Clinical trial NCT02202200: Phase I-II Study With Tumor Molecular Pharmacodynamic (MPD) Evaluation and Pharmacokinetics of PD-0332991 in Patients Suffering Metastatic Melanoma
Official title: An Open Label Multicenter, Phase I-II Study With Tumor Molecular Pharmacodynamic (MPD) Evaluation and Pharmacokinetics of PD-0332991 in Patients Suffering Metastatic Melanoma With BRAFv600 Mutated and CDKN2A Loss and Expression of Rb and Treated by Vemurafenib
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Melanoma BRAF V600E/K Mutated
CDNKN2A Loss Defined
Keywords: Melanoma
BRAF mutated
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2014-07-28
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: An open label multicentre, phase I-II study with tumour molecular pharmacodynamics (MPD) evaluation and pharmacokinetics of PD-0332991 added to vemurafenib in patients suffering metastatic melanoma with BR.

The main objective is to establish the Maximum Tolerated Dose (MTD) of PD-0332991 when added to standard vemurafenib therapy (960 mg BID). The estimated MTD is defined as the dose of PD-0332991 combined with vemurafenib that will be associated with a prespecified proportion of patients experiencing a Dose-Limiting Toxicity (DLT), ie, 1/3.


Eligibility criteria: Inclusion Criteria:

* Age \> 18 years
* Stage IV or un-resectable stage III melanoma
* Presence of BRAF V600E/K mutation and CDNKN2A loss and expression of Rb using immunohistochemistry in a recent metastatic sample (\< 6 months)
* A previous exposure to BRAF inhibitor or combination of BRAF and MEK inhibitors therapy is allowed unless it has been stopped more than 3 months before study enrolment(This will defined the two strata of the trial)
* No previous therapy by MEK inhibitor unless associated with BRAF inhibitors
* No previous therapy with the AKT/PI3K pathway inhibitor
* Patients should have a tumour available for repeated biopsies for pharmacodynamics evaluation
* Life expectancy of \> 3 months
* ECOG performance status \<2
* Signed informed consent
* Patient with health insurance coverage
* No patient under guardianship or curators

Exclusion Criteria:

* Inadequate hepatic function defined as serum bilirubin\>25 μmol/l, transaminases \> 3.0 times the upper limit of normal (ULN) or 5ULN in cases of liver metastases;
* Inadequate bone marrow function defined as absolute neutrophil count\<1500/mcl, platelets\<150000/mcl and haemoglobin\<8g/dL
* Inadequate renal function with serum creatinine\>2.0mg/dl) and /or creatinine clearance\< 60 ml/min
* Untreated brain metastases : Patients with brain metastases will be eligible if they have completed treatment 1 months prior to the start of study medication, have discontinued corticosteroid treatment for these metastases for at least 5 days, and are neurologically asymptomatic
* Myocardial infarct or unstable angina within the past 6 months
* Concomitant take of drugs known to be strong inhibitor or inducers of CYP314
* HIV positive.
* Chemotherapy, immunotherapy within 4 weeks
* Drugs interfering with PD-0332991 and vemurafenib metabolism
* Malabsorption syndrome or other condition that would interfere with enteral absorption
* Congenital long QT syndrome or screening QTc \> 470 msec
* Need for chronic corticosteroid therapy of ≥10 mg of prednisone per day

Primary outcomes:
measure: Occurrence within the first 2 cycles of treatment of a DLT
timeFrame: 42 Days
Secondary outcomes:
measure: Efficacy
timeFrame: 42 Days
measure: 1 year survival rate
timeFrame: 1 year
measure: Tolerance
timeFrame: 6 months
Other outcomes:
measure: Pharmacodynamic
timeFrame: 42 days
Locations:
city: Paris
country: France
facility: Saint-Louis Hospital
Study officials:
References:
citation: Louveau B, Resche-Rigon M, Lesimple T, Da Meda L, Pracht M, Baroudjian B, Delyon J, Amini-Adle M, Dutriaux C, Reger de Moura C, Sadoux A, Jouenne F, Ghrieb Z, Vilquin P, Bouton D, Tibi A, Huguet S, Rezai K, Battistella M, Mourah S, Lebbe C. Phase I-II Open-Label Multicenter Study of Palbociclib + Vemurafenib in BRAF V600MUT Metastatic Melanoma Patients: Uncovering CHEK2 as a Major Response Mechanism. Clin Cancer Res. 2021 Jul 15;27(14):3876-3883. doi: 10.1158/1078-0432.CCR-20-4050. Epub 2021 May 4.