Carcinoma, Non-Small-Cell Lung
Conditions
Keywords
Performance Status 2, Pembrolizumab, MK-3475
Brief summary
This study is to determine that pembrolizumab is safe and tolerable at the selected dose for the treatment of Non-Small Cell Lung Cancer (NSCLC) in patients with a performance status of 2. All patients will receive pembrolizumab.
Detailed description
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. There are several studies which demonstrate a role for the immune system in fighting lung cancer. However, there are multiple mechanisms by which cancer dampens this response. The PD-1 receptor-ligand interaction is one of the major pathways hijacked by tumours to help evade detection and elimination by the cells of the immune system. A number of compounds which block this pathway, including the drug pembrolizumab, have shown impressive results in some patients. At present all of the trials with pembrolizumab reported thus far have been in patients with a good Performance Status (PS) of 0-1, a measure of daily activity. Unfortunately many patients with lung cancer have impaired performance status, making them ineligible for trials of new therapies including anti PD-1. Clinical trials of standard-of-care therapy have been successfully performed in the PS=2 only population demonstrating the feasibility of performing clinical trials in this population. In this trial, the investigators would like to determine whether this drug can be used to treat Performance status 2 patients with a lower general daily activity. The purpose of this trial is to determine that pembrolizumab is safe and tolerable. The investigators would also like to see how well the treatment works, find out more information about tumour shrinkage, and learn more about the disease and how it changes over time.
Interventions
DRUGpembrolizumab
anti PD-1
Sponsors
Merck Sharp & Dohme LLC
University of Birmingham
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
Core Inclusion Criteria: * Histologically confirmed PD-L1 status defined NSCLC. Biopsy must be within 70 days of first treatment with pembrolizumab. * Eastern Cooperative Oncology Group (ECOG) performance status 2. * Life expectancy \> 12 weeks. * Uni-dimensionally measurable disease according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 * Computerised Tomography (CT) scan of chest and abdomen within 28 days of starting pembrolizumab. * Adequate haematological function: * Platelet count ≥100 x 109 /L. * Neutrophils ≥1.5 x 109/L. * Haemoglobin ≥ 90 g/L. * Adequate hepatic function: * Serum bilirubin ≤1.5 x upper limit of normal (ULN). * Serum transaminases ≤2.5 x ULN. * Adequate renal function: Creatinine clearance \<1.5 times ULN concurrent with creatinine clearance \>50 ml/min. * Provision of signed and dated, written informed consent prior to any trial specific procedures, sampling and analyses. Core
Exclusion criteria
* Patients who do not meet the criteria of performance status = 2 on the ECOG Performance scale. * Untreated symptomatic brain or leptomeningeal metastatic disease. * Medical or psychiatric conditions compromising informed consent. * Any medical condition which in the opinion of the investigator would compromise the ability of the patient to participate in the trial or which would jeopardise compliance with the protocol. * Radiotherapy within 28 days of trial treatment. * Active autoimmune disease that has required systemic treatment in past 2 years * Chronic usage of steroids or other immunosuppressant medication. * Previous history of pneumonitis. * Any evidence of clinical autoimmunity.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity Rate | Date of patient registration until 6 months after the administration of the last treatment (a maximum of 2 years treatment and 6 months followup after end of treatment) | Adverse events will be recorded in relation to each cycle of treatment and graded according to CTCAE criteria. The toxicity co-primary outcome measure for the trial is defined as the occurrence of a treatment-related dose delay or treatment discontinuation due to toxicity. |
| Durable Clinical Benefit | ≥18 weeks, up to maximum of 2 years | Patients will have CT scans every 9 weeks from baseline until disease progression. On each occasion, overall tumour burden will be assessed using RECIST version 1.1. The efficacy co-primary outcome measure for the trial is durable clinical benefit defined as the occurrence of CR, PR or SD without prior progressive disease at or after the second scheduled CT scan (scheduled to occur at 18 weeks). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression | Time to progression up to 2 years | This is defined as the time from commencement of trial treatment to the date of CT scan when progressive disease first recorded. Patients with no recorded progression at the time of analysis or who die without recorded progression will be censored at the date of the CT scan when they were last recorded with an evaluable measure that was not progression. |
| Progression-free Survival Time | Progression-free survival time up to 2 years | This is defined as the time from commencement of trial treatment to the date of CT scan when progressive disease first recorded or date of death without previously recorded progression. Patients who are alive with no recorded progression at the time of analysis will be censored at the date of the CT scan when they were last recorded with an evaluable measure that was not progression. |
| Objective Response | ≥18 weeks, up to maximum of 2 years | Objective response (OR) is the occurrence of Complete Response (CR) or Partial Response (PR) as the best overall response. OR will be based on responses confirmed using the subsequent 9-weekly scan but OR based on unconfirmed responses will also be reported. |
