Nivolumab After Surgery and Chemotherapy in Treating Patients With Stage IB-IIIA Non-small Cell Lung Cancer (An ALCHEMIST Treatment Trial) (ANVIL)

Study Description

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Brief Summary:

This phase III ALCHEMIST trial studies how well nivolumab after surgery and chemotherapy work in treating patients with stage IB-IIIA non-small cell lung cancer. Monoclonal antibodies, such as nivolumab, may stimulate the immune system in different ways and kill tumor cells remaining after surgery and standard of care chemotherapy.

Condition or disease	Intervention/treatment	Phase
Stage IB Non-Small Cell Lung Carcinoma AJCC v7; Stage II Non-Small Cell Lung Cancer AJCC v7; Stage IIA Non-Small Cell Lung Carcinoma AJCC v7; Stage IIB Non-Small Cell Lung Carcinoma AJCC v7; Stage IIIA Non-Small Cell Lung Cancer AJCC v7	Other: Laboratory Biomarker Analysis; Biological: Nivolumab	Phase 3

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate whether adjuvant therapy with nivolumab will result in improved overall survival (OS) and/or disease-free survival (DFS) over standard observation in patients with stage IB >= 4 cm, II and IIIA, non-small cell lung cancer (NSCLC) following surgical resection and standard adjuvant therapy.

SECONDARY OBJECTIVES:

I. To evaluate the safety profile of nivolumab when given as an adjuvant therapy.

II. To evaluate and compare disease free and overall survival in patients with tumors that express programmed cell death ligand (PD-L)1 in various patterns associated with nivolumab and standard observation.

III. To evaluate and compare disease free and overall survival in patients with tumors that have high mutational load associated with nivolumab and standard observation.

IV. To evaluate OS and DFS by stage. V. To evaluate OS and DFS by each stratification factor. VI. To evaluate the OS and DFS rates at 1 year, 2 years, and 5 years.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1. Courses repeat every 4 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity.

ARM II: Patients are followed serially with imaging for 1 year.

After completion of study treatment, patients are followed up at 6 weeks, every 3 months for 2 years, every 6 months for 2 years, and then every 12 months for 6 years.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	714 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Adjuvant Nivolumab in Resected Lung Cancers (ANVIL) - A Randomized Phase III Study of Nivolumab After Surgical Resection and Adjuvant Chemotherapy in Non-Small Cell Lung Cancers
Actual Study Start Date :	May 6, 2016
Estimated Primary Completion Date :	July 1, 2024

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Arm I (nivolumab); Patients receive nivolumab IV over 30 minutes on day 1. Courses repeat every 4 weeks for up to 1 year in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo
No Intervention: Arm II (observation); Patients are followed serially with imaging for 1 year.

Outcome Measures

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Primary Outcome Measures :

1. Overall survival (OS) [ Time Frame: Time from randomization to death from any cause, assessed up to 10 years ]
   OS distributions will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate the treatment hazard ratios. The primary comparisons of OS will use a logrank tests stratified on the randomization stratification factors with a one-sided type I error rate of 2.0% for OS. Other comparisons of groups will be made using the logrank test and Cox modeling. Point estimates of all endpoints will be accompanied by the corresponding confidence intervals adjusted for the type I error rates associated with the endpoint. Subset analyses are planned for all stratification factors and all known prognostic factors such as performance status, age, gender, etc.
2. Disease-free survival (DFS) [ Time Frame: Time from randomization to the earliest event defined as disease any new lung cancer (even in the opposite lung), or death from any cause at any known point in time, assessed up to 10 years ]
   DFS distributions will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate the treatment hazard ratios. The primary comparisons of DFS will use a logrank tests stratified on the randomization stratification factors with a one-sided type I error rate of 0.5% for DFS. Other comparisons of groups will be made using the logrank test and Cox modeling. Point estimates of all endpoints will be accompanied by the corresponding confidence intervals adjusted for the type I error rates associated with the endpoint. Subset analyses are planned for all stratification factors and all known prognostic factors such as performance status, age, gender, etc.

