PLX3397 KIT in Acral aNd mucOsal Melanoma

The PIANO trial is an open-label, single-arm, multicentre phase II trial of PLX3397 in advanced acral and mucosal melanoma. All eligible patients will receive PLX3397 1000mg/day as monotherapy and will remain on treatment as long as they are deriving benefit (at the treating Investigator's discretion).

The primary objective of this study is to assess the efficacy of PLX3397 by review of the number of patients who are progression-free at 6 months. Additional objectives include assessing the safety of PLX3397, overall survival and (for a sub-set of patients) biomarker research.

A maximum of 24 eligible patients may be treated in this study. In order to recruit 24 patients, it is expected that a total of approximately 240 patients will need to be consented and screened for the KIT mutation, as only KIT mutant patients are eligible (and this is estimated to be 10-15% of this patient population). An interim analysis by the Independent Data Monitoring Committee will be done after 9 patients have been recruited and if less than 2 out of the 9 patients have demonstrated progression free survival at 6 months the trial will be terminated.

As only KIT mutant patients are eligible for inclusion, the very first step following consent is for patients' KIT mutation status to be tested. Only patients who have KIT mutations are eligible. Wherever possible, archival tissue samples taken at the time of diagnosis will be requested but if a suitable sample is not available or if following testing no result is obtained an additional fresh tumour sample would be collected via a biopsy. The tissue sample will be sent to specialist laboratories for KIT testing and the results of this test take 1-2 weeks. If the patient is found to have a KIT mutation which is not associated with PLX3397 resistance, they will return to clinic to complete the following study parameters and investigations upto 4 weeks prior to the start of treatment except those examinations which are marked with an (*) ;

• Demographic details
• Medical and surgical history including discussions of current medications
• Tumour evaluation according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria v1.1 using CT or MRI scans of the thorax, abdomen and pelvis within 28 days of scheduled start of treatment
• Vital signs and standard physical examination (to include blood pressure, pulse, temperature, height and weight)*
• Eastern Cooperative Oncology Group (ECOG) performance status*
• Laboratory investigations: full blood count, biochemistry (Urea \& Electrolytes, creatinine, calcium, albumin, liver function tests, lactate dehydrogenase (LDH), glucose, phosphate) and clotting screen*
• Women of childbearing potential will have a urine or serum pregnancy test( within 72 hours of study entry)
• Electrocardiograph (ECG)*

If a patient undergoes a protocol-specified screening procedure as part of standard of care and the procedure occurs within 4 weeks then this data may be used for screening purposes and the test would not need to be repeated.

If the screening visit confirms that the patient is still eligible to take part in the study, they would return to clinic for a "baseline visit" and the following procedures would occur:

• Physical examination (including blood pressure and weight)
• Urine or serum pregnancy test in women of childbearing potential
• Electrocardiograph (ECG)
• ECOG Performance status
• Laboratory investigations: full blood count, biochemistry (U\&Es, creatinine, calcium, albumin, liver function tests, LDH, glucose, phosphate) and clotting screen
• 1 x 8ml whole blood sample (Pharmacodynamics/pharmacokinetics (PK/PD)analysis) to be sent to Plexxikon's vendor for central analysis
• Adverse event (including treatment toxicity) assessments (see section 9.1 for definition of an adverse event).
• Review of concurrent medications
• PLX3397 prescription

• PET scan (first 9 patients only)

  • If the baseline visit is \< 7 days since screening these investigations will not need to be repeated.

The patient would then return to clinic at day 15, day 29 (week 4), week 8 and then every 4 weeks in year 1 and every 8 weeks thereafter (until discontinuation of PLX3397). All visits have a window of +/- 3 days. The following procedures would be done at these visits:

• Physical examination (including blood pressure and weight).
• Electrocardiograph (ECG)
• ECOG Performance Status (PS)
• Laboratory investigations: full blood count, biochemistry (U\&Es, creatinine, calcium, albumin, liver function tests, LDH, glucose, phosphate) and clotting screen.
• 1 x 8ml whole blood sample (PK/PD analysis) at Day 15 only (sent to Plexxikon's vendor for central analysis)
• Adverse event (including treatment toxicity) assessments until 30 days after discontinuation of PLX3397.
• Review of concurrent medications.
• Assessment of compliance with study medication.
• CT or MRI scans of the thorax, abdomen and pelvis at week 12, week 26 and every 12 weeks thereafter.
• Urine or serum pregnancy testing in women of childbearing potential on every visit ( except day 15 on treatment).
• PET scan after 2 weeks of therapy (day 15 ±3 days) - first 9 patients only

When the patient has discontinued the PLX3397 they then enter the follow-up phase of the study. Patients will be followed up until death or for 12 months after the last patient has discontinued study treatment. Patients can be followed up by telephone call every 6 months to assess current status and subsequent therapies. Alternatively follow-up can be in clinic especially in the case of complaints which may indicate late toxicity.

Translational Research

A subset of patients from named sites (The Christie National Health Service (NHS) Foundation Trust and The Royal Marsden NHS Foundation Trust) will also be asked to provide additional, optional consent to take part in translational research. 5 patients will have biopsies taken at 3 timepoints (baseline, at day 15 and on disease progression) and blood samples taken at 4 timepoints (baseline, at day 15, week 12 and on disease progression). In addition, a further 7 patients will give blood samples only (to give a total of 12 patients giving blood samples). Wherever possible translational blood samples will be taken at the same time as the standard trial blood samples which confirm that the patient is still eligible for study inclusion.