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

  • STATUS
    Recruiting
  • End date
    Aug 1, 2023
  • participants needed
    528
  • sponsor
    BioMed Valley Discoveries, Inc
Updated on 2 July 2021

Summary

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.

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.

Details
Condition Advanced Solid Tumor, BRAF Gene Mutation, Advanced Malignant Solid Tumor, MAP2K1 Gene Mutation, MAP2K2 Gene Mutation, BRAF Gene Alteration, MEK Mutation, MEK Alteration, MAP2K1 Gene Alteration, MAP2K2 Gene Alteration
Treatment Physician's choice, Ulixertinib
Clinical Study IdentifierNCT04488003
SponsorBioMed Valley Discoveries, Inc
Last Modified on2 July 2021

Eligibility

Yes No Not Sure

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
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