Phase I-II Study With Tumor Molecular Pharmacodynamic (MPD) Evaluation and Pharmacokinetics of PD-0332991 in Patients Suffering Metastatic Melanoma

NCT ID: NCT02202200

Last Updated: 2016-04-18

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 40 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-05-31
• Study Completion Date: 2018-08-31

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.

Conditions

Melanoma BRAF V600E/K Mutated; CDNKN2A Loss Defined

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

PD-0332991

Group Type: EXPERIMENTAL

PD- 0332991

Intervention Type: DRUG

PD-0332991 Inhibitor of cyclin-dependant kinase (CDK) 8 schedules will be evaluated PD-0332991 PO QD either at 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg and 200 mg

All patients will receive vemurafenib as background therapy ,bid at 720mg bid for the first group (during the first 2 cycle then 960 mg bid if good tolerance) and 960mg bid for all other patients

Interventions

PD- 0332991

PD-0332991 Inhibitor of cyclin-dependant kinase (CDK) 8 schedules will be evaluated PD-0332991 PO QD either at 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg and 200 mg

All patients will receive vemurafenib as background therapy ,bid at 720mg bid for the first group (during the first 2 cycle then 960 mg bid if good tolerance) and 960mg bid for all other patients

Intervention Type: DRUG

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Saint-Louis Hospital

Paris, Paris, France

Site Status: RECRUITING

Countries

France

Facility Contacts

Celeste Lebbe, MDPHD

Role: primary

celeste.lebbe@sls.aphp.fr

+33 1 42 49 49 49

References

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.

Reference Type: DERIVED

PMID: 33947696 (View on PubMed)

Other Identifiers

D20121106

Identifier Type: -

Identifier Source: org_study_id