A Study of APR-246 in Combination With Dabrafenib in Resistant Patients With BRAF V600 Mutant Melanoma
Primary Purpose
Melanoma
Status
Terminated
Phase
Phase 1
Locations
Belgium
Study Type
Interventional
Intervention
APR-246
Dabrafenib
Sponsored by

About this trial
This is an interventional treatment trial for Melanoma focused on measuring Melanoma, Malignant melanoma, Skin cancer, Resistant cancer, Unresectable cancer, Metastatic cancer, BRAF mutant
Eligibility Criteria
Inclusion Criteria:
- Patients with confirmed BRAF V600 mutation-positive unresectable and/or metastatic malignant cutaneous melanoma, as determined locally by a validated test and treated with dabrafenib/trametinib first line combination therapy or second line after first line immunotherapy.
- Patients that have progressed according to RECIST 1.1 after at least 4 weeks of treatment with dabrafenib/trametinib and remained on dabrafenib full dose (150mg bid) treatment for the study.
- Measurable disease according to RECIST 1.1 criteria. For phase II only, metabolic measurable disease (according to PERCIST).
- Availability of tissue from a metastatic lesion. A new biopsy is required unless inaccessible. An archival sample is accepted in that case after discussion with the sponsor.
- ECOG Performance Status of 0 or 1.
- Patients able to swallow and retain oral medication.
- Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
- For female patients of childbearing potential, a pregnancy test (serum) will be performed within 7 days before inclusion. Woman of childbearing potential must be willing to use one highly effective form of contraception during anticancer treatment and for at least six months thereafter. Men must agree to use condom during the course of this study and at least six months after the last administration of the study treatment and contraception should be considered for partner of childbearing potential.
- Adequate organ system function.
- Signed informed consent before any study specific procedure and/or treatment happens.
Exclusion Criteria:
- Presence of uveal melanoma and/or other non-cutaneous melanomas.
- Current use of a prohibited medication or need for any of these medications during treatment with study drug and within 28 days before the first administration of APR-246. I.e., no anti-cancer other than that given in this clinical trial, no immunotherapy, no hormonal cancer therapy, no radiation therapy (except palliative) and no experimental medications are permitted during the trial. All alternative therapies must first be approved by the sponsor. Supportive care therapies are allowed.
- Unresolved toxicity greater than NCI-CTCAE(v4) Grade 1 from previous anti-cancer therapy except alopecia.
- Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs.
- Known HIV, active hepatitis B or hepatitis C infection.
- Primary malignancy of the central nervous system.
- History of familial long QT, serious ventricular arrhythmia (no VT > 130 bpm and > 5 extra beats per minute), no QTc ≥ 480 msec calculated from a single ECG reading or a mean of 3 ECG readings using Fridericia's correction (QTcF = QT/RR0.33) or bradycardia (< 45 bpm).
- Untreated or symptomatic brain metastasis, leptomeningeal disease or spinal cord compression. Patients who are on a stable dose of corticosteroids > 1 month or off corticosteroids for 2 weeks can be enrolled.
- History of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting, or thrombo-embolic event within the past 24 weeks from signature of ICF.
- Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
- Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drugs, or excipients.
- Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity.
- Pregnant or lactating woman.
