

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disease Control Rate (DCR) After 12 Weeks Induction	The primary objective of this single arm phase II trial is to determine whether neoadjuvant and adjuvant anti-PD-L1 therapy bracketing standard chemoradiation therapy and consolidation therapy is worthy of further investigation. The primary endpoint will be the disease control rate (DCR) after 12 weeks induction immunotherapy.	12 weeks
Secondary	Objective Response Rate (ORR)	Objective response rate (ORR) is the rate of best overall response (complete or partial response) after 12 weeks of neoadjuvant atezolizumab therapy. ORR and its 90% Clopper-Pearson Confidence interval will be estimated.	12 weeks
Secondary	Median PFS	Progression-free survival (PFS) is defined as the time from the start of neoadjuvant therapy to disease progression or recurrence (first disease recurrence or death, whichever comes first). The Kaplan-Meier estimator will be used to estimate median PFS and confidence intervals.	38.3 months
Secondary	Progression Free Survival (PFS) at 12 and 24 Months	Progression-free survival (PFS) is defined as the time from the start of neoadjuvant therapy to disease progression or recurrence (first disease recurrence or death, whichever comes first). The Kaplan-Meier estimator will be used to estimate median PFS and confidence intervals. A progression occurs when at least one of the following are true: At least one new malignant lesion, which also includes any lymph node that was normal at baseline (< 1.0 cm short axis) and increased to = 1.0 cm short axis during follow-up.; At least a 20% increase in PBSD (sum of the longest diameter for all target lesions plus the sum of the short axis of all the target lymph nodes at current evaluation) taking as reference the MSD (Section 11.4.1). In addition, the PBSD must also demonstrate an absolute increase of at least 0.5 cm from the MSD.; See Section 11.3.2 for details in regards to the requirements for PD via FDG-PET imaging.	12 and 24 Months
Secondary	Median OS	Overall Survival (OS) is defined as the time from the start of neoadjuvant therapy to death. The Kaplan-Meier estimator will be used to estimate median OS.	38.3 Months
Secondary	Overall Survival at 12 and 24 Months	Overall Survival (OS) is defined as the time from the start of neoadjuvant therapy to death. The Kaplan-Meier estimator will be used to estimate OS at 12 months and 24 months, and their confidence intervals.	12 and 24 Months