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Firstline Pembrolizumab Alone or in Combination With Pemetrexed and Carboplatin in Induction/Maintenance or Postprogression in Treating Patients With Stage IV Non-squamous Non-small Cell Lung Cancer

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ClinicalTrials.gov Identifier: NCT03793179
Recruitment Status : Recruiting
First Posted : January 4, 2019
Last Update Posted : May 17, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase III trial studies whether pembrolizumab alone as a first-line treatment, followed by pemetrexed and carboplatin with or without pembrolizumab after disease progression is superior to induction with pembrolizumab, pemetrexed and carboplatin followed by pembrolizumab and pemetrexed maintenance in treating patients with stage IV non-squamous non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as pemetrexed and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether giving first-line pembrolizumab followed by pemetrexed and carboplatin with or without pembrolizumab works better in treating patients with non-squamous non-small cell cancer.

Condition or disease Intervention/treatment Phase
Lung Non-Squamous Non-Small Cell Carcinoma PD-L1 Positive Stage IIIB Lung Cancer AJCC v8 Stage IVA Lung Cancer AJCC v8 Drug: Carboplatin Biological: Pembrolizumab Drug: Pemetrexed Phase 3

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate overall survival (OS) in each of the 2 experimental arms (Arms A and B) to control (Arm C).

SECONDARY OBJECTIVES:

I. To evaluate progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for Arm C versus each of Arms A and B.

II. To evaluate best objective response rates per RECIST 1.1 for Arm C versus each of Arms A and B.

III. To estimate toxicity within each of the treatment arms via the Common Terminology Criteria for Adverse Events (CTCAE) criteria.

IV. To compare outcomes between Arms A and B. V. To compare outcomes by treatment arm within subgroups defined by a cutpoint of PD-L1 expression at >= 50%.

BIOMARKER OBJECTIVES:

I. To collect and bank tissue and blood for future research studies, including potential development of a prognostic and predictive signature for MK-3475 (pembrolizumab) in combination with chemotherapy versus MK-3475 (pembrolizumab) alone.

OUTLINE: Patients are randomized to 1 of 3 arms.

ARM A: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. At time of disease progression, patients receive pemetrexed IV over 10 minutes and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then may receive pemetrexed IV over 10 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. At time of disease progression, patients receive pembrolizumab IV over 30 minutes, pemetrexed IV over 10 minutes, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive pembrolizumab IV over 30 minutes and pemetrexed IV over 10 minutes on day 1. Cycles repeat every 21 days for up to 2 years for pembrolizumab in the absence of disease progression or unacceptable toxicity and until to disease progression for pemetrexed.

ARM C: Patients receive patients receive pembrolizumab IV over 30 minutes, pemetrexed IV over 10 minutes, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive pembrolizumab IV over 30 minutes and pemetrexed IV over 10 minutes on day 1. Cycles repeat every 21 days for up to 2 years for pembrolizumab in the absence of disease progression or unacceptable toxicity and until to disease progression for pemetrexed.

After completion of study treatment, patients are followed up for 5 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 846 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: INSIGNA : A Randomized, Phase III Study of Firstline Immunotherapy Alone or in Combination With Chemotherapy in Induction/Maintenance or Postprogression in Advanced Nonsquamous Non-Small Cell Lung Cancer (NSCLC) With Immunobiomarker SIGNature-Driven Analysis
Actual Study Start Date : February 28, 2019
Estimated Primary Completion Date : September 30, 2021
Estimated Study Completion Date : September 30, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arm Intervention/treatment
Experimental: Arm A (pembrolizumab, pemetrexed, carboplatin)
Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. At time of disease progression, patients receive pemetrexed IV over 10 minutes and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then may receive pemetrexed IV over 10 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Drug: Pemetrexed
Given IV
Other Names:
  • MTA
  • Multitargeted Antifolate

