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

Primary Purpose

Melanoma BRAF V600E/K Mutated, CDNKN2A Loss Defined

Status

Unknown status

Phase

Phase 1

Locations

France

Study Type

Interventional

Intervention

PD- 0332991

About this trial

This is an interventional treatment trial for Melanoma BRAF V600E/K Mutated focused on measuring Melanoma, BRAF mutated

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Saint-Louis HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

PD-0332991

Arm Description

Outcomes

Primary Outcome Measures

Occurrence within the first 2 cycles of treatment of a DLT

DLTs, serious adverse events and adverse events leading to treatment discontinuations will be determined as follows: Any grade 3 or more non-haematological toxicity excluding: Grade 3 asymptomatic increase in liver function tests (AST, ALT, ALP) reversible within 7 days for subjects without liver involvement, or grade 4 for subjects with liver involvement. Grade 3 vomiting if it is encountered despite adequate and optimal therapy (e.g. 5HT3 antagonists and corticosteroids). Grade 3 diarrhoeas if encountered despite adequate and optimal anti diarrhoea therapy. Confirmed grade 3 QTc prolongation (QTc >500 msec) that persists after correction of other possible causes such as electrolyte imbalance Grade 4 hyperlipidemia if it is encountered despite adequate and optimal therapy. Any grade 4 neutropenia of > 5 days duration, or febrile neutropenia lasting for more than 1 day. Grade 4 thrombocytopenia > 1 day, or grade 3 with bleeding.

Secondary Outcome Measures

Efficacy

Occurrence of clinical benefit (defined as Complete Response (CR), Partial Response (PR) or stable disease (SD)) and progressive disease based on the best overall response which depends on the tumour evaluations assessed using RECIST at the end of each 2 cycles.

1 year survival rate

survival

Tolerance

Occurrence of clinically significant changes in a laboratory parameter and/or vital signs judged to be related to the trial medication within the first 6 months.

Full Information

NCT ID

NCT02202200

First Posted

July 25, 2014

Last Updated

April 15, 2016

Sponsor

Assistance Publique - Hôpitaux de Paris

1. Study Identification

Unique Protocol Identification Number

NCT02202200

Brief Title

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

Acronym

OPTIMUM

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

2. Study Status

Record Verification Date

April 2016

Overall Recruitment Status

Unknown status

Study Start Date

May 2014 (undefined)

Primary Completion Date

November 2016 (Anticipated)

Study Completion Date

August 2018 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Assistance Publique - Hôpitaux de Paris

4. Oversight

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Melanoma BRAF V600E/K Mutated, CDNKN2A Loss Defined

Keywords

Melanoma, BRAF mutated

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

PD-0332991

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

PD- 0332991

Intervention Description

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

Primary Outcome Measure Information:

Title

Occurrence within the first 2 cycles of treatment of a DLT

Description

Time Frame

42 Days

Secondary Outcome Measure Information:

Title

Efficacy

Description

Time Frame

42 Days

Title

1 year survival rate

Description

survival

Time Frame

1 year

Title

Tolerance

Description

Occurrence of clinically significant changes in a laboratory parameter and/or vital signs judged to be related to the trial medication within the first 6 months.

Time Frame

6 months

Other Pre-specified Outcome Measures:

Title

Pharmacodynamic

Description

Changes from baseline of ANC and platelet levels Efficiency on the cell-cycle machinery and proliferation (tumor sample) Induction of senescence: will be evaluated using the senescence β-Galactosidase assay (Cell Signaling Technology) Induction of apoptosis: will be performed using TUNEL staining with the ApopTag Peroxidase In Situ Apoptosis Detection Kit (Millipore).

Time Frame

42 days

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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

Facility Information:

Facility Name

Saint-Louis Hospital

City

Paris

ZIP/Postal Code

75010

Country

France

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Celeste Lebbe, MDPHD

Phone

+33 1 42 49 49 49

celeste.lebbe@sls.aphp.fr

First Name & Middle Initial & Last Name & Degree

celeste lebbe, MD-PHD

12. IPD Sharing Statement

Citations:

PubMed Identifier

33947696

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.

Results Reference

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

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