Sites / Locations
- Institut Jules Bordet
- Universitair Ziekenhuis Antwerpen
- CHU UCL Namur - site Sainte-Elisabeth
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
APR-246 + Dabrafenib
Arm Description
Outcomes
Primary Outcome Measures
Phase Ib: Adverse Events (AEs)
Clinical and laboratory adverse events (AEs) and serious adverse events (SAEs) will be reported and graded
Phase Ib: Dose Limiting Toxicities (DLTs)
Phase II: Objective response rate by RECIST1.1
Secondary Outcome Measures
Clinical benefit rate
Proportion of patients with a CR, PR or Stable Disease (SD) ≥ 4 months
Duration of response
Progression free survival (PFS)
Area under the plasma concentration versus time curve (AUC) for APR-246
Plasma drug concentration at a specified time t (Ct) for APR-246
Maximum observed plasma concentration (Cmax) of APR-246
Time to reach maximum plasma concentration following drug administration (tmax) for APR-246
Assessment of metabolic response
According to classical PERCIST criteria (30%) modified PERCIST criteria (15%) and the consistency classification
Full Information
NCT ID
NCT03391050
First Posted
December 19, 2017
Last Updated
July 29, 2019
Sponsor
Aprea Therapeutics
Collaborators
Jules Bordet Institute
1. Study Identification
Unique Protocol Identification Number
NCT03391050
Brief Title
A Study of APR-246 in Combination With Dabrafenib in Resistant Patients With BRAF V600 Mutant Melanoma
Official Title
A Phase Ib/II Study to Investigate the Safety and Clinical Activity of APR-246 in Combination With Dabrafenib in Patients With BRAF V600 Mutant Unresectable and/or mEtastatic Cutaneous MElanoma Resistant to Dabrafenib/Trametinib Combination
Study Type
Interventional
2. Study Status
Record Verification Date
July 2019
Overall Recruitment Status
Terminated
Why Stopped
Target patient population - difficult to find patientes
Study Start Date
January 18, 2018 (Actual)
Primary Completion Date
August 8, 2018 (Actual)
Study Completion Date
August 8, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Aprea Therapeutics
Collaborators
Jules Bordet Institute
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The purpose of this study is to make a preliminary assessment of the efficacy of a combined APR-246 and dabrafenib therapy regimen in patients with BRAFV600 mutant unresectable and/or metastatic cutaneous melanoma resistant to the dabrafenib/trametinib combination. In addition, the study aims to assess the safety profile of the combined APR-246 and dabrafenib therapy regimen, to explore potential biomarkers, and to further describe the anti-tumour activity of the combination of APR-246 and dabrafenib. The trial will enroll up to 31 evaluable patients.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Melanoma
Keywords
Melanoma, Malignant melanoma, Skin cancer, Resistant cancer, Unresectable cancer, Metastatic cancer, BRAF mutant
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
3 (Actual)
8. Arms, Groups, and Interventions
Arm Title
APR-246 + Dabrafenib
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
APR-246
Intervention Description
Intravenous infusion
Intervention Type
Drug
Intervention Name(s)
Dabrafenib
Intervention Description
Oral administration
Primary Outcome Measure Information:
Title
Phase Ib: Adverse Events (AEs)
Description
Clinical and laboratory adverse events (AEs) and serious adverse events (SAEs) will be reported and graded
Time Frame
Up to 30 days after last study treatment day, or at end of study visit due to progression, whichever occurs later (treatment cycles are stopped due to progression, toxicity or patient's decision)
Title
Phase Ib: Dose Limiting Toxicities (DLTs)
Time Frame
Until end of cycle 1 (cycle length is 28 days)
Title
Phase II: Objective response rate by RECIST1.1
Time Frame
Until progression (assessed up to 12 months)
Secondary Outcome Measure Information:
Title
Clinical benefit rate
Description
Proportion of patients with a CR, PR or Stable Disease (SD) ≥ 4 months
Time Frame
Until progression (assessed up to 12 months)
Title
Duration of response
Time Frame
Until progression (assessed up to 12 months)
Title
Progression free survival (PFS)
Time Frame
Until progression (assessed up to 12 months)
Title
Area under the plasma concentration versus time curve (AUC) for APR-246
Time Frame
Until Cycle 1 Day 8 (Phase Ib) or Cycle 1 Day 1 (Phase II)
Title
Plasma drug concentration at a specified time t (Ct) for APR-246
Time Frame
Until Cycle 1 Day 8 (Phase Ib) or Cycle 1 Day 1 (Phase II)
Title
Maximum observed plasma concentration (Cmax) of APR-246
Time Frame
Until Cycle 1 Day 8 (Phase Ib) or Cycle 1 Day 1 (Phase II)
Title
Time to reach maximum plasma concentration following drug administration (tmax) for APR-246
Time Frame
Until Cycle 1 Day 8 (Phase Ib) or Cycle 1 Day 1 (Phase II)
Title
Assessment of metabolic response
Description
According to classical PERCIST criteria (30%) modified PERCIST criteria (15%) and the consistency classification
Time Frame
Until Cycle 2 Day 1 (cycle length is 28 days)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patients with confirmed BRAF V600 mutation-positive unresectable and/or metastatic malignant cutaneous melanoma, as determined locally by a validated test and treated with dabrafenib/trametinib first line combination therapy or second line after first line immunotherapy.
