A randomised phase II feasibility study of INTERmittent versus continuous dosing of oral targeted combination therapy In patients with BRAFV600 mutant stage 3 unresectable or metastatic Melanoma

Research summary

Melanoma is the most lethal form of skin cancer: over 13,000 patients are diagnosed in the United Kingdom (UK) annually. Although the majority of patients are diagnosed with primary tumours that can be removed by surgery, around 20% will relapse. Recent developments in non-surgical treatments for metastatic melanoma have extended median survival from around 8 months to 2 years. Even so, for the majority of patients with advanced melanoma, this remains a terminal diagnosis: 5-year survival in 2011 was 16%.

A strong scientific rationale argues for intermittent dosing of MAPkinase inhibitors. However, the concept of administering less rather than more treatment may be challenging in practice. A survey of metastatic melanoma patients receiving BRAF targeted agents identified that despite experiencing toxicity, most patients were either undecided or reluctant to consider interrupting their treatment either for 1 or 2 weeks (P Corrie, unpublished data). This feasibility trial aims to determine if intermittent dosing is deliverable, based on patient and professional willingness to take part in a randomised trial evaluating less than standard durations of treatment.

INTERIM is a multi-centre, open-label, two-arm, randomised phase II feasibility trial aimed at investigating the role of intermittent dosing of the combination BRAF and MEK inhibitor regimen, dab+tram. The trial will evaluate treatment compliance, PFS and QoL, to inform whether a subsequent definitive trial is justified and how it should be designed. The trial will incorporate detailed clinician and patient (using patient-reported outcome measures) evaluation of frequently occurring and problematic skin toxicities and will address the cost-effectiveness of an intermittent dosing regimen. In addition, tissue and blood samples will be collected to demonstrate proof of principle as well as to explore the role of circulating tumour DNA (ctDNA) as a non-invasive predictive biomarker in BRAF mutant melanoma.

Approximately 20 UK sites will participate. INTERIM is centrally co-ordinated at the Cambridge Clinical Trials Unit – Cancer Theme (CCTU-CT). Approximately 100 patients will be randomised 1:1. The time from consent to randomisation is up to 28 days. The duration of treatment is until disease progression or beyond, at the investigator’s discretion. A minimum of 9 months follow-up from the date of randomisation is required for all surviving patients.

Main inclusion criteria

  1. Signed informed consent for the INTERIM trial

  2. Aged ≥ 18 years old

  3. Histologically or cytologically confirmed BRAFV600 mutant melanoma

  4. AJCC disease stage 3 unresectable or stage 4

  5. Radiologically and/or clinically measurable disease, by RECIST version 1.1; baseline tumour assessments must be done within 28 days prior to randomisation

  6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

  7. Predicted life expectancy >12 weeks

  8. Adequate bone marrow function

    1. Absolute neutrophil count (ANC) ≥1.2 x 109 /L

    2. Haemoglobin (Hb) ≥ 90 g/L

    3. Platelets ≥75 x 109 /L

    4. White blood cell count (WBC) ≥ 2 x 109 /L

  9. Adequate liver function

    1. Aspartate aminotransferase (AST) and/or alanine transaminase (ALT) ≤3 x upper limit of normal range (ULN)

    2. Total bilirubin <1.5 x ULN (except if the patient has Gilbert Syndrome or liver metastases, in which case the bilirubin must be <3 x ULN)

  10. Adequate renal function defined as a serum creatinine ≤1.5 x ULN or calculated creatinine clearance by Cockcroft-Gault of ≥40 mL/min

  11. Received no prior BRAF or MEK inhibitors for metastatic disease (Prior adjuvant therapy is allowed)

  12. Plan to start dabrafenib + trametinib treatment

  13. If radiotherapy has previously been given; there is measurable disease which has not been irradiated

  14. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, completion of QoL questionnaires and other procedures described in the protocol

  15. Confirmation of archival tumour tissue sample available

  16. Women of child-bearing potential (WCBP) and all sexually active male patients must agree to use effective contraception methods throughout treatment as per section 10.8 of this protocol

Main exclusion criteria

The presence of any of the following will exclude patients:

  1. Concomitant immunotherapy being administered to treat advanced melanoma

  2. Other invasive malignancies diagnosed within the last year which are not in complete remission, or for which additional therapy is required

  3. Significant acute or chronic medical or psychiatric condition, disease or laboratory abnormality which in the judgment of the investigator would place the patient at undue risk or interfere with the trial. Examples include, but are not
    limited to:

    1. Patients with uncontrolled ischaemic heart or other cardiovascular event (myocardial infarction (MI), new angina, stroke transient ischaemic attack (TIA), or new congestive cardiac failure (CCF)) within the last 6 months

    2. Patients with stable but significant cardiovascular disease defined by heart failure (New York Heart Association Functional Classification (NYHF) III or IV) or frequent angina. Patients with baseline QTC interval > 480 msec.

    3. Presence of active infection

    4. Cirrhotic liver disease, known chronic active or acute hepatitis B, or hepatitis C

    5. Known allergy or hypersensitivity to dabrafenib or trametinib, or their excipients

  4. Women who are pregnant, plan to become pregnant or are lactating during the trial period

  5. Other investigational anti-cancer drugs

  6. Use of strong inducers and inhibitors of CYP3A or CYP2C8

Chief investigator

Dr Pippa Corrie

Contact details

Cancer Theme Email: [email protected]