Carcinoma, Non-Small-Cell Lung
Conditions
Keywords
Pembrolizumab, MK-3475
Brief summary
This is an open label, multi-institutional, single arm phase II trial of consolidation therapy with pembrolizumab, following initial treatment with concurrent chemoradiation in patients with inoperable or unresectable stage IIIA or IIIB NSCLC. No randomization or blinding is involved.
Detailed description
OUTLINE: This is a multi-center study. Eligible patients must have completed concurrent chemoradiation with a standard chemotherapy regimen (either cisplatin/etoposide or carboplatin/paclitaxel) and a dose of radiation ranging from 59.4-66.6Gy, with restaging completed 28 days to 56 days post-chemoradiation. Patients with progressive disease will not be eligible for investigational treatment. Patients with stable disease/response will be eligible to register for investigational treatment of consolidation therapy to begin a minimum of 28 days and a maximum of 56 days from completion of chemoradiotherapy. INVESTIGATIONAL TREATMENT: Pembrolizumab, 200 mg IV every 3 weeks (until progressive disease (PD), unacceptable toxicity, or after 12 months (52 weeks) of therapy with pembrolizumab. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Hematopoietic: * Absolute neutrophil count (ANC) ≥1,500/mcL * Platelets ≥100,000/mcL * Hemoglobin ≥9 g/dL or ≥5.6 mmol/L Renal: * Serum creatinine OR measured or calculated creatinine clearance ≤1.5 X institutional upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels \> 1.5 X institutional ULN (glomerular filtration rate (GFR) can also be used in place of creatinine or CrCl) Hepatic: * Serum total bilirubin ≤ 1.5 X institutional ULN OR direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 institutional ULN * Aspartate transaminase (AST), serum glutamic oxaloacetic transaminase (SGOT), alanine transaminase (ALT), serum glutamic pyruvic transaminase (SGPT) ≤ 2.5 X institutional ULN Coagulation: * International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X institutional ULN unless subject is receiving anticoagulant therapy as long as PT/INR/PTT is within therapeutic range of intended use of anticoagulants.
Interventions
DRUGPembrolizumab
Pembrolizumab, 200 mg IV every 3 weeks (until PD, unacceptable toxicity, or after 12 months of therapy with pembrolizumab.
Sponsors
Merck Sharp & Dohme LLC
Hoosier Cancer Research Network
Nasser Hanna, M.D.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histological or cytological evidence of NSCLC * Must have unresectable or inoperable stage IIIA or IIIB disease. Patients are considered unresectable or inoperable based on the judgment of the treating physician * Must have completed concurrent chemoradiation with a standard chemotherapy regimen (either cisplatin/etoposide or carboplatin/paclitaxel) and a dose of radiation ranging from 59.4-66.6Gy * Must have stable disease or disease response as evidenced on CT evaluation a minimum of 28 days and a maximum of 56 days following the completion of chemoradiation * Women of childbearing potential must be willing to use two methods of contraception or abstain from heterosexual activity from the point of registration through 120 days after the last dose of study drug * Male subjects of childbearing potential must agree to use an adequate method of contraception starting with the first dose of the study drug through 120 days after the last dose of the study drug * Age ≥ 18 years at the time of consent * Written informed consent and HIPAA authorization for release of personal health information
Exclusion criteria
* Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment * Active central nervous system (CNS) metastases. Subjects must undergo a head computed tomography (CT) scan or brain MRI within 28 days prior to registration for protocol therapy to exclude brain metastases if symptomatic or without prior brain imaging * Treatment with any investigational agent within 28 days prior to registration for protocol therapy * Prior chemotherapy, adjuvant therapy, or radiotherapy for lung cancer, other than standard concurrent chemoradiation as described above * Prior therapy with a PD-1, PD-L1, or CTLA-4 inhibitor or a lung cancer-specific vaccine therapy * Presence of metastatic disease (stage IV NSCLC) is not allowed. Subjects must be evaluated with a PET scan within 28 days prior to registration for protocol therapy to exclude metastatic disease * No active second cancers * Evidence of active autoimmune disease requiring systemic treatment within the past 90 days or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be excluded from the study * Interstitial lung disease or history of pneumonitis requiring treatment with corticosteroids * Diagnosis of immunodeficiency or is receiving chronic systemic corticosteroid therapy or