Patients that have progressed according to RECIST 1.1 after at least 4 weeks of treatment with dabrafenib/trametinib and remained on dabrafenib full dose (150mg bid) treatment for the study.
Measurable disease according to RECIST 1.1 criteria. For phase II only, metabolic measurable disease (according to PERCIST).
Availability of tissue from a metastatic lesion. A new biopsy is required unless inaccessible. An archival sample is accepted in that case after discussion with the sponsor.
ECOG Performance Status of 0 or 1.
Patients able to swallow and retain oral medication.
Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
For female patients of childbearing potential, a pregnancy test (serum) will be performed within 7 days before inclusion. Woman of childbearing potential must be willing to use one highly effective form of contraception during anticancer treatment and for at least six months thereafter. Men must agree to use condom during the course of this study and at least six months after the last administration of the study treatment and contraception should be considered for partner of childbearing potential.
Adequate organ system function.
Signed informed consent before any study specific procedure and/or treatment happens.
Exclusion Criteria:
Presence of uveal melanoma and/or other non-cutaneous melanomas.
Current use of a prohibited medication or need for any of these medications during treatment with study drug and within 28 days before the first administration of APR-246. I.e., no anti-cancer other than that given in this clinical trial, no immunotherapy, no hormonal cancer therapy, no radiation therapy (except palliative) and no experimental medications are permitted during the trial. All alternative therapies must first be approved by the sponsor. Supportive care therapies are allowed.
Unresolved toxicity greater than NCI-CTCAE(v4) Grade 1 from previous anti-cancer therapy except alopecia.
Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs.
Known HIV, active hepatitis B or hepatitis C infection.
Primary malignancy of the central nervous system.
History of familial long QT, serious ventricular arrhythmia (no VT > 130 bpm and > 5 extra beats per minute), no QTc ≥ 480 msec calculated from a single ECG reading or a mean of 3 ECG readings using Fridericia's correction (QTcF = QT/RR0.33) or bradycardia (< 45 bpm).
Untreated or symptomatic brain metastasis, leptomeningeal disease or spinal cord compression. Patients who are on a stable dose of corticosteroids > 1 month or off corticosteroids for 2 weeks can be enrolled.
History of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting, or thrombo-embolic event within the past 24 weeks from signature of ICF.
Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.
Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drugs, or excipients.
Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity.
Pregnant or lactating woman.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ahmad Awada, PhD
Organizational Affiliation
Jules Bordet Institute, Brussels, Belgium
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Joseph Kerger, MD
Organizational Affiliation
Jules Bordet Institute, Brussels, Belgium
Official's Role
Principal Investigator
Facility Information:
Facility Name
Institut Jules Bordet
City
Bruxelles
ZIP/Postal Code
1000
Country
Belgium
Facility Name
Universitair Ziekenhuis Antwerpen
City
Edegem
ZIP/Postal Code
2650
Country
Belgium
Facility Name
CHU UCL Namur - site Sainte-Elisabeth
City
Namur
ZIP/Postal Code
5000
Country
Belgium
12. IPD Sharing Statement
Citations:
PubMed Identifier
22965953
Citation
Lehmann S, Bykov VJ, Ali D, Andren O, Cherif H, Tidefelt U, Uggla B, Yachnin J, Juliusson G, Moshfegh A, Paul C, Wiman KG, Andersson PO. Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J Clin Oncol. 2012 Oct 10;30(29):3633-9. doi: 10.1200/JCO.2011.40.7783. Epub 2012 Sep 10.
Results Reference
background
PubMed Identifier
27421096
Citation
Deneberg S, Cherif H, Lazarevic V, Andersson PO, von Euler M, Juliusson G, Lehmann S. An open-label phase I dose-finding study of APR-246 in hematological malignancies. Blood Cancer J. 2016 Jul 15;6(7):e447. doi: 10.1038/bcj.2016.60. No abstract available.
Results Reference
background
Links:
URL
http://www.aprea.com/
Description
Aprea Therapeutics AB's website (Sponsor)
Learn more about this trial
A Study of APR-246 in Combination With Dabrafenib in Resistant Patients With BRAF V600 Mutant Melanoma
We'll reach out to this number within 24 hrs