Encorafenib + Binimetinib + Pembrolizumab in Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma (IMMU-TARGET)

A Randomized Phase I / II Open Label, Multicentre Study of Encorafenib Plus Binimetinib and PD-1 Antibody Pembrolizumab in Patients With Unresectable or Metastatic BRAF V600 Mutant Melanoma

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.

Study Overview

• Status: Completed
• Conditions: Malignant Melanoma
• Intervention / Treatment: Drug: Encorafenib; Drug: Binimetinib; Drug: Pembrolizumab; Drug: Pembrolizumab alone

Detailed Description

There is growing interest to understand the best strategies to use targeted therapies and novel immunotherapy for the treatment of advanced melanoma. This study will explore the combination of encorafenib plus binimetinib with the PD-1 antibody pembrolizumab in patients with BRAF mutant melanoma. Combination of two clinically effective approaches, targeting the mutant BRAF pathway by BRAF/MEK inhibition and modulating immunological checkpoint control by administration of a PD-1 antibody, should prolong PFS and OS even further. This study will investigate the influence of maintenance therapy on PFS and OS after triple therapy. Patients with disease control after 6 months of triple therapy will be randomized to receive 2 different maintenance therapies further on to investigate if administration of pembrolizumab only is sufficient for maintenance of disease control. For reasons of safety a phase I study is performed to determine the optimal dosing and schedule of the combination therapy (encorafenib, binimetinib, pembrolizumab).

In the phase II-part, patient will receive triple therapy with the doses defined in phase I for a 6 months induction period. Patients with complete or partial response or stable disease after the 6 months period will be randomized for maintenance therapy:

Arm A: Therapy as in induction period. Arm B: Therapy with pembrolizumab only with a dose of 200 mg every 3 weeks.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Baden-Württemberg
    • Freiburg, Baden-Württemberg, Germany, 79106
      • Universitatsklinikum Freiburg
  • Bavaria
    • Augsburg, Bavaria, Germany, 86179
      • Klinikum Augsburg Süd
    • München, Bavaria, Germany, 81675
      • Klinikum rechts der Isar
    • Nürnberg, Bavaria, Germany, 90419
      • Klinikum Nurnberg Nord
  • Berlin
    • Berlin Friedrichshain, Berlin, Germany, 10249
      • Vivantes Klinikum Im Friedrichshain
  • Hessen
    • Gießen, Hessen, Germany, 35392
      • Universitatsklinikum Giessen und Marburg GmbH, Klinik fur Dermatologie und Allergologie
  • Nordrhein-Westfalen
    • Aachen, Nordrhein-Westfalen, Germany, 52074
      • Universitatsklinikum der RWTH Aachen
  • North Rhine-Westphalia
    • Essen, North Rhine-Westphalia, Germany, 45122
      • University Hospital Essen, Department of Dermatology, Skin Cancer Center
    • Krefeld, North Rhine-Westphalia, Germany, 47805
      • Helios Klinikum Krefeld
  • Rheinland-Pfalz
    • Ludwigshafen am Rhein, Rheinland-Pfalz, Germany, 67063
      • Gesellschaft für Klinische Forschung Ludwigshafen mbH
  • Saxony-Anhalt
    • Dessau, Saxony-Anhalt, Germany, 06847
      • Städtisches Klinikum Dessau

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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
• All treatment-related toxicities of prior adjuvant or neoadjuvant systemic therapy (except alopecia) must be ≤ Grade 1 according to the CTCAE version 4.03:
• Able to take oral medications.
• Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication.
• Female patients of childbearing potential and male patients with partners of childbearing potential must agree to always use a highly effective form of contraception according to CTFG starting with the first dose of study therapy during the course of this study and for at least 120 days after the last dose of study medication

Exclusion Criteria:

• 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).
• Impairment of gastrointestinal function or gastrointestinal disease (e.g. ulcerative disease, uncontrolled nausea, vomiting, malabsorption syndrome, small bowel resection).
• Evidence of interstitial lung disease or active, non-infectious pneumonitis or history of (non-infectious) pneumonitis that required steroids.
• Active infection requiring systemic therapy.
• Pregnancy or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit until up to 120 days after the last dose of trial treatment.
• Positive test for HIV.
• Positive test for Hep B or Hep C.
• Receiving a live vaccine within 30 days prior to the first dose of trial treatment.
• Known hypersensitivity reaction to any of the components of study treatment.
• Medical, psychiatric, cognitive or other conditions, including known alcohol or drug abuse that would not permit the subject to complete the study or sign informed consent.
• Patients taking non-topical medication known to be a strong inhibitor of CYP3A4.
• History of life-threatening toxicity related to prior immune therapy (e.g. anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) or kinase inhibition (e.g. BRAF and/or MEK inhibitor) except those that are unlikely to re-occur with standard countermeasures (e.g. hormone replacement after adrenal crisis).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: Triple therapy; Encorafenib, binimetinib and pembrolizumab. Doses as determined in phase I	Drug: Encorafenib; Dose determined in phase I. Start dose: 450 mg qd; Other Names: Braftovi; Drug: Binimetinib; Dose determined in phase I. Start dose: 45 mg bid; Other Names: Mektovi; Drug: Pembrolizumab; Dose determined in phase I. Start dose: 200 mg q3w; Other Names: Keytruda
Experimental: Arm B: Pembrolizumab alone; Pembrolizumab with a dose of 200 mg every 3 weeks.	Drug: Pembrolizumab alone; 200 mg q3w; Other Names: Keytruda

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	All adverse events (AEs) / serious adverse events (SAEs) NCI CTCEA (Common Terminology Criteria for Adverse Events) Grade ≥ 3	24 months
Objective response rate	Number of patients with complete response (CR), partial response (PR) and stable disease (SD) as best response.	24 months
Overall survival time	Time from the date of first administration of study drug to the date of death due to any cause.	24 months
1-year survival rate	Number of patients alive in the time period from date of first administration of study drug until 1 year after date of first administration	12 months
2-year survival rate	Number of patients alive in the time period from date of first administration of study drug until 2 years after date of first administration	24 months

Collaborators and Investigators

• Sponsor: Prof. Dr. med. Dirk Schadendorf
• Investigators: Principal Investigator: Dirk Schadendorf, Prof. Dr., University Hospital, Essen

Publications and helpful links

General Publications

• 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 Oct 13;158:72-84. doi: 10.1016/j.ejca.2021.09.011. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): April 24, 2018
• Primary Completion (Actual): November 30, 2020
• Study Completion (Actual): November 30, 2020

Study Registration Dates

• First Submitted: September 12, 2016
• First Submitted That Met QC Criteria: September 12, 2016
• First Posted (Estimate): September 15, 2016

Study Record Updates

• Last Update Posted (Actual): February 16, 2021
• Last Update Submitted That Met QC Criteria: February 13, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Unresectable or metastatic BRAF V600 mutant melanoma; Encorafenib, binimetinib, pembrolizumab
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Antineoplastic Agents; Antineoplastic Agents, Immunological; Pembrolizumab
• Other Study ID Numbers: IST-818-201X

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No