other immunosuppressive therapy (excludes inhaled corticosteroids) within 7 days of first dose of study drug * History of psychiatric illness or social situations that would limit compliance with study requirements * Clinically active infection as judged by the treating investigator (≥ Grade 2 by CTCAE v4) including known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C * Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Death or Distant Metastasis | From start of treatment until death or distant metastasis (estimate 18 months) up to a maximum of 47 months. | Time to Death or Distant Metastasis is defined as the time from the date of randomization until the first date of distant metastasis or death in the absence of distant metastasis. Distant metastasis is defined as any new lesion that was outside of the radiation field according to RECIST 1.1 or proven by biopsy. The Primary objective in the study was to determine if consolidation therapy with pembrolizumab following concurrent chemoradiation improves time to death or distant metastatic disease, depending on which occurs first, in subjects with inoperable or unresectable stage IIIA or IIIB NSCLC. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | From start of treatment until Progression based on RECIST 1.1 or death up to a maximum value of 47 months | Progression Free Survival is defined as the time from randomization until the date of objective disease progression (RECIST 1.1) or death (by any cause in the absence of progression). Progression is defined using RECIST 1.1 as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. One of the secondary objectives in the study is to determine if consolidation therapy with pembrolizumab following concurrent chemoradiation improves progression free survival in subjects with inoperable or unresectable stage IIA or IIIB non-small cell lung cancer(NSCLC). PFS has been estimated by Kaplan-Meier method. |
| Overall Survival | From the date of randomization up to a maximum value of 47 months or death. | Overall Survival is defined as the time from the date of randomization until death due to any cause. One of the secondary objectives in the study is to determine if consolidation therapy with pembrolizumab following concurrent chemoradiation improves Overall Survival in subjects with inoperable or unresectable stage IIA or IIIB non-small cell lung cancer(NSCLC). OS has been estimated by Kaplan-Meier method. |
| Number of Participants Experiencing Grade 3-4 AE With Adverse Events as a Measure of Safety and Tolerability | From the time of consent until 30 days after last dose of pembrolizumab up to a maximumof 18 months. | One of the secondary objective in this study is to assess toxicity and tolerability of pembrolizumab consolidation therapy following concurrent chemoradiation in subjects with stage IIIA or IIIB NSCLC. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Experimental Arm Pembrolizumab -200 mg IV 3 weeks
Pembrolizumab: Pembrolizumab, 200 mg IV every 3 weeks (until PD, unacceptable toxicity, or after 12 months of therapy with pembrolizumab. | 92 |
| Total | 92 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Follow up | Death | 33 |
| Follow up | Disease Progression | 1 |
| Follow up | Patient does not meet eligibility for study. | 1 |
| Follow up | Patient went home to Russia | 1 |
| Follow up | Research department closed by the practice. | 5 |
| Follow up | study terminated | 1 |
| Follow up | Withdrawal by Subject | 3 |
| Study Treatment | Adverse Event | 19 |
| Study Treatment | Death | 3 |
| Study Treatment | Disease Progression | 23 |
| Study Treatment | other complicating Diseases | 1 |
| Study Treatment | Withdrawal by Subject | 7 |
Baseline characteristics
| Characteristic | Experimental Arm |
|---|---|
| Age, Continuous | 64.4 years STANDARD_DEVIATION 8.6 |
| Disease Stage IIIA | 55 Participants |
| Disease Stage IIIB | 37 Participants |
| PD-L1 Missing/Not collected | 39 Participants |
| PD-L1 Negative | 11 Participants |
| PD-L1 Positive(1-49%) | 11 Participants |
| PD-L1 Positive(>=50%) | 31 Participants |
| Prior Chemo Received Carboplatin/Paclitaxel | 65 Participants |
| Prior Chemo Received Carboplatin/Paclitaxel & Carboplatin/Pemetrexed | 1 Participants |
| Prior Chemo Received Cisplatin/Etoposide | 24 Participants |
| Prior Chemo Received Cisplatin/Pemetrexed | 2 Participants |
| Prior Radiation Dose | 61.0 Gray STANDARD_DEVIATION 6.2 |
| Race/Ethnicity, Customized Ethnicity Non-Hispanic | 90 Participants |
| Race/Ethnicity, Customized Ethnicity Unknown | 2 Participants |
| Race/Ethnicity, Customized Race Asian | 4 Participants |
| Race/Ethnicity, Customized Race Black or African American | 3 Participants |
| Race/Ethnicity, Customized Race Unknown | 1 Participants |
| Race/Ethnicity, Customized Race White | 84 Participants |
