National Lung Matrix Trial: Multi-drug Phase II Trial in Non-Small Cell Lung Cancer

National Lung Matrix Trial: Multi-drug, Genetic Marker-directed, Non-comparative, Multi-centre, Multi-arm Phase II Trial in Non-small Cell Lung Cancer

The trial consists of a series of parallel multi-centre single arm phase II trial arms, each testing an experimental targeted drug in a population stratified by multiple pre-specified actionable target putative biomarkers. The primary objective is to evaluate whether there is a signal of activity in each drug-(putative)biomarker cohort separately. A Bayesian adaptive design is adopted to achieve this objective and statistical details are given in the Protocol.

The trial is primarily an enrichment putative biomarker design, including patients who are positive for at least one of the actionable targets included in the trial. Patients who are positive for just one putative biomarker will receive the experimental targeted drug specific for that putative biomarker. Putative biomarkers within each drug cohort have been chosen such that in the majority of cases it is not expected that patients will be positive for two or more putative biomarkers within the same drug. In the rare situation that patients are positive for two or more putative biomarkers relevant across different drugs, treatment will be allocated in accordance with the following strategy:

• All amplifications and rearrangements will be treated with targeted agent appropriate to them irrespective of concomitant mutations. This will yield crucial predictive biomarker information.
• For concomitant mutations decisions will be made by the Chief Investigator on a case-by-case basis and based on close consideration of pathway preference and likely dominance of one signal pathway over another together with any pre-clinical efficacy studies that address the activity of the drugs in the presence of concomitant mutations. A trumping strategy has been devised for this purpose.

Core inclusion and exclusion criteria are presented below. Additional inclusion/exclusion criteria apply to each arm and are presented in the relevant arm supplements of the protocol.

Inclusion Criteria:

• Prior anti-cancer treatment:

  • Patients who refuse any standard of care first line therapy, are eligible to receive National Lung Matrix Trial treatment as first line therapy, providing they explicitly consent to this effect.
  • Patients who have previously consented to and received standard of care first line therapy 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 whose disease has increased in size but is not classed as progressive disease as per RECIST criteria, will be eligible. Patients with no change at all in dimension of disease (i.e. true stability) after first line therapy will not be eligible.
  • 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.
  • 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 Section 6.4 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 or MRI scan of head, chest and abdomen within 28 days of treatment demonstrating measurable disease as per RECIST version 1.1 (see Appendix 1: Response Evaluation Criteria in Solid Tumours Version 1.1). (The same imaging modality must be used throughout treatment).

• Adequate haematological function within 7 days of treatment.

  • Haemoglobin ≥ 90 g/L.
  • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
  • 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).

  • Total serum bilirubin ≤ 1.5 x upper limit of normal (ULN). (Note that this will not apply to patients with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of evidence of haemolysis or hepatic pathology), who may be allowed inclusion at the discretion of the local Investigator).
  • Alanine transferase (ALT) ≤ 2.5 x ULN.
  • Aspartate transferase (AST) ≤ 2.5 x ULN.

• Adequate renal function within 7 days of treatment.

  • Creatinine clearance (CLcr) >50 ml/min (measured or calculated by Cockcroft and Gault equation - see Appendix 4: Cockcroft Gault Formula - Creatinine Clearance). If calculated CLcr is <50 ml/min a direct measurement of glomerular filtration rate (GFR) such as EDTA may be performed. If the value is >50 ml/min the patient is eligible.

• Age ≥ 18 years.

• Females must agree to use adequate contraceptive measures (as defined in 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:

  • Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
  • Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
  • 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.

Exclusion Criteria:

• Major surgery (excluding placement of vascular access) 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 local 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 - Appendix 3: Common Toxicity Criteria Gradings).
• 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 local 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 local 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 and lactating patients (patients of childbearing potential must have a negative pregnancy test prior to registration).

Cardiac exclusion criteria, performance status and prior treatment washout periods are detailed within the National Lung Matrix Trial arm-specific eligibility criteria.