A Study to Evaluate Ulixertinib to Treat Patients with Advanced Malignancies Harboring MEK or Atypical BRAF Alterations

Overview

About this study

The purpose of this study is to evaluate 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.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

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 10^9 cells/L;
    • Absolute neutrophil count ≥ 1.5 x 10^9 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 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.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Scottsdale/Phoenix, Ariz.

Mayo Clinic principal investigator

Tanios Bekaii-Saab, M.D.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

Jacksonville, Fla.

Mayo Clinic principal investigator

Jeremy Jones, M.D.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

Rochester, Minn.

Mayo Clinic principal investigator

Wen Wee Ma, M.B.B.S.

Open for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

More information

Publications

  • Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF- and RAS-mutant cell lines. In this multicenter phase I trial (NCT01781429), 135 patients were enrolled to an accelerated 3 + 3 dose-escalation cohort and six distinct dose-expansion cohorts. Dose escalation included 27 patients, dosed from 10 to 900 mg twice daily and established the recommended phase II dose (RP2D) of 600 mg twice daily. Ulixertinib exposure was dose proportional to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108-patient expansion cohort, 32% of patients required dose reduction. The most common treatment-related adverse events were diarrhea (48%), fatigue (42%), nausea (41%), and dermatitis acneiform (31%). Partial responses were seen in 3 of 18 (17%) patients dosed at or above maximum tolerated dose and in 11 of 81 (14%) evaluable patients in dose expansion. Responses occurred in patients with -, V600-, and non-V600 -mutant solid tumors. Here, we describe the first-in-human dose-escalation study of an ERK1/2 inhibitor for the treatment of patients with advanced solid tumors. Ulixertinib has an acceptable safety profile with favorable pharmacokinetics and has shown early evidence of clinical activity in - and V600- and non-V600-mutant solid-tumor malignancies. . Read More on PubMed
  • Aberrant activation of signaling through the RAS-RAF-MEK-ERK (MAPK) pathway is implicated in numerous cancers, making it an attractive therapeutic target. Although BRAF and MEK-targeted combination therapy has demonstrated significant benefit beyond single-agent options, the majority of patients develop resistance and disease progression after approximately 12 months. Reactivation of ERK signaling is a common driver of resistance in this setting. Here we report the discovery of BVD-523 (ulixertinib), a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and ERK1/2 selectivity. BVD-523 treatment resulted in reduced proliferation and enhanced caspase activity in sensitive cells. Interestingly, BVD-523 inhibited phosphorylation of target substrates despite increased phosphorylation of ERK1/2. In xenograft studies, BVD-523 showed dose-dependent growth inhibition and tumor regression. BVD-523 yielded synergistic antiproliferative effects in a -mutant melanoma cell line xenograft model when used in combination with BRAF inhibition. Antitumor activity was also demonstrated in and models of acquired resistance to single-agent and combination BRAF/MEK-targeted therapy. On the basis of these promising results, these studies demonstrate BVD-523 holds promise as a treatment for ERK-dependent cancers, including those whose tumors have acquired resistance to other treatments targeting upstream nodes of the MAPK pathway. Assessment of BVD-523 in clinical trials is underway (NCT01781429, NCT02296242, and NCT02608229). . Read More on PubMed
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CLS-20506262

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