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

NCT03391050 | Terminated Phase 1 DMC

• 1 other identifier: APR-633
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 3

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.

Conditions

Melanoma

Keywords

Melanoma; Malignant melanoma; Skin cancer; Resistant cancer; Unresectable cancer; Metastatic cancer; BRAF mutant

Outcome Measures

Primary Outcomes (3)

• Phase Ib: Adverse Events (AEs)

  Clinical and laboratory adverse events (AEs) and serious adverse events (SAEs) will be reported and graded

  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)

• Phase Ib: Dose Limiting Toxicities (DLTs)

  Until end of cycle 1 (cycle length is 28 days)

• Phase II: Objective response rate by RECIST1.1

  Until progression (assessed up to 12 months)

Secondary Outcomes (8)

• Clinical benefit rate

  Until progression (assessed up to 12 months)

• Duration of response

  Until progression (assessed up to 12 months)

• Progression free survival (PFS)

  Until progression (assessed up to 12 months)

• Area under the plasma concentration versus time curve (AUC) for APR-246

  Until Cycle 1 Day 8 (Phase Ib) or Cycle 1 Day 1 (Phase II)

• Plasma drug concentration at a specified time t (Ct) for APR-246

  Until Cycle 1 Day 8 (Phase Ib) or Cycle 1 Day 1 (Phase II)

Study Arms (1)

APR-246 + Dabrafenib

EXPERIMENTAL

Drug: APR-246; Drug: Dabrafenib

Interventions

APR-246 DRUG

Intravenous infusion

APR-246 + Dabrafenib

Dabrafenib DRUG

Oral administration

APR-246 + Dabrafenib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Adequate organ system function.
• Signed informed consent before any study specific procedure and/or treatment happens.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Aprea Therapeutics: lead
• Jules Bordet Institute: collaborator

Study Sites (3)

Institut Jules Bordet

Brussels, 1000, Belgium

Location

Universitair Ziekenhuis Antwerpen

Edegem, 2650, Belgium

Location

CHU UCL Namur - site Sainte-Elisabeth

Namur, 5000, Belgium

Location

Related Publications (2)

• 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.

  PMID: 22965953 BACKGROUND

• 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.

  PMID: 27421096 BACKGROUND

Related Links

• Aprea Therapeutics AB's website (Sponsor)

MeSH Terms

Conditions

Melanoma; Skin Neoplasms; Neoplasm Metastasis

Interventions

eprenetapopt; dabrafenib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Ahmad Awada, PhD

  Jules Bordet Institute, Brussels, Belgium

  STUDY CHAIR

• Joseph Kerger, MD

  Jules Bordet Institute, Brussels, Belgium

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 19, 2017
• First Posted: January 5, 2018
• Study Start: January 18, 2018
• Primary Completion: August 8, 2018
• Study Completion: August 8, 2018
• Last Updated: July 31, 2019

Record last verified: 2019-07

Locations

BE (3)