Experimental: Arm B (pembrolizumab, pemetrexed, carboplatin)
Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. At time of disease progression, patients receive pembrolizumab IV over 30 minutes, pemetrexed IV over 10 minutes, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive pembrolizumab IV over 30 minutes and pemetrexed IV over 10 minutes on day 1. Cycles repeat every 21 days for up to 2 years for pembrolizumab in the absence of disease progression or unacceptable toxicity and until to disease progression for pemetrexed.
Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Drug: Pemetrexed
Given IV
Other Names:
  • MTA
  • Multitargeted Antifolate

Active Comparator: Arm C (pembrolizumab, pembrolizumab, carboplatin)
Patients receive patients receive pembrolizumab IV over 30 minutes, pemetrexed IV over 10 minutes, and carboplatin IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive pembrolizumab IV over 30 minutes and pemetrexed IV over 10 minutes on day 1. Cycles repeat every 21 days for up to 2 years for pembrolizumab in the absence of disease progression or unacceptable toxicity and until to disease progression for pemetrexed.
Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Drug: Pemetrexed
Given IV
Other Names:
  • MTA
  • Multitargeted Antifolate




Primary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: From randomization to death from any cause, assessed up to 5 years post treatment ]
    OS distributions will be estimated using the Kaplan-Meier method.


Secondary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: From randomization to documented disease progression or death from any cause, assessed up to 5 years post treatment ]
    PFS distributions will be estimated using the Kaplan-Meier method.

  2. Best objective response [ Time Frame: Up to 5 years post treatment ]
    Best objective response will be evaluated via Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.

  3. Incidence of adverse events [ Time Frame: Up to 30 days post treatment ]
    Toxicities will be reported via the Common Terminology Criteria for Adverse Events (CTCAE) criteria version 5.0. Toxicity rates between arms in the overall population will be compared using Fisher's exact tests with a one-sided type I error rate of 1.25%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes.

  4. PD-L1 positivity [ Time Frame: At baseline ]
    PD-L1 positivity will be defined as >= 1% Tumor Proportion Score (TPS) for the purpose of enrollment onto the trial. Strongly PD-L1 positive is defined as >= 50% TPS; weakly positive is defined as 1% - 49% TPS.



Information from the National Library of Medicine

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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 histologically or cytologically confirmed stage IV non-squamous non‐small cell lung cancer (NSCLC) (includes M1a, M1b stage disease, American Joint Committee on Cancer [AJCC] 8th edition). Patients with T4NX disease (stage IIIB) with nodule in ipsilateral lung lobe are eligible if they are not candidates for combined chemotherapy and radiation
  • Patients must have PD-L1 expression Tumor Proportion Score (TPS) >= 1% in tumor cells. The assay must have been performed by a Clinical Laboratory Improvement Act (CLIA) (or equivalent) certified laboratory
  • Patients must have measurable or non-measurable disease. Presence of malignant pleural fluid alone is allowed as study eligibility.

    • NOTE: If patient receives pemetrexed, follow institutional guidelines to drain fluids
  • Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
  • Patients must NOT have received the following:

