Encorafenib + Binimetinib + Pembrolizumab in Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma

NCT02902042 | Completed Phase 1

• 1 other identifier: IST-818-201X
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 11

Brief Summary

This study will investigate the influence of maintenance therapy on progression-free survival (PFS) and overall survival (OS) after combination therapy with BRAF/MEK (MAP-ERK kinase) inhibitors and PD-1 antibody pembrolizumab. In the safety phase I part the optimal dose of pembrolizumab in combination with BRAF inhibitor and MEK inhibitor and the safety of this three-drugs-combination regime will be determined. In the randomized part 2 different maintenance therapies will be tested for toxicity and efficacy. Patients with disease control after 6 months of triple therapy will be randomized to receive 2 different maintenance therapies further on, either continuation of triple therapy or administration of pembrolizumab alone.

Conditions

Malignant Melanoma

Keywords

Unresectable or metastatic BRAF V600 mutant melanoma; Encorafenib, binimetinib, pembrolizumab

Outcome Measures

Primary Outcomes (5)

• Phase I: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability of the triple combination treatment]

  Dose limiting toxicities (DLT) will be determined within 42 days of therapy start (first pembrolizumab injection) and are defined as all ≥ grade 4 hematological toxicities and certain non-hematological toxicities ≥ CTCAE grade 3.

  42 days

• Phase II: Progression-free survival (PFS)

  Time from administration of first study drug to the date of first documented progression (according Recist criteria version 1.1) or death due to any cause, whichever occurs first.

  24 months

• Phase II: PFS rate at 12 months

  Rate of patients with PFS after 12 months of therapy

  12 months

• Phase II: PFS rate at 18 months

  Rate of patients with PFS after 18 months of therapy

  18 months

• Phase II: PFS rate at 24 months

  Number of patients with PFS after 24 months of therapy

  24 months

Secondary Outcomes (5)

• Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]

  24 months

• Objective response rate

  24 months

• Overall survival time

  24 months

• 1-year survival rate

  12 months

• 2-year survival rate

  24 months

Study Arms (2)

Arm A: Triple therapy

EXPERIMENTAL

Encorafenib, binimetinib and pembrolizumab. Doses as determined in phase I

Drug: Encorafenib; Drug: Binimetinib; Drug: Pembrolizumab

Arm B: Pembrolizumab alone

EXPERIMENTAL

Pembrolizumab with a dose of 200 mg every 3 weeks.

Drug: Pembrolizumab alone

Interventions

Encorafenib DRUG

Dose determined in phase I. Start dose: 450 mg qd

Also known as: Braftovi

Arm A: Triple therapy

Binimetinib DRUG

Dose determined in phase I. Start dose: 45 mg bid

Also known as: Mektovi

Arm A: Triple therapy

Pembrolizumab DRUG

Dose determined in phase I. Start dose: 200 mg q3w

Also known as: Keytruda

Arm A: Triple therapy

Pembrolizumab alone DRUG

200 mg q3w

Also known as: Keytruda

Arm B: Pembrolizumab alone

Eligibility Criteria

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

You may qualify if:

• Willing and able to provide written informed consent/assent for the trial.
• Being ≥ 18 years of age on day of signing informed consent.
• Histologically confirmed diagnosis of locally advanced, unresectable or metastatic melanoma AJCC (2017) Stage IIIB, IIIC, IIID or IV with no active brain metastasis. All known CNS lesions must have been only treated with stereotactic therapy or surgery at least 4 weeks prior to the first dose of trial treatment AND they are stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline); there is no evidence of new or enlarging brain metastases, and the patient must not have used steroids in dosing exceeding 10 mg daily of prednisone equivalent for at least 3 weeks prior to trial treatment.
• Treatment naive patient for locally advanced unresectable or metastatic melanoma. Prior adjuvant or neoadjuvant systemic therapy is permitted (in stage II, III and IV with no evidence of disease) if all related adverse events have either returned to baseline or stabilized.
• (i) Anti-PD-1, anti-CTLA-4, BRAF/MEK inhibitor therapy with at least 6 months between the last dose and date of recurrence.
• (ii) Interferon therapy and chemotherapy with the last dose at least 6 weeks prior to registration.
• (iii) Radiotherapy with the last radiation at least 28 days prior to registration. Participants must have recovered from all radiation-related toxicities. Note: radiated lesions cannot be used as measurable lesions unless there is clear evidence of progression.
• Patients who are in follow-up period of a clinical trial in adjuvant setting may be enrolled.
• Measurable disease, i.e., present with at least one measurable lesion per RECIST, version 1.1, for the definition of a measureable lesion.
• Presence of BRAF mutation V600 in tumor tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion prior to enrollment.
• Performance status of 0 or 1 on the ECOG Performance Scale.
• Adequate organ function: ANC ≥1,500 /mcL, Platelets ≥100,000 / mcL, Hemoglobin ≥9 g/dL OR ≥5.6 mmol/L, Serum creatinine OR Measured or calculated CrCl ≤1.5 X ULN OR ≥50 mL/min for subject with creatinine levels \> 1.5 X institutional ULN, Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN, AST and ALT ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases.
• Adequate cardiac function:
• LVEF ≥ 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram
• Corrected QT (QTc) interval ≤ 480ms

