| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic or locally advanced 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 | 21.1 |
| 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 |
| The primary objective is to evaluate whether there is a signal of activity (adequate tumour response) in each drug-biomarker cohort to justify further investigation in that molecularly-defined group. |
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| E.2.2 | Secondary objectives of the trial |
To collect tissue linked to clinical outcome data for future exploratory analysis to investigate the molecular phenotype of tumours in responding versus non-responding patients and to further develop the clinical diagnostic test necessary to support further investigation of the agent in the relevant molecularly-defined group.
To identify predictive biomarkers for activity of the various drugs used in the various molecular cohorts.
To determine the mechanisms of resistance to the target therapies utilised. |
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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 thinks is appropriate. As a minimum patients must have failed one or more lines of treatment (either radiological documentation of disease progression or due to toxicity).
• Patients who have progressed after surgical resection and adjuvant therapy will be eligible for entry without the need for the administration of first line metastatic therapy if they have progressed within 6 months of completing their adjuvant treatment.
• Patients will also be eligible without the necessity for first line regimen if they have relapsed within 6 months of completion of definitive chemoradiation.
• Consented and provided an adequate specimen to adequately characterise the molecular genotype of the tumour in the molecular pre-screening according to the molecular exclusion rules (see protocol for definition of an adequate sample).
• Histological or cytologically confirmed NSCLC stage III (not suitable for radical radiotherapy or surgery) or stage IV. This includes patients who may have abnormal histology, but IHC strongly support either squamous cell carcinoma (p63 positivity) or adenocarcinoma (Thyroid transcription factor 1 [TTF1] positivity). If a physician and pathologist are convinced after multi-disciplinary review that the patient has stage III or IV NSCLC but where all the IHC is negative and the morphology does not distinguish a specific sub-type, these patients will be eligible for non-histology specific cohorts.
• CT scan of head, chest and abdomen within 28 days of treatment demonstrating measurable disease as per RECIST version 1.1.
• Adequate haematological function within 7 days of treatment.
o Haemoglobin ≥ 90 g/L.
o Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
o Platelets ≥ 100 x 109/L.
•Adequate hepatic function within 7 days of treatment in patients with no liver metastasis (see arm specific entry criteria for adequate hepatic function in patients with liver metastases).
o Total serum bilirubin ≤ 1.5 x upper limit of normal (ULN).
o Alanine transferase (ALT) ≤ 2.5 x ULN.
o Aspartate transferase (AST) ≤ 2.5 x ULN.
• Adequate renal function within 7 days of treatment.
o Creatinine clearance (CLcr) >50 ml/min (measured or calculated by Cockcroft and Gault equation).
• Age ≥ 18 years.
• Females must agree to use adequate contraceptive measures (as defined in protocol section 6.3), should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:
o Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
o Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
o Women aged under 50 years old would be consider postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the post-menopausal range for the institution.
• Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses.
Arm-specific eligibility criteria also apply as detailed in the protocol. Performance status eligibility criteria are detailed within the arm-specific eligibility criteria.
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| E.4 | Principal exclusion criteria |
• Major surgery (excluding placement of vascular access), chemotherapy, radiotherapy, any investigational agents or other anti-cancer therapy within 4 weeks prior to treatment.
• Nausea, vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease) that would preclude adequate absorption.
• Any psychological, familial, sociological or geographical condition hampering protocol compliance.
• Concurrent malignancies or invasive cancers diagnosed within past 3 years except for adequately treated basal cell carcinoma of the skin and in situ carcinoma of the uterine cervix.
• Judgement by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
• Any unresolved toxicity of grade 2, 3 or 4 from previous treatment (excluding alopecia) at Registration (see CTCAE).
• Patients who have previous symptomatic brain metastases or spinal cord compression are excluded unless they have had adequate treatment, no evidence of progression or symptoms, and have had no requirement for steroid treatment in the previous 28 days before commencement of trial treatment.
• Patients with asymptomatic brain metastases picked up at screening CT scan are not excluded providing that in the view of the investigator they do not require immediate radiotherapy or surgical intervention, and have had no requirement for steroid treatment in the previous 28 days before commencement of trial treatment.
• As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus. Screening for chronic conditions is not required.
• Pregnant or breast-feeding women.
Arm-specific eligibility criteria also apply as detailed in the protocol. Cardiac exclusion criteria are detailed within the arm-specific eligibility criteria.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The trial design for each drug-biomarker cohort is essentially the same but the primary outcome measure representing signal of activity and the values that determine the go/no-go decision at interim and final analysis may differ across the different cohorts.
The primary outcome measure for trial Arms A, B, D, E, F & G is Best Objective Response Rate (ORR):
Patients will have CT scans every 6 weeks from baseline until disease progression. On each occasion, overall tumour burden will be assessed using RECIST version 1.1 (Eisenhauer et al. 2009). Best response is the best response recorded over the whole period of assessment and could be complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD) or inevaluable for response (for which reasons such as early death due to disease or early death due to toxicity will be specified). Best objective response rate (ORR) will be calculated as the proportion of patients with CR or PR based on a denominator that includes all eligible patients that have received at least one cycle of treatment. Best objective response rate will be based on responses confirmed using the subsequent 6-weekly scan but best objective response rate based on unconfirmed responses will also be reported.
Best percentage change in sum of target lesion diameters (PCSD):
At each evaluation, the longest diameters of all selected target lesions will be measured and summed and the percentage change from the baseline measurement will be calculated. The best percentage change is the one that reflects either the greatest decrease or the least increase over the whole period of assessment.
The primary outcome measure for trial Arm C is Progression Free Survival (PFS):
PFS 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.
The primary outcome measure for trial Arm NA is Best Objective Response Rate (ORR) and Progression Free Survival at 6 months (PFS6).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The Bayesian adaptive trial design allows interim analysis at any point in the trial but a formal interim analysis is planned per cohort after 15 patients have been recruited in each drug-putative biomarker cohort at which decisions to stop recruitment early to the cohort for futility will be made based on the posterior probability distribution at that time.
Primary analysis of primary end points for the study will be performed at interim analysis (when 15 patients have been recruited into each cohort) and following the recruitment of 30 patients into each cohort. |
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| E.5.2 | Secondary end point(s) |
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.
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.
Toxicity - Adverse events will be recorded in relation to each cycle of treatment and graded according to CTCAE criteria (see Appendix 5). 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. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Primary analysis of secondary end points for the study will be performed at interim analysis (when 15 have been patients recruited into each cohort) and following the recruitment of 30 patients into each cohort. |
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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 | 29 |
| 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
|
| 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 National Lung Matrix 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 | 3 |
| 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 | 3 |
| 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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