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A Study of APR-246 in Combination With Dabrafenib in Resistant Patients With BRAF V600 Mutant Melanoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03391050
Recruitment Status : Terminated (Target patient population - difficult to find patientes)
First Posted : January 5, 2018
Last Update Posted : July 31, 2019
Jules Bordet Institute
Information provided by (Responsible Party):
Aprea Therapeutics

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.

Condition or disease Intervention/treatment Phase
Melanoma Drug: APR-246 Drug: Dabrafenib Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 3 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : January 18, 2018
Actual Primary Completion Date : August 8, 2018
Actual Study Completion Date : August 8, 2018

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma
Drug Information available for: Dabrafenib

Arm Intervention/treatment
Experimental: APR-246 + Dabrafenib Drug: APR-246
Intravenous infusion

Drug: Dabrafenib
Oral administration

Primary Outcome Measures :
  1. Phase Ib: Adverse Events (AEs) [ 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) ]
    Clinical and laboratory adverse events (AEs) and serious adverse events (SAEs) will be reported and graded

  2. Phase Ib: Dose Limiting Toxicities (DLTs) [ Time Frame: Until end of cycle 1 (cycle length is 28 days) ]
  3. Phase II: Objective response rate by RECIST1.1 [ Time Frame: Until progression (assessed up to 12 months) ]

Secondary Outcome Measures :
  1. Clinical benefit rate [ Time Frame: Until progression (assessed up to 12 months) ]
    Proportion of patients with a CR, PR or Stable Disease (SD) ≥ 4 months

  2. Duration of response [ Time Frame: Until progression (assessed up to 12 months) ]
  3. Progression free survival (PFS) [ Time Frame: Until progression (assessed up to 12 months) ]
  4. 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) ]
  5. 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) ]
  6. Maximum observed plasma concentration (Cmax) of APR-246 [ Time Frame: Until Cycle 1 Day 8 (Phase Ib) or Cycle 1 Day 1 (Phase II) ]
  7. 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) ]
  8. Assessment of metabolic response [ Time Frame: Until Cycle 2 Day 1 (cycle length is 28 days) ]
    According to classical PERCIST criteria (30%) modified PERCIST criteria (15%) and the consistency classification

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03391050

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Institut Jules Bordet
Bruxelles, Belgium, 1000
Universitair Ziekenhuis Antwerpen
Edegem, Belgium, 2650
CHU UCL Namur - site Sainte-Elisabeth
Namur, Belgium, 5000
Sponsors and Collaborators
Aprea Therapeutics
Jules Bordet Institute
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Study Chair: Ahmad Awada, PhD Jules Bordet Institute, Brussels, Belgium
Principal Investigator: Joseph Kerger, MD Jules Bordet Institute, Brussels, Belgium
Additional Information:
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Responsible Party: Aprea Therapeutics Identifier: NCT03391050    
Other Study ID Numbers: APR-633
First Posted: January 5, 2018    Key Record Dates
Last Update Posted: July 31, 2019
Last Verified: July 2019

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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
Keywords provided by Aprea Therapeutics:
Malignant melanoma
Skin cancer
Resistant cancer
Unresectable cancer
Metastatic cancer
BRAF mutant
Additional relevant MeSH terms:
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Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action