You may not qualify if:

• Currently participating in or having participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
• Diagnosis of immunodeficiency or receiving systemic steroid therapy in dosing exceeding 10 mg daily of prednisone equivalent or any other form of immunosuppressive therapy within 7 days prior to study Day 1.
• Prior therapy (except if given as adjuvant or neoadjuvant therapy for melanoma) with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti-CTLA-4 antibody or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways (except for interferon given as adjuvant or neoadjuvant therapy for melanoma).
• Prior therapy (except if given as adjuvant or neoadjuvant therapy for melanoma) with a BRAF inhibitor (including but not limited to vemurafenib, dabrafenib, encorafenib) and / or MEK inhibitor (including but not limited to trametinib, AZD6244, binimetinib, cobimetinib).
• Any previous anti-cancer treatment, extensive radiotherapy or investigational agent for locally advanced unresectable or metastatic melanoma.
• Known additional malignancy that is progressing or required active treatment within 3 years prior to the study.
• Known active CNS metastases and/or carcinomatous meningitis.
• Presence of uveal melanoma.
• History of leptomeningeal metastases.
• History or current evidence of CSR or RVO or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus, history of hyperviscosity or hypercoagulability syndromes).
• History of retinal degenerative disease.
• History of allogeneic bone marrow transplantation or organ transplantation.
• History of Gilbert's syndrome.
• Uncontrolled arterial hypertension despite medical treatment.
• Patients who have neuromuscular disorders associated with elevated creatine kinase (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).

Sponsors & Collaborators

• Prof. Dr. med. Dirk Schadendorf: lead

Study Sites (11)

Universitätsklinikum Freiburg

Freiburg im Breisgau, Baden-Wurttemberg, 79106, Germany

Location

Klinikum Augsburg Süd

Augsburg, Bavaria, 86179, Germany

Location

Klinikum rechts der Isar

München, Bavaria, 81675, Germany

Location

Klinikum Nürnberg Nord

Nuremberg, Bavaria, 90419, Germany

Location

Universitätsklinikum Gießen und Marburg GmbH, Klinik für Dermatologie und Allergologie

Giessen, Hesse, 35392, Germany

Location

Universitätsklinikum der RWTH Aachen

Aachen, North Rhine-Westphalia, 52074, Germany

Location

University Hospital Essen, Department of Dermatology, Skin Cancer Center

Essen, North Rhine-Westphalia, 45122, Germany

Location

HELIOS Klinikum Krefeld

Krefeld, North Rhine-Westphalia, 47805, Germany

Location

Gesellschaft für Klinische Forschung Ludwigshafen mbH

Ludwigshafen am Rhein, Rhineland-Palatinate, 67063, Germany

Location

Städtisches Klinikum Dessau

Dessau, Saxony-Anhalt, 06847, Germany

Location

Vivantes Klinikum im Friedrichshain

Friedrichshain, State of Berlin, 10249, Germany

Location

Related Publications (1)

• Zimmer L, Livingstone E, Krackhardt A, Schultz ES, Goppner D, Assaf C, Trebing D, Stelter K, Windemuth-Kieselbach C, Ugurel S, Schadendorf D. Encorafenib, binimetinib plus pembrolizumab triplet therapy in patients with advanced BRAFV600 mutant melanoma: safety and tolerability results from the phase I IMMU-TARGET trial. Eur J Cancer. 2021 Nov;158:72-84. doi: 10.1016/j.ejca.2021.09.011. Epub 2021 Oct 13.

  PMID: 34655839 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

encorafenib; binimetinib; pembrolizumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Study Officials

• Dirk Schadendorf, Prof. Dr.

  University Hospital, Essen

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. Dr. med.

Study Record Dates

• First Submitted: September 12, 2016
• First Posted: September 15, 2016
• Study Start: April 24, 2018
• Primary Completion: November 30, 2020
• Study Completion: November 30, 2020
• Last Updated: February 16, 2021

Record last verified: 2021-02

Data Sharing

• IPD Sharing: Will not share

Locations

DE (11)