    • Prior systemic chemotherapy or immunotherapy for advanced metastatic NSCLC. Patients treated with any prior checkpoint inhibitors for lung cancer are ineligible. Chemotherapy for non-metastatic disease (e.g. adjuvant therapy) or immunotherapy for locally advanced stage III disease is allowed if at least 6 months have elapsed since the prior therapy and registration. Local therapy, e.g. palliative radiation, is allowed as long as a period of 14 days has passed since completion
    • Methotrexate (MTX) given in low doses for non-malignant conditions with last dose at least 14 days prior to date of registration will be allowed. Other low dose chemotherapeutics for non-malignant conditions will be considered, but review by the study chair is required
  • Patients with known EGFR mutations (except exon 20 insertion), BRAF mutations (V600) or ALK or ROS1 translocations that can be treated with oral tyrosine kinase inhibitors are excluded
  • Patients with symptomatic brain metastases are excluded. Patients with treated or asymptomatic brain metastases are eligible if off steroids for at least 14 days prior to protocol treatment. Anticonvulsants are allowed
  • Patients with another active malignancy within the last 2 years are excluded. Adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years are permitted
  • Patients must not have known pre-existing and clinically active interstitial lung disease, or a known history of (non infectious) pneumonitis that required steroids, or current pneumonitis
  • Patients must not have significant gastrointestinal disorders with diarrhea as a major symptom (e.g. Crohn's disease, malabsorption, etc.)
  • Patients must not have history of auto-immune condition requiring ongoing or intermittent systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
  • Patients must not have history of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure, New York Heart Association (NYHA) classification of 3, unstable angina or poorly controlled arrhythmia, or myocardial infarction within 6 months prior to registration
  • Patients must not have any other concomitant serious illness or organ system dysfunction that in the opinion of the investigator would either compromise patient safety or interfere with the evaluation of the safety of the study drug
  • Patients must not receive any other investigational agents during the course of therapy
  • Women must not be pregnant or breast-feeding due to potential harm to the fetus or infant from cytotoxic chemotherapy and the unknown risk of MK-3475 (pembrolizumab). Patients must also not expect to conceive or father children from the time of registration, while on study treatment, and continue for 120 days after the last dose of study treatment

    • All females of childbearing potential must have a blood test or urine study within 72 hours 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: has achieved menarche at some point; has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) 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 use an accepted and effective method of contraception or abstain from sexual intercourse from time of registration, while on study treatment, and continue for 120 days after the last dose of study treatment
  • Absolute neutrophil count (ANC) >= 1500/mm^3 (within 14 days of randomization)
  • Platelets >= 100,000/mm^3 (within 14 days of randomization)
  • Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 Or if patient on therapeutic anticoagulation, PT/INR =< 3.0 (within 14 days of randomization)
  • Partial thromboplastin time (PTT) =< institutional upper limit of normal (ULN) OR, if patient is on therapeutic anticoagulation, PTT must be =< 1.5 x ULN (within 14 days of randomization)
  • Total bilirubin =< 1.5 mg/dL (obtained within 14 days of randomization)
  • Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) < 5 x upper limit of normal (ULN) (obtained within 14 days of randomization)
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 5 x upper limit of normal (ULN) (obtained within 14 days of randomization)
  • Calculated creatinine clearance >= 45ml/min to be eligible to receive pemetrexed (obtained within 14 days prior to randomization)
  • Serum creatinine =< 1.5 x institutional upper limit of normal (ULN) (obtained within 14 days prior to randomization)
  • Patients must not have a known history of active tuberculosis (TB)
  • Patients must not have a diagnosis of immunodeficiency or receive systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of protocol treatment
  • Patients must not have received a live vaccine within 30 days prior to randomization. Seasonal flu vaccines that do not contain live virus are permitted
  • Patients who are known to be human immunodeficiency virus (HIV) positive are eligible if they meet the following eligibility requirements:

    • They must be stable on their anti-retroviral regimen, and they must be healthy from an HIV perspective
    • They must have a CD4+ T-cell count 250 cells/mcL
    • They must not be receiving prophylactic therapy for an opportunistic infection
  • Patients must not have known active hepatitis B (e.g., hepatitis B virus surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C Virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03793179


  Show 503 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Hossein Borghaei ECOG-ACRIN Cancer Research Group

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03793179     History of Changes
Other Study ID Numbers: NCI-2018-03695
NCI-2018-03695 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
EA5163 ( Other Identifier: ECOG-ACRIN Cancer Research Group )
EA5163 ( Other Identifier: CTEP )
U10CA180820 ( U.S. NIH Grant/Contract )
First Posted: January 4, 2019    Key Record Dates
Last Update Posted: May 17, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Carboplatin
Pembrolizumab
Pemetrexed
Antineoplastic Agents
Antineoplastic Agents, Immunological
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors