| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| non small cell lung cancer (NSCLC) |
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| E.1.1.1 | Medical condition in easily understood language |
| Commonest form of lung cancer, non small cell lung cancer (NSCLC) |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
There are 2 co-primary objectives:
1. To determine that pembrolizumab is safe and tolerable at the selected dose of 200 mg in non-small cell lung cancer patients with a performance status of 2.
2. To allow detection of disease control and the durability of disease control to ascertain if further investigation in subsequent studies is justified.
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| E.2.2 | Secondary objectives of the trial |
To determine the patient's quality of life when undergoing trial treatment, assessed by questionnaires.
To look at secondary measures of response to the drug including how long patients are on treatment before progression and overall survival time.
To identify predictive markers of activity, response and resistance to the drug.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Patients must have completed all standard of care therapy that the treating oncologist deems appropriate. All lines of therapy will be allowed.
• Histologically confirmed NSCLC where it is possible to assess PD-L1 status on tumour biopsy. Biopsy must be within 70 days of first treatment with pembrolizumab. All patients who have had systemic therapy since the biopsy must have a repeat biopsy that is evaluable for PD-L1.
• Patients must have a performance status of 2 on the ECOG Performance scale with no deterioration over the previous 2 weeks assessed by consenting physician.
• Life expectancy >12 weeks.
• Uni-dimensionally measurable disease according to RECIST v1.1.
• CT scan of chest and abdomen within 28 days of starting Pembrolizumab demonstrating measurable disease as per RECIST version 1.1.
• Demonstrate adequate haematological and organ function as defined below. All screening tests should be performed within 7 days of treatment.
• Age ≥ 18 years.
• Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses.
• Patients must agree to the use of contraception as detailed in protocol and patient information sheet
System Laboratory Value
Haematological
Absolute neutrophil count ≥ 1.5 x 109/L.
Haemoglobin ≥ 90 g/L or ≥5.6 mmol/L.
Platelets ≥ 100 x 109/L
Hepatic function
Total serum bilirubin ≤ 1.5 x ULN
Alanine transferase (ALT) ≤ 2.5 x ULN.
Aspartate transferase (AST) ≤ 2.5 x ULN.
Renal function
Creatinine clearance <1.5 times ULN concurrent with creatinine clearance >50 ml/min (calculated by Cockcroft and Gault equation or alternative method). If this is ≤50 ml/min then an isotopic GFR may be undertaken and must be >50 ml/min
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| E.4 | Principal exclusion criteria |
• Untreated symptomatic brain or leptomeningeal metastatic disease.
• Medical or psychiatric conditions comprising 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.
• Patient who has had chemotherapy, radioactive or biological cancer therapy within 4 weeks prior to the first dose of study therapy, or who has not recovered to CTCAE grade 1 or better from the adverse events due to cancer therapeutics administered more than 4 weeks earlier. Patient who has had erlotinib, gefitinib, afatinib, or crizotinib within 1 week prior to the first dose of study therapy, or who has not recovered to CTCAE Grade 1 or better from the adverse events due to any of these drugs administered more than 1 week earlier. Patient who has had ipilimumab therapy may be enrolled if requirements specified in Inclusion Criterion are met.
• Active autoimmune disease that has required systemic treatment in 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.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 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.
• Patient has risk factors for bowel obstruction or bowel perforation (examples include but not limited to a history of acute diverticulitis, intra-abdominal abscess and abdominal carcinomatosis).
• Patient has a known history of malignancy, unless the patient has undergone potentially curative therapy with no evidence of that disease for 5 years.
• Previous history of pneumonitis or significantly reduced transfer coefficient (KCO).
• Female patients of child bearing potential should be using adequate contraceptive measures, should not be breast feeding and must have a negative pregnancy test prior to start of dosing.
• Patient previously had a severe hypersensitivity reaction to treatment with another monoclonal antibody.
• Patient had prior treatment targeting PD-1: PD-L1 axis or was previously randomized in any Pembrolizumab trial.
• Patient is positive for Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), active Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA (qualitative) is detected); patients with negative Hepatitis C antibody testing may not need RNA testing.
• Known history of tuberculosis
• Patient has an active infection requiring therapy.
• Has received a live vaccine within 30 days prior to the first dose of trial treatment.
• Patient is, at the time of signing informed consent, a regular user (including “recreational use”) of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol).
• Patients with symptomatic ascites or pleural effusion. A patient who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
PePS2 to has two co-primary outcome measures:
• Toxicity defined as the occurrence of a treatment-related dose reduction or dose delay or treatment discontinuation due to toxicity.
Adverse events will be recorded in relation to each cycle of treatment and graded according to CTCAE criteria. The incidence of each adverse event (all grades and grade 3/4) will be reported as a per-patient-cycle rate and as a per-patient rate. The toxicity co-primary outcome measure for the trial is defined as the occurrence of a treatment-related dose reduction or dose delay or treatment discontinuation due to toxicity.
• Response defined as the occurrence of a complete response (CR), partial response (PR) or stable disease (SD) ≥18 weeks.
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 response co-primary outcome measure for the trial is defined as the occurrence of CR, PR or SD for 18 weeks or greater.
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| E.5.2 | Secondary end point(s) |
Health Related Quality of Life
Quality of life will be assessed using the FACT-L questionnaire and EQ- 5D questionnaire. This is defined as the functional effect of a medical condition and/or its consequent treatment upon a patient. The purpose of HR QoL 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.
Time to Progression (TTP)
This is defined as the time from registration into trial 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 (PFS)
This is defined as the time from registration into trial 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.
Overall survival time (OS)
This is defined as the time from registration into trial to the date of death. Patients who are alive at the time of analysis will be censored at the date last seen alive.
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of trial will be 6 months after the last data capture. This will allow sufficient time for the completion of protocol procedures, data collection and data input. The PePS2 Trial Office will notify the MHRA and main REC that the trial has ended and will provide them with a summary of the clinical trial report within 12 months of the end of trial.
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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