| Sex: Female, Male Female | 33 Participants |
| Sex: Female, Male Male | 59 Participants |
| Smoking Status Current smoker | 16 Participants |
| Smoking Status Former smoker | 71 Participants |
| Smoking Status Never smoker | 5 Participants |
| Tumor Histologic Type Non-Squamous | 51 Participants |
| Tumor Histologic Type Squamous | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 41 / 93 |
| other Total, other adverse events | 93 / 93 |
| serious Total, serious adverse events | 26 / 93 |
Outcome results
Primary
Time to Death or Distant Metastasis
Time to Death or Distant Metastasis is defined as the time from the date of randomization until the first date of distant metastasis or death in the absence of distant metastasis. Distant metastasis is defined as any new lesion that was outside of the radiation field according to RECIST 1.1 or proven by biopsy. The Primary objective in the study was to determine if consolidation therapy with pembrolizumab following concurrent chemoradiation improves time to death or distant metastatic disease, depending on which occurs first, in subjects with inoperable or unresectable stage IIIA or IIIB NSCLC.
Time frame: From start of treatment until death or distant metastasis (estimate 18 months) up to a maximum of 47 months.
Population: This includes all subjects with exception of one subject.This patient had change in diagnosis from non-small cell carcinoma to uterine adenocarcinoma while on study. In retrospect, patient does not meet eligibility for study. Therefore, this subject was included in the safety results, but not the efficacy results.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Arm | Time to Death or Distant Metastasis | 30.7 months |
Secondary
Number of Participants Experiencing Grade 3-4 AE With Adverse Events as a Measure of Safety and Tolerability
One of the secondary objective in this study is to assess toxicity and tolerability of pembrolizumab consolidation therapy following concurrent chemoradiation in subjects with stage IIIA or IIIB NSCLC.
Time frame: From the time of consent until 30 days after last dose of pembrolizumab up to a maximumof 18 months.
Population: This includes all subjects with exception of one subject.This patient had change in diagnosis from non-small cell carcinoma to uterine adenocarcinoma while on study. In retrospect, patient does not meet eligibility for study. Therefore, this subject was included in the safety results, but not the efficacy results.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental Arm | Number of Participants Experiencing Grade 3-4 AE With Adverse Events as a Measure of Safety and Tolerability | 52 Participants |
Secondary
Overall Survival
Overall Survival is defined as the time from the date of randomization until death due to any cause. One of the secondary objectives in the study is to determine if consolidation therapy with pembrolizumab following concurrent chemoradiation improves Overall Survival in subjects with inoperable or unresectable stage IIA or IIIB non-small cell lung cancer(NSCLC). OS has been estimated by Kaplan-Meier method.
Time frame: From the date of randomization up to a maximum value of 47 months or death.
Population: This includes all subjects with exception of one subject.This patient had change in diagnosis from non-small cell carcinoma to uterine adenocarcinoma while on study. In retrospect, patient does not meet eligibility for study. Therefore, this subject was included in the safety results, but not the efficacy results.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Arm | Overall Survival | 35.8 months |
Secondary
Progression Free Survival
Progression Free Survival is defined as the time from randomization until the date of objective disease progression (RECIST 1.1) or death (by any cause in the absence of progression). Progression is defined using RECIST 1.1 as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. One of the secondary objectives in the study is to determine if consolidation therapy with pembrolizumab following concurrent chemoradiation improves progression free survival in subjects with inoperable or unresectable stage IIA or IIIB non-small cell lung cancer(NSCLC). PFS has been estimated by Kaplan-Meier method.
Time frame: From start of treatment until Progression based on RECIST 1.1 or death up to a maximum value of 47 months
Population: This includes all subjects with exception of one subject.This patient had change in diagnosis from non-small cell carcinoma to uterine adenocarcinoma while on study. In retrospect, patient does not meet eligibility for study. Therefore, this subject was included in the safety results, but not the efficacy results.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental Arm | Progression Free Survival | 18.7 months |