| Duration of Objective Response | Survival time up to 2 years or date of death | This is defined as the time from commencement of trial treatment to the date of the subsequent CT scan when progressive disease is first confirmed or date of death without previously recorded progression. This outcome is calculated and reported separately for patients who achieve an Objective Response (OR) or Stable Disease (SD). Patients experiencing OR or SD who are alive with no recorded progression at the time of analysis will be censored at the date of the CT scan when they were last recorded with an evaluable measure that was not progression. |
| Duration of Stable Disease | Survival time up to 2 years or date of death | This is defined as the time from commencement of trial treatment to the date of the subsequent CT scan when progressive disease is first confirmed or date of death without previously recorded progression. This outcome is calculated and reported separately for patients who achieve an Objective Response (OR) or Stable Disease (SD). Patients experiencing OR or SD who are alive with no recorded progression at the time of analysis will be censored at the date of the CT scan when they were last recorded with an evaluable measure that was not progression. |
| Overall Survival Time | Survival time up to 2 years or date of death | This is defined as the time from commencement of trial treatment to the date of death. Patients who are alive at the time of analysis will be censored at the date last seen alive. |
| Health Related Quality of Life | Through study completion, up to a maximum of 2 years | This is defined as the functional effect of a medical condition and/or its consequent treatment upon a patient. The purpose of Health Related Quality of Life (HRQoL) measurement is to quantify the degree to which the medical condition or its treatment impacts the individual's life in a valid and reproducible way. HRQoL will be assessed over time using Functional Assessment of Cancer Therapy - Lung (FACT-L) questionnaire and EQ-5D questionnaire. |
Countries
United Kingdom
Participant flow
Recruitment details
The trial opened to recruitment on 7th November 2016 and the first patient was recruited on 4th January 2017. The trial was opened to recruitment at 10 National Health Service (NHS) hospitals across the United Kingdom. The last patient was recruited on 13th February 2018.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab Pembrolizumab: 200 mg Q3W, intravenous administration for a maximum of 2 years, or until progression or unacceptable toxicity. | 62 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Lack of disease progression | 1 |
Baseline characteristics
| Characteristic | Pembrolizumab | — |
|---|---|---|
| Age, Continuous Age at Registration (years) | 69.85 years | — |
| Charlson Co-Morbidity Index Score 0 | 3 Participants | — |
| Charlson Co-Morbidity Index Score 1 | 0 Participants | — |
| Charlson Co-Morbidity Index Score 10 | 9 Participants | — |
| Charlson Co-Morbidity Index Score 11 | 2 Participants | — |
| Charlson Co-Morbidity Index Score 12 | 4 Participants | — |
| Charlson Co-Morbidity Index Score 2 | 1 Participants | — |
| Charlson Co-Morbidity Index Score 3 | 4 Participants | — |
| Charlson Co-Morbidity Index Score 4 | 4 Participants | — |
| Charlson Co-Morbidity Index Score 5 | 4 Participants | — |
| Charlson Co-Morbidity Index Score 6 | 2 Participants | — |
| Charlson Co-Morbidity Index Score 7 | 3 Participants | — |
| Charlson Co-Morbidity Index Score 8 | 7 Participants | — |
| Charlson Co-Morbidity Index Score 9 | 19 Participants | — |
| Charlson Co-Morbidity Index Score | 7.58 units on a scale | — |
| Duration of Abstinence | 15.38 years | — |
| Histology Adenocarcinoma | 43 Participants | — |
| Histology Adenosquamous Carcinoma | 0 Participants | — |
| Histology Not Otherwise Specified | 1 Participants | — |
| Histology Other | 6 Participants | — |
| Histology Squamous Cell Carcinoma | 12 Participants | — |
| Line of Therapy First | 25 Participants | — |
| Line of Therapy Subsequent | 37 Participants | — |
| PD-L1 Staining Result Negative (<1%) | 28 Participants | — |
| PD-L1 Staining Result Positive (1-49%) | 16 Participants | — |
| PD-L1 Staining Result Strong Positive (50-100%) | 15 Participants | — |
| Percentage of Tumour Cells Expressing PD-L1 | 24.89 % | — |
| Previous Therapy Biological | 2 participants | — |
| Previous Therapy Chemotherapy | 44 participants | — |
| Previous Therapy Immunological | 1 participants | — |
| Previous Therapy Radiotherapy | 28 participants | — |
| Previous Therapy Surgery | 13 participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Sample Type Archived biopsy sample | 52 Participants | — |
| Sample Type New biopsy sample | 7 Participants | — |
| Sex: Female, Male Female | 28 Participants | — |
| Sex: Female, Male Male | 34 Participants | — |
| Smoking Pack Years | 43.78 years | — |
| Smoking Status Current smoker | 11 Participants | — |
| Smoking Status Ex-smoker | 45 Participants | — |
| Smoking Status Never smoked | 3 Participants | — |
| Smoking Status Not Known | 3 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 48 / 60 |
| other Total, other adverse events | 58 / 60 |
| serious Total, serious adverse events | 51 / 60 |
Outcome results
Primary
Durable Clinical Benefit
Patients will have CT scans every 9 weeks from baseline until disease progression. On each occasion, overall tumour burden will be assessed using RECIST version 1.1. The efficacy co-primary outcome measure for the trial is durable clinical benefit defined as the occurrence of CR, PR or SD without prior progressive disease at or after the second scheduled CT scan (scheduled to occur at 18 weeks).
Time frame: ≥18 weeks, up to maximum of 2 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pembrolizumab | Durable Clinical Benefit | Patients Not Experiencing DCB Event | 38 Participants |
| Pembrolizumab | Durable Clinical Benefit | Patients Experiencing Durable Clinical Benefits Event | 22 Participants |
Primary
Toxicity Rate
Adverse events will be recorded in relation to each cycle of treatment and graded according to CTCAE criteria. The toxicity co-primary outcome measure for the trial is defined as the occurrence of a treatment-related dose delay or treatment discontinuation due to toxicity.
Time frame: Date of patient registration until 6 months after the administration of the last treatment (a maximum of 2 years treatment and 6 months followup after end of treatment)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pembrolizumab | Toxicity Rate | Patients Experiencing Toxicity Event | 18 Participants |
| Pembrolizumab | Toxicity Rate | Patients Not Experiencing Toxicity Event | 42 Participants |
Secondary
Duration of Objective Response
This is defined as the time from commencement of trial treatment to the date of the subsequent CT scan when progressive disease is first confirmed or date of death without previously recorded progression. This outcome is calculated and reported separately for patients who achieve an Objective Response (OR) or Stable Disease (SD). Patients experiencing OR or SD who are alive with no recorded progression at the time of analysis will be censored at the date of the CT scan when they were last recorded with an evaluable measure that was not progression.
Time frame: Survival time up to 2 years or date of death
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | Duration of Objective Response | 14.6 months |
Secondary
Duration of Stable Disease
This is defined as the time from commencement of trial treatment to the date of the subsequent CT scan when progressive disease is first confirmed or date of death without previously recorded progression. This outcome is calculated and reported separately for patients who achieve an Objective Response (OR) or Stable Disease (SD). Patients experiencing OR or SD who are alive with no recorded progression at the time of analysis will be censored at the date of the CT scan when they were last recorded with an evaluable measure that was not progression.
Time frame: Survival time up to 2 years or date of death
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | Duration of Stable Disease | 4.39 months |
Secondary
Health Related Quality of Life
This is defined as the functional effect of a medical condition and/or its consequent treatment upon a patient. The purpose of Health Related Quality of Life (HRQoL) measurement is to quantify the degree to which the medical condition or its treatment impacts the individual's life in a valid and reproducible way. HRQoL will be assessed over time using Functional Assessment of Cancer Therapy - Lung (FACT-L) questionnaire and EQ-5D questionnaire.
Time frame: Through study completion, up to a maximum of 2 years
Secondary
Objective Response
Objective response (OR) is the occurrence of Complete Response (CR) or Partial Response (PR) as the best overall response. OR will be based on responses confirmed using the subsequent 9-weekly scan but OR based on unconfirmed responses will also be reported.
Time frame: ≥18 weeks, up to maximum of 2 years
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pembrolizumab | Objective Response | No | 44 Participants |
| Pembrolizumab | Objective Response | Yes | 16 Participants |
Secondary
Overall Survival Time
This is defined as the time from commencement of trial treatment to the date of death. Patients who are alive at the time of analysis will be censored at the date last seen alive.
Time frame: Survival time up to 2 years or date of death
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | Overall Survival Time | 9.8 months |
Secondary
Progression-free Survival Time
This is defined as the time from commencement of trial treatment to the date of CT scan when progressive disease first recorded or date of death without previously recorded progression. Patients who are alive with no recorded progression at the time of analysis will be censored at the date of the CT scan when they were last recorded with an evaluable measure that was not progression.
Time frame: Progression-free survival time up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | Progression-free Survival Time | 4.39 months |
Secondary
Time to Progression
This is defined as the time from commencement of trial treatment to the date of CT scan when progressive disease first recorded. Patients with no recorded progression at the time of analysis or who die without recorded progression will be censored at the date of the CT scan when they were last recorded with an evaluable measure that was not progression.
Time frame: Time to progression up to 2 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | Time to Progression | 11.9 months |