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

NCT04488003 | Terminated Phase 2 Results FDA Drug

• 1 other identifier: BVD-523-ABC
• Study Type: interventional
• Target: 104
• Locations: 1 country
• Sites: 22

Brief 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.

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

Keywords

atypical BRAF, non-V600

Outcome Measures

Primary Outcomes (1)

• Part A: Overall Response Rate (ORR) According to RECIST 1.1

  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.

  Up to 25 months

Secondary Outcomes (3)

• Part A: Progression Free Survival (PFS) According to RECIST 1.1

  18 months

• Part A: Overall Survival (OS) According to RECIST 1.1

  18 months

• Part A: Pharmacokinetic Concentration of BVD-523 at Steady State

  Single time point drawn at Visit 4/approximately day 15 (or whenever the patient reaches steady state).

Study Arms (3)

Part A: Ulixertinib

EXPERIMENTAL

Oral, 600 mg, twice daily, for 28-days in each treatment cycle

Drug: Ulixertinib

Part B: Ulixertinib

EXPERIMENTAL

Oral, 600 mg, twice daily, for 28-days in each treatment cycle

Drug: Ulixertinib

Part B: Physician's choice of treatment

EXPERIMENTAL

Physician'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.

Drug: Physician's Choice

Interventions

Ulixertinib DRUG

Oral, 600 mg, twice daily, for 28-days in each treatment cycle

Also known as: BVD-523, BVD523

Part A: Ulixertinib; Part B: Ulixertinib

Physician's Choice DRUG

Physician'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)).

Part B: Physician's choice of treatment

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• BioMed Valley Discoveries, Inc: lead

Study Sites (22)

Mayo Clinic

Phoenix, Arizona, 85054, United States

Location

Hoag Memorial Hospital Presbyterian

Newport Beach, California, 92663, United States

Location

Christiana Care Health Services / Helen F. Graham Cancer Center

Newark, Delaware, 19713, United States

Location

Johns Hopkins Sibley Memorial Hospital

Washington D.C., District of Columbia, 20016, United States

Location

University of Florida

Gainesville, Florida, 32610, United States

Location

Mayo Clinic

Jacksonville, Florida, 32224, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Metro-Minnesota Community Oncology Research Consortium (MMCORC)

Saint Louis Park, Minnesota, 55416, United States

Location

Washington University School of Medicine - Siteman Cancer Center

St Louis, Missouri, 63110, United States

Location

Columbia University Irving Medical Center

New York, New York, 10032, United States

Location

Montefiore Medical Center

The Bronx, New York, 10461, United States

Location

Duke University Medical Center / Duke Cancer Institute

Durham, North Carolina, 27710, United States

Location

Kettering Cancer Center

Kettering, Ohio, 45429, United States

Location

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, 15213, United States

Location

Avera Cancer Institute

Sioux Falls, South Dakota, 57105, United States

Location

Tennessee Oncology, PLLC - Sarah Cannon (SCRI)

Nashville, Tennessee, 37203, United States

Location

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Virginia Cancer Specialists, PC

Fairfax, Virginia, 22031, United States

Location

University of Washington/Seattle Cancer Care Alliance

Seattle, Washington, 98109, United States

Location

University of Wisconsin Clinical Science Center

Madison, Wisconsin, 53792, United States

Location

Marshfield Medical Center

Marshfield, Wisconsin, 54449, United States

Location

Related Publications (2)

• Germann UA, Furey BF, Markland W, Hoover RR, Aronov AM, Roix JJ, Hale M, Boucher DM, Sorrell DA, Martinez-Botella G, Fitzgibbon M, Shapiro P, Wick MJ, Samadani R, Meshaw K, Groover A, DeCrescenzo G, Namchuk M, Emery CM, Saha S, Welsch DJ. Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib). Mol Cancer Ther. 2017 Nov;16(11):2351-2363. doi: 10.1158/1535-7163.MCT-17-0456. Epub 2017 Sep 22.

  PMID: 28939558 BACKGROUND

• Sullivan RJ, Infante JR, Janku F, Wong DJL, Sosman JA, Keedy V, Patel MR, Shapiro GI, Mier JW, Tolcher AW, Wang-Gillam A, Sznol M, Flaherty K, Buchbinder E, Carvajal RD, Varghese AM, Lacouture ME, Ribas A, Patel SP, DeCrescenzo GA, Emery CM, Groover AL, Saha S, Varterasian M, Welsch DJ, Hyman DM, Li BT. First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study. Cancer Discov. 2018 Feb;8(2):184-195. doi: 10.1158/2159-8290.CD-17-1119. Epub 2017 Dec 15.

  PMID: 29247021 BACKGROUND

Related Links

• BioMed Valley Discoveries

MeSH Terms

Interventions

ulixertinib

Limitations and Caveats

Early termination leading to small numbers of patients analyzed.

Results Point of Contact

• Title: Caroline Emery, PhD
• Organization: Biomed Valley Discoveries

cemery@biomed-valley.com

816-960-4615

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: July 17, 2020
• First Posted: July 27, 2020
• Study Start: January 7, 2021
• Primary Completion: February 15, 2023
• Study Completion: May 23, 2023
• Last Updated: June 4, 2024
• Results First Posted: June 4, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (22)