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Efficacy of Nilotinib in First or Second Line Treatment of Primary Melanomas Stage III Unresectable Melanomas. (NILOMEL)

Primary Purpose

Malignant Skin Melanoma T0, Stage III Melanoma, Stage IV Melanoma

Status
Unknown status
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Nilotinib
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Malignant Skin Melanoma T0 focused on measuring Malignant Skin Melanoma T0, stage III unresectable melanomas,, or stage IV melanomas with c-KIT mutation, or amplification.

Eligibility Criteria

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

Inclusion Criteria:

  • Patients with histologically proven melanoma with either c-KIT mutation or C-KIT amplification (without BRAF or NRAS mutation)
  • Unresectable primary or stage III or stage IV melanoma
  • Measurable disease (RECIST)
  • The inclusion of patients with primary tumor or metastasis accessible to sequential biopsies will be favored. If such lesions are present, biopsies are mandatory and not optional
  • No more than 1 previous specific therapy excluding tyrosine kinase inhibitors. 4 weeks wash out will be needed after cytotoxic therapy , 12 weeks wash out after anti -CTLA4 therapy or any immunological treatment
  • No radiotherapy within 4 weeks ; previously irradiated lesion will not be considered as measurable unless progression at inclusion
  • ECOG performance status < 2
  • WBC ≥ 3,000/mm³
  • PNN ≥ 1,500/mm³ (G-CSF allowed)
  • platelets ≥ 100,000/mm³
  • Hb ≥ 9.0 g/dL ( transfusions allowed as well as recombinant erythropoetin)
  • Creatinin clearance > 40ml/mn
  • Normal kalemia
  • Normal magnesemia
  • Total bilirubin <1.5N ; ASAT and ALAT <2.5N
  • PT/INR and PTT normal
  • NYHA class < 3
  • Signed Written Informed Consent
  • Affiliated to the National Health Insurance

Exclusion Criteria:

  • Patients refusal
  • Age < 18 years
  • Fertile women who do not want or cannot use effective contraception during the study and up to 8 weeks after the end of study
  • Women pregnant or nursing
  • Women with positive pregnancy test at inclusion or before treatment initiation
  • Fertile and sexually active men whose partner are fertile women who do not use effective contraception
  • Clinical and/or radiographic evidence of active cerebral metastases
  • Severe evolutive infection
  • Known HIV infection
  • Concomitant therapy with any other anti-cancer, immunomodulator or immunosuppressing agent or radiotherapy (except palliative care if bone metastases, after acceptance of principal investigator).
  • Previous use of tyrosine kinase inhibitors
  • More than one line of prior systemic therapies of melanoma by anti-cancer agent or immunotherapy.
  • Received experimental treatment within 4 weeks of inclusion
  • Pace-maker

  • Cardiac dysfunction, as evaluated by one of:

    • Ejection fraction < 45% (less than 28 days from inclusion)
    • Congenital prolonged QT
    • QTc > 450 ms
    • Ventricular tachyarrhythmia within the past 6 months
    • Bradycardia at rest < 50/mn
    • Major conduction dysfunction
    • Myocardial infarction within the previous 6 months
    • Unstable angina
  • Uncontrolled hypertension
  • Digestive disease that may inhibited NILITINIB absorption
  • Concomitant medication that may increase QT
  • Taking CYP3A4 inhibitors
  • Eating Sevilla oranges (or Sevilla oranges derivates), grapefruit (or grapefruit juice), grapes (or grapes juice), pomegranate (or pomegranate juice)
  • Hereditary galactose intolerance, Lapp-lactase deficiency or glucose-galactose malabsorption.

Sites / Locations

  • Hôpital Saint-LouisRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Nilotinib

Arm Description

Outcomes

Primary Outcome Measures

Objective response
Partial or complete response per Response Evaluation Criteria in Solid Tumors (RECIST).

