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.
Inclusion Criteria:
- Patients with KIT mutated histologically proven advanced mucosal or acral melanoma in
which the mutation is not known to be associated with PLX3397 resistance
- Unresectable locally advanced or metastatic disease
- The presence of one or more clinically or radiologically measurable lesions at least
10mm in size
- ECOG performance status 0, 1 or 2
- Life expectancy greater than 12 weeks
- Age 18 or greater
- Women must be postmenopausal (no menstrual period for a minimum of 1 year) or have a
negative serum pregnancy test on entry in the study (even if surgically sterilised).
Men and women of childbearing potential must use adequate birth control measures for
the duration of the study and should continue such precautions for 3 months after
receiving the last dose of study treatment
- At least 28 days since major surgery and 7 days since skin/tumour biopsy
- Serum alanine transaminase (ALT) ≤2.5 x upper limit of normal (ULN) or serum aspartate
aminotransferase≤2.5 x ULN
- Total serum bilirubin ≤1.5 x ULN
- Serum creatinine ≤1.5 x ULN
- Haemoglobin ≥90 g/L, absolute neutrophil count ≥1.5 x 109/L, platelets ≥100 x 109/L
- Prothrombin time (PT) ≤1.5 x ULN
- The ability to swallow and retain oral medication
- The capacity to understand the patient information sheet and the ability to provide
written informed consent
- Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests and other study procedures
Exclusion Criteria:
- Intracranial disease, unless there has been radiological evidence of stable
intracranial disease > 6 months. In the case of a solitary brain metastasis, evidence
of a disease-free interval of at least 3 months post surgery. All patients previously
treated for brain metastases must be stable off corticosteroid therapy for at least 28
days
- Women who are pregnant, nursing, or planning pregnancy within 6 months after the last
treatment
- Men who plan to father a child within 3 months of the last treatment
- Use of any investigational drug within 30 days prior to screening
- Significant cardiac disease including patients who have or who are at significant risk
of developing prolongation of corrected QT interval (QTc)
- Severe and/or uncontrolled medical disease
- Known chronic liver disease
- Known HIV infection
- Previous radiotherapy to 25% or more of the bone marrow and/or radiation therapy in
the 4 weeks prior to study entry
- Prior exposure to a KIT inhibitor
- Patients with KIT mutations that are known to be associated with PLX3397 resistance
- Use of Chinese or herbal medication
- Any malabsorption syndrome (i.e. partial gastrectomy, small bowel resection, crohn's
disease or ulcerative colitis)
