Clinical Trials /

Study of Ulixertinib for Patients With Advanced Malignancies Harboring MEK or Atypical BRAF Alterations

NCT04488003

Description:

This BVD-523-ABC study builds on the safety and clinical activity experience of previous studies that have evaluated ulixertinib as a novel targeted cancer treatment in cohorts of patients with specific genetic alterations and tumor histologies that result in aberrant MAPK pathway signaling. Early clinical data have demonstrated anti-tumor activity with ulixertinib treatment and have identified specific groups of patients for whom additional development is warranted.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Ulixertinib for Patients With Advanced Malignancies Harboring MEK or Atypical BRAF Alterations
  • Official Title: A Two-Part, Phase II, Multi-center Study of the ERK Inhibitor Ulixertinib (BVD-523) for Patients With Advanced Malignancies Harboring MEK or Atypical BRAF Alterations

Clinical Trial IDs

  • ORG STUDY ID: BVD-523-ABC
  • NCT ID: NCT04488003

Conditions

  • Advanced Solid Tumor
  • BRAF Gene Mutation
  • BRAF Gene Alteration
  • MEK Mutation
  • MEK Alteration
  • MAP2K1 Gene Mutation
  • MAP2K1 Gene Alteration
  • MAP2K2 Gene Mutation
  • MAP2K2 Gene Alteration

Interventions

DrugSynonymsArms
UlixertinibBVD-523, BVD523Part A: Ulixertinib
Physician's ChoicePart B: Physician's choice of treatment

Purpose

This BVD-523-ABC study builds on the safety and clinical activity experience of previous studies that have evaluated ulixertinib as a novel targeted cancer treatment in cohorts of patients with specific genetic alterations and tumor histologies that result in aberrant MAPK pathway signaling. Early clinical data have demonstrated anti-tumor activity with ulixertinib treatment and have identified specific groups of patients for whom additional development is warranted.

Detailed Description

      This multi-center, phase II study will be conducted in two parts and assess the clinical
      benefit, safety, pharmacokinetics, and pharmacodynamics of ulixertinib (BVD-523) in patients
      with advanced malignancies.

      Part A (tumor histology agnostic) will be open label and enroll patients to one of six groups
      based on their tumor alteration.

        -  Group 1: Patients with tumors, other than colorectal cancer (CRC), having a BRAF
           alteration that results in an amino acid change at positions G469, L485, or L597.

        -  Group 2: Patients with tumors, other than CRC, having a defined Class 2 BRAF alteration
           (see Appendix 2 of protocol).

        -  Group 3: Patients with tumors, other than CRC, having an atypical BRAF alteration (non
           V600) that is not specified in Group 1 or Group 2.

        -  Group 4: Patients with CRC having any atypical BRAF alteration.

        -  Group 5: Patients with tumors, other than CRC, harboring alterations in MEK1/2.

        -  Group 6: Patients with CRC harboring alterations in MEK1/2.

      Part B (tumor histology specific) will randomly enroll patients with one of up to three
      specified tumor histologies to receive either ulixertinib or the physician's choice of
      treatment in a 2:1 ratio. Tumors must harbor a specified MEK or atypical BRAF alteration. If
      a patient progresses on physician's choice of treatment, crossover to the ulixertinib arm is
      permitted.The specific histologies to be included in this part will be selected based on
      available data and discussion with the clinical investigators, the medical monitor, and the
      sponsor.
    

Trial Arms

NameTypeDescriptionInterventions
Part A: UlixertinibExperimentalOral, 600 mg, twice daily, for 28-days in each treatment cycle
  • Ulixertinib
Part B: UlixertinibExperimentalOral, 600 mg, twice daily, for 28-days in each treatment cycle
  • Ulixertinib
Part B: Physician's choice of treatmentExperimentalPhysician's choice will be restricted to two approved (not off-label) treatments for each tumor histology (agents targeting BRAF or MEK kinases and experimental agents are not permitted as physician choice). If a patient progresses on physician's choice of treatment, crossover to the ulixertinib arm is permitted.
  • Physician's Choice

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with a locally advanced or metastatic malignancy, that has progressed
             following systemic therapy for their disease, if available, or for which the patient
             is not a candidate or refuses.

          -  Tumors harboring a MEK or atypical BRAF alteration.

          -  Provide signed and dated informed consent prior to initiation of any study-related
             procedures that are not considered standard of care (SoC).

          -  Male or female patients aged ≥18 years.

          -  Patients must have measurable disease by RECIST version 1.1.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 2.

          -  Adequate renal function [creatinine ≤1.5 times ULN (upper limit of normal)] or a
             glomerular filtration rate (GFR) of ≥50 mL/min (using Cockcroft-Gault).

          -  Adequate hepatic function [total bilirubin ≤1.5 times ULN; AST (aspartate
             transaminase) and ALT (alanine transaminase) ≤3 times ULN or ≤5 times ULN if the
             elevation is due to liver involvement by tumor].

          -  Adequate bone marrow function (hemoglobin ≥9.0 g/dL; platelets ≥100 x 109 cells/L;
             absolute neutrophil count ≥1.5 x 109 cells/L).

          -  Adequate cardiac function: Left ventricular ejection fraction (LVEF) of >50% as
             assessed by multi-gated acquisition (MUGA) or ultrasound/echocardiography (ECHO); and
             a corrected QT interval (QTc) <480ms by the Fridericia method (QTcF).

          -  Contraception - women: Negative pregnancy test for females of child-bearing potential;
             must be surgically sterile, postmenopausal (no menstrual cycle for at least 12
             consecutive months), or compliant with a medically approved contraceptive regimen
             during and for 3 months after the last administration of study drug. Abstinence is not
             considered an adequate contraceptive regimen.