Secondary Outcome Measures :

1. Incidence of toxicity graded according to Common Terminology Criteria for Adverse Events version 5.0 [ Time Frame: Up to 10 years ]
   Toxicity rates will be compared using Fisher's exact tests with a one-sided type I error rate of 2.5%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes. Point estimates of all endpoints will be accompanied by the corresponding confidence intervals adjusted for the type I error rates associated with the endpoint. Subset analyses are planned for all stratification factors and all known prognostic factors such as performance status, age, gender, etc.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Patients must have undergone complete surgical resection of their stage IB (>= 4 cm), II or IIIA NSCLC according to the American Joint Committee on Cancer (AJCC) 7th edition and have had negative surgical margins
• Baseline chest computed tomography (CT) must be performed within 1 month (30 days) of randomization to ensure no evidence of disease; if clinically indicated, additional imaging studies must be performed to rule out metastatic disease
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Patients must be registered to the ALCHEMIST-SCREEN (ALLIANCE A151216) trial prior to randomization
• Non-squamous tumors must not be positive for epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R mutation and anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangement (results ascertained in centrally as part of ALCHEMIST-SCREEN protocol)
• Tumors must have PD-L1 status tested centrally as part of the ALCHEMIST-SCREEN protocol
• Women must not be pregnant or breast-feeding
• All females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse during the treatment period and for 31 weeks after the last nivolumab infusion
• Patients must NOT have uncontrolled intercurrent illness including, but not limited to, serious ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements
• No prior treatment with an immune checkpoint inhibitor (anti-programmed cell death [PD]-1, anti-PD-L1, anti-cytotoxic T-lymphocyte-associated protein 4 [CTLA4] monoclonal antibody)

• Patients must have adequately recovered from surgery and any administered chemotherapy/radiotherapy at the time of randomization (NOTE: adjuvant chemotherapy and/or radiation is not required)

  • Minimum time between date of surgery and randomization is 4 weeks (28 days)

  • Maximum time allowed between surgery and randomization:

    • 3 months (90 days) if no chemotherapy is administered
    • 8 months (240 days) if adjuvant chemotherapy was administered
    • 10 months (300 days) if adjuvant chemotherapy and radiation therapy was administered
• Patients must have completed and recovered from any adjuvant chemotherapy 2 or more weeks prior to randomization (6 weeks for mitomycin and nitrosoureas; 4 weeks for post-operative radiation therapy) (NOTE: adjuvant chemotherapy and/or radiation is not required)
• Serum aspartate transaminase (aspartate aminotransferase [AST]) and serum alanine transaminase (alanine aminotransferase [ALT]) =< 2.5 x upper limit normal
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (except in subjects with Gilbert syndrome who must have a total bilirubin < 3.0 x ULN)
• White blood cell (WBC) >= 2000/uL
• Neutrophils >= 1000/uL
• Platelets >= 100 x 10^3/uL
• Hemoglobin >= 8 g/dL
• Serum creatinine =< 2 x ULN
• Prior to randomization patients with any non-hematologic toxicity from surgery, chemotherapy and radiation therapy must have recovered to grade =< 1 with the exception of alopecia, ototoxicity and neuropathy
• Patients must not be receiving any other investigational anti-cancer agents while on study
• Patients must not have known or suspected autoimmune disease; subjects with type I diabetes mellitus, hypothyroidism requiring hormone replacement, or skin disorders not requiring systemic treatment are permitted to enroll
• Patients must not have a condition requiring systemic corticosteroids equivalent to > 10 mg prednisone per day or other immunosuppressive medications within 2 weeks of randomization; inhaled, intra-articular, and epidural steroids are permissible
• Patients must not have known interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
• Patients must not have a known history of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection that is untreated and/or with a detectable viral load
• Patients must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab

Contacts and Locations

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Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

Principal Investigator:	Jamie E Chaft	ECOG-ACRIN Cancer Research Group

More Information

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Responsible Party:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT02595944 History of Changes
Other Study ID Numbers:	NCI-2015-01916; NCI-2015-01916 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); EA5142; s16-02074; EA5142 ( Other Identifier: ECOG-ACRIN Cancer Research Group ); EA5142 ( Other Identifier: CTEP ); U10CA180820 ( U.S. NIH Grant/Contract )
First Posted:	November 4, 2015
Last Update Posted:	February 20, 2019
Last Verified:	December 2018

Additional relevant MeSH terms:

Carcinoma; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site	Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms; Nivolumab; Antibodies, Monoclonal; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs