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Testing the Timing of Pembrolizumab Alone or With Chemotherapy as First Line Treatment and Maintenance in Non-small Cell Lung Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03793179
Recruitment Status : Recruiting
First Posted : January 4, 2019
Last Update Posted : March 23, 2023
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. Chemotherapy drugs, 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 Stage IIIB Lung Cancer AJCC v8 Stage IIIC Lung Cancer AJCC v8 Stage IV Lung Cancer AJCC v8 Drug: Carboplatin Biological: Pembrolizumab Drug: Pemetrexed Phase 3

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Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 846 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: EA5163/S1709 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 : December 31, 2028
Estimated Study Completion Date : December 31, 2028

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. Within 6 weeks 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
  • Carboplatinum
  • 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
  • Pemfexy

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. Within 6 weeks 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
  • Carboplatinum
  • 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
  • Pemfexy

Active Comparator: Arm C (pembrolizumab, pembrolizumab, carboplatin)
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
  • Carboplatinum
  • 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
  • Pemfexy




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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Layout table for eligibility information
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, and M1c stage disease, American Joint Committee on Cancer [AJCC] 8th edition). Patients with stage IIIB and IIIC disease are eligible if they are not candidates for combined chemotherapy and radiation. Prior chemo-radiation therapy (RT) for stage III with recurrence is allowed
  • Patients must have PD-L1 expression Tumor Proportion Score (TPS) >= 1% in tumor cells. If PD-L1 expression TPS is unevaluable or the testing could not be completed, the patients are not eligible. 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. The presence of malignant pleural fluid alone is sufficient to satisfy this eligibility criterion. Baseline imaging assessments and measurements used to evaluate all measurable or non-measurable sites of disease must be done within 4 weeks prior to study registration

    • NOTE: If patient receives pemetrexed, follow institutional guidelines to drain fluids
  • Patients must be >= 18 years of age
  • Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
  • Patients with treated brain metastases are eligible if follow-up brain imaging obtained at least 14 days after central nervous system (CNS)-directed therapy shows no evidence of progression. CNS progression counts as progression and patients must move on to the next phase after CNS treatment. Patients with asymptomatic new (at screening) or progressive brain metastases (active brain metastases at screening) are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy

    • Patients are eligible if off steroids for at least 14 days prior to protocol treatment
    • Anticonvulsants are allowed
    • Patients with asymptomatic, sub-centimeter brain metastasis who at the discretion of investigators do not need immediate CNS directed therapies are eligible
  • Patients with prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
  • Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
  • Patients must use accepted and effective method(s) of contraception or by abstaining 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 prior to randomization)
  • Platelets >= 100,000/mm^3 (within 14 days prior to randomization)
  • Prothrombin time (PT)/international normalized ratio (INR) only if on active anticoagulation with warfarin or any formulations of heparin) =< 3.0 (within 14 day prior to randomization)
  • Total bilirubin =< 1.5 mg/dL (obtained within 14 days prior to randomization)
  • Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) < 5 x upper limit of normal (ULN) (obtained within 14 days prior to randomization)
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 5 x upper limit of normal (ULN) (obtained within 14 days prior to randomization)
  • Calculated creatinine clearance >= 45 ml/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)
  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
  • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable or on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load

Exclusion Criteria:

  • Patients must NOT have received the following:

    • Prior systemic chemotherapy or immunotherapy for advanced metastatic NSCLC. Patients treated with any prior checkpoint inhibitors for metastatic lung cancer are ineligible. Chemotherapy for non-metastatic disease (e.g. adjuvant therapy) or immunotherapy for locally advanced Stage III disease, or treated with neoadjuvant IO is allowed if at least 6 months have elapsed between the last dose of the prior therapy and study registration. Local therapy, e.g. palliative radiation, is allowed as long as a period of 14 days has passed between completion of local therapy and the start of protocol treatment. Registration prior to treatment during the 14 days is allowed. Palliative radiation must be to non-target lesions. Palliative radiation to pre-existing lesions while on protocol treatment is allowed as long as these areas have not grown to RECIST defined progression. Development of any new metastasis is considered progression. Concurrent radiation and protocol treatment is not allowed; protocol treatment may resume after completion of radiation as long as patient does not have greater than grade 2 side effects from radiation per physician discretion.
    • 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
    • Palliative radiation to non-target lesions (bone metastasis) is allowed if the patient develops symptoms
  • Patients with known EGFR mutations (except exon 20 insertion), BRAF mutations (V600) or ALK or ROS1 translocations or other driver mutations that can be treated with oral tyrosine kinase inhibitors are excluded
  • 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 (including Guillain-Barre Syndrome or Multiple Sclerosis) requiring ongoing or intermittent systemic treatment in the past 2 years prior to registration (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 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
  • Patients must not be pregnant or breast-feeding due to potential harm to the fetus or infant from cytotoxic chemotherapy and the unknown risk of pembrolizumab (MK-3475). All patients of childbearing potential must have a blood test or urine study within 72 hours prior to registration to rule out pregnancy. A patient of childbearing potential is anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point; 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) 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)
  • 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. Patients are permitted to receive inactivated vaccines and any non-live vaccines including those for the seasonal influenza and COVID-19 (Note: intranasal influenza vaccines, such as Flu-Mist are live attenuated vaccines and are not allowed). If possible, it is recommended to separate study drug administration from vaccine administration by about a week (primarily, in order to minimize an overlap of adverse events)

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


Locations
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