          -  Contraception - men: Must be surgically sterile, or compliant with a medically
             approved contraceptive regimen during and for 3 months after the last administration
             of study drug.

          -  Willing and able to participate in the trial and comply with all trial requirements.

          -  Patients with a prior or concurrent malignancy whose natural history or treatment does
             not have the potential to interfere with the safety or efficacy assessment of the
             investigational agent may be included after consultation with the medical monitor.

        Exclusion Criteria:

          -  Gastrointestinal (GI) condition that could impair absorption of study medication
             (specific cases e.g., remote history of GI surgery, may be enrolled after discussion
             with the medical monitor) or inability to ingest study medication.

          -  Uncontrolled or severe intercurrent medical condition.

          -  Known uncontrolled brain metastases. Stable brain metastases either treated or being
             treated with a stable dose of steroids/anticonvulsants, with no dose change in the
             previous 4 weeks, can be allowed.

          -  Having received any cancer-directed therapy (chemotherapy, hormonal therapy, biologic
             or immunotherapy, etc.) within 28 days or 5 half-lives (whichever is shorter) prior to
             the first dose of study drug. Patients previously treated with radiotherapy must have
             recovered from the acute toxicities associated with such treatment.

          -  Major surgery within 4 weeks prior to first dose.

          -  Any use of an investigational drug within 28 days or 5 half-lives (whichever is
             shorter) prior to the first dose of study drug. A minimum of 10 days between
             termination of the prior investigational drug and administration of study drug is
             required. In addition, any drug-related toxicity except alopecia should have recovered
             to Grade 1 or less.

          -  Prior therapy with any ERK inhibitor (e.g. LY3214996, LTT462).

          -  Groups 1-4: Prior therapy with any BRAF and/or MEK inhibitor (e.g. encorafenib,
             dabrafenib, vemurafenib, binimetinib, trametinib, cobimetinib) is excluded. Prior BRAF
             and/or MEK inhibitor therapy is permitted for Groups 5 and 6.

          -  For Part B, agents targeting BRAF or MEK kinases and experimental agents are not
             permitted as physician's choice

          -  Pregnant or breast-feeding women.

          -  Any evidence of serious active infections. Patients are allowed to enroll if they have
             been fever-free for at least 48 hours and are on an active treatment that is not
             prohibited in Appendix 1 of the protocol.

          -  Any important medical illness or abnormal laboratory finding that would increase the
             risk of participating in this study (based on the investigator's judgment).

          -  A history or current evidence/risk of retinal vein occlusion (RVO) or central serous
             retinopathy (CSR).

          -  Concurrent therapy with any other investigational agent.

          -  Concurrent therapy with drugs known to be strong inhibitors or inducers of CYP1A2,
             CYP2D6, and CYP3A4.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part A: Overall Response Rate (ORR) according to RECIST 1.1
Time Frame:Up to 30 months
Safety Issue:
Description:ORR will be defined as the percentage of patients achieving a Best Overall Response (BOR) of confirmed Complete Response (CR) and/or Partial Response (PR). Patients will be evaluated at baseline & at periodic follow-up visits through the time their participation in the study is complete.The best responses will occur at different time points for each patient.

Secondary Outcome Measures

Measure:Part A: Duration of Response (DOR) according to RECIST 1.1
Time Frame:Up to 30 months
Safety Issue:
Description:Time from first response to disease progression (DP) or death; assessed until DP, death, or initiation of subsequent anticancer therapy. Patients with no event will be censored at the last available tumor assessment.
Measure:Part A: Progression Free Survival (PFS) according to RECIST 1.1
Time Frame:18 months
Safety Issue:
Description:PFS will be defined as time from first day of study drug to disease progression or death. Patients with no event will be censored at the last available tumor assessment. This analysis will be based on investigator assessment.
Measure:Part A: Overall Survival (OS) according to RECIST 1.1
Time Frame:18 months
Safety Issue:
Description:OS will be defined as time from first day of study drug to death. Patients with no event will be censored at the last date the patient is known to be alive.
Measure:Part A: Cmax of BVD-523 at steady state
Time Frame:Single time point drawn at Visit 4/approximately day 15 (or whenever the patient reaches steady state).
Safety Issue:
Description:Single time point taken prior to taking study drug (trough) at steady state. Steady state is defined as patients who have received at least 5 days, or 10 consecutive doses, of study drug.
Measure:Part B: Overall Survival (OS) of ulixertinib compared to physician's choice of treatment
Time Frame:18 months
Safety Issue:
Description:OS will be defined time from first day of study drug to death. Patients with no event will be censored at the last date the patient is known to be alive.
Measure:Part B: Overall Response Rate (ORR) of ulixertinib compared to physician's choice of treatment, according to RECIST 1.1
Time Frame:Up to 30 months
Safety Issue:
Description:ORR will be defined as the percentage of patients achieving a Best Overall Response (BOR) of confirmed Complete Response (CR) and/or Partial Response (PR). Patients will be evaluated at baseline & at periodic follow-up visits through the time their participation in the study is complete.The best responses will occur at different time points for each patient.
Measure:Part B: Duration of Response (DOR) of ulixertinib compared to physician's choice of treatment, according to RECIST 1.1
Time Frame:Up to 30 months
Safety Issue:
Description:Time from first response to disease progression or death; assessed until DP, death, or initiation of subsequent anticancer therapy. Patients with no event will be censored at the last available tumor assessment.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:BioMed Valley Discoveries, Inc

Trial Keywords

  • atypical BRAF, non-V600

Last Updated

July 24, 2020