Secondary Outcome Measures

Disease control
Complete or partial response or stable disease per Response Evaluation Criteria in Solid Tumors (RECIST).
Objective response
Partial or complete response per Response Evaluation Criteria in Solid Tumors (RECIST).
Metabolic response
Metabolic response as evaluated by TEP-SCAN
Tolerance
Tolerance will be evaluated according to National Cancer Institute (NCI) Criteria for Adverse Events, CTCAE v3.0

Full Information

First Posted
July 21, 2010
Last Updated
February 7, 2011
Sponsor
Assistance Publique - Hôpitaux de Paris
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1. Study Identification

Unique Protocol Identification Number
NCT01168050
Brief Title
Efficacy of Nilotinib in First or Second Line Treatment of Primary Melanomas Stage III Unresectable Melanomas.
Acronym
NILOMEL
Official Title
Phase II Multicentric Uncontrolled National Trial Assessing the Efficacy of Nilotinib in First or Second Line Treatment of Primary Melanomas , Stage III Unresectable Melanomas, or Stage IV Melanomas With c-KIT Mutation or Amplification.
Study Type
Interventional

2. Study Status

Record Verification Date
February 2011
Overall Recruitment Status
Unknown status
Study Start Date
July 2010 (undefined)
Primary Completion Date
December 2013 (Anticipated)
Study Completion Date
December 2013 (Anticipated)

3. Sponsor/Collaborators

Name of the Sponsor
Assistance Publique - Hôpitaux de Paris

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
NILOMEL is a phase II multicentric uncontrolled open national trial assessing the efficacy of Nilotinib in first or second line treatment of primary melanomas , stage III unresectable melanomas, or Stage IV melanomas with c-KIT mutation or amplification. The primary objective is overall response rate (partial and complete response) according to RECIST 1.1 criteria, assessed using CT-SCAN (stage IV melanoma) or MRI (unresectable melanoma) after 6 months therapy with Nilotinib 800 mg/d. Secondary objectives include: Disease control rate (complete, partial response and stable disease) Metabolic response Tolerance NCI CTCAE Version 3.0 Biomarkers associated to response and disease control.
Detailed Description
NILOMEL is a phase II multicentric uncontrolled open national trial assessing the efficacy of Nilotinib in first or second line treatment of primary melanomas , stage III unresectable melanomas, or Stage IV melanomas with c-KIT mutation or amplification (in case of c-KIT amplification, no B-RAF nor N-Ras mutation should be detected). The primary objective is overall response rate (partial and complete response) according to RECIST 1.1 criteria, assessed using CT-SCAN (stage IV melanoma) or MRI (unresectable melanoma) after 6 months therapy with Nilotinib 800 mg/d. Secondary objectives include: Disease control rate (complete, partial response and stable disease) according to RECIST Metabolic response rate (TEP-SCAN) Tolerance NCI CTCAE Version 3.0 Biomarkers associated to response and disease control (evaluated at M0, M1 and M6). Protein analysis of c-KIT, PI3K, MAPK and STAT signalling pathways as well as PDGFR and Ephrin signalling pathways. Patients with progressive disease after 3 months therapy will be withdrawn. Patient with stable disease after 3 months will continue Nilotinib until evaluation at 6 months. Patients with stable disease or progressive disease at 6 months will continue Nilotinib until progression. The trial has been planned using a one-stage design (Fleming TR) . We considered that a response rate under 7.5% would define the null hypothesis of no efficacy . To detect a response rate of 30% or more with power 90% using a one-sided test at the 0.05 level, 25 patients have to be recruited. Accrual for 2.5 years total study duration: 3 years

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Malignant Skin Melanoma T0, Stage III Melanoma, Stage IV Melanoma, Amplification
Keywords
Malignant Skin Melanoma T0, stage III unresectable melanomas,, or stage IV melanomas with c-KIT mutation, or amplification.

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
25 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Nilotinib
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Nilotinib
Intervention Description
Nilotinib 400 mg twice per day
Primary Outcome Measure Information:
Title
Objective response
Description
Partial or complete response per Response Evaluation Criteria in Solid Tumors (RECIST).
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Disease control
Description
Complete or partial response or stable disease per Response Evaluation Criteria in Solid Tumors (RECIST).
Time Frame
6 months
Title
Objective response
Description
Partial or complete response per Response Evaluation Criteria in Solid Tumors (RECIST).
Time Frame
3 months
Title
Metabolic response
Description
Metabolic response as evaluated by TEP-SCAN
Time Frame
6 months
Title
Tolerance
Description
Tolerance will be evaluated according to National Cancer Institute (NCI) Criteria for Adverse Events, CTCAE v3.0
Time Frame
1 year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with histologically proven melanoma with either c-KIT mutation or C-KIT amplification (without BRAF or NRAS mutation) Unresectable primary or stage III or stage IV melanoma Measurable disease (RECIST) The inclusion of patients with primary tumor or metastasis accessible to sequential biopsies will be favored. If such lesions are present, biopsies are mandatory and not optional No more than 1 previous specific therapy excluding tyrosine kinase inhibitors. 4 weeks wash out will be needed after cytotoxic therapy , 12 weeks wash out after anti -CTLA4 therapy or any immunological treatment No radiotherapy within 4 weeks ; previously irradiated lesion will not be considered as measurable unless progression at inclusion ECOG performance status < 2 WBC ≥ 3,000/mm³ PNN ≥ 1,500/mm³ (G-CSF allowed) platelets ≥ 100,000/mm³ Hb ≥ 9.0 g/dL ( transfusions allowed as well as recombinant erythropoetin) Creatinin clearance > 40ml/mn Normal kalemia Normal magnesemia Total bilirubin <1.5N ; ASAT and ALAT <2.5N PT/INR and PTT normal NYHA class < 3 Signed Written Informed Consent Affiliated to the National Health Insurance Exclusion Criteria: Patients refusal Age < 18 years Fertile women who do not want or cannot use effective contraception during the study and up to 8 weeks after the end of study Women pregnant or nursing Women with positive pregnancy test at inclusion or before treatment initiation Fertile and sexually active men whose partner are fertile women who do not use effective contraception Clinical and/or radiographic evidence of active cerebral metastases Severe evolutive infection Known HIV infection Concomitant therapy with any other anti-cancer, immunomodulator or immunosuppressing agent or radiotherapy (except palliative care if bone metastases, after acceptance of principal investigator). Previous use of tyrosine kinase inhibitors More than one line of prior systemic therapies of melanoma by anti-cancer agent or immunotherapy. Received experimental treatment within 4 weeks of inclusion Pace-maker Cardiac dysfunction, as evaluated by one of: Ejection fraction < 45% (less than 28 days from inclusion) Congenital prolonged QT QTc > 450 ms Ventricular tachyarrhythmia within the past 6 months Bradycardia at rest < 50/mn Major conduction dysfunction Myocardial infarction within the previous 6 months Unstable angina Uncontrolled hypertension Digestive disease that may inhibited NILITINIB absorption Concomitant medication that may increase QT Taking CYP3A4 inhibitors Eating Sevilla oranges (or Sevilla oranges derivates), grapefruit (or grapefruit juice), grapes (or grapes juice), pomegranate (or pomegranate juice) Hereditary galactose intolerance, Lapp-lactase deficiency or glucose-galactose malabsorption.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Zakia Idir, PhD
Phone
+33 1 4484 1747
Email
zakia.idir@sls.aphp.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Celeste Lebbe, MD, PhD
Organizational Affiliation
Hôpital Saint-Louis, Paris, France
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hôpital Saint-Louis
City
Paris
ZIP/Postal Code
75010
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Celeste Lebbe, MD, PhD
Email
celeste.lebbe@sls.aphp.fr
First Name & Middle Initial & Last Name & Degree
Celeste Lebbe, MD, PhD

12. IPD Sharing Statement

Learn more about this trial

Efficacy of Nilotinib in First or Second Line Treatment of Primary Melanomas Stage III Unresectable Melanomas.

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