Clinical trial NCT04488003: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
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
Lead sponsor: BioMed Valley Discoveries, Inc
Sponsor class: INDUSTRY
First posted: 2020-07-27
Enrollment: 104
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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. Targeted enrollment per group was 38 patients with a total targeted enrollment of 228 patients. Actual enrollment was total of 104 patients with 77 patients allocated to treatment.

* 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. Total enrollment was targeted to approximately 80-100 patients per histology with up to three histologies included; however, the study was terminated prior to any patients enrolling in Part B.

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.

Primary outcomes:
measure: Part A: Overall Response Rate (ORR) According to RECIST 1.1
timeFrame: Up to 25 months
Secondary outcomes:
measure: Part A: Progression Free Survival (PFS) According to RECIST 1.1
timeFrame: 18 months
measure: Part A: Overall Survival (OS) According to RECIST 1.1
timeFrame: 18 months
measure: Part A: Pharmacokinetic Concentration of BVD-523 at Steady State
timeFrame: Single time point drawn at Visit 4/approximately day 15 (or whenever the patient reaches steady state).
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Mayo Clinic
state: Arizona
city: Newport Beach
country: United States
facility: Hoag Memorial Hospital Presbyterian
state: California
city: Newark
country: United States
facility: Christiana Care Health Services / Helen F. Graham Cancer Center
state: Delaware
city: Washington
country: United States
facility: Johns Hopkins Sibley Memorial Hospital
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis Park
country: United States
facility: Metro-Minnesota Community Oncology Research Consortium (MMCORC)
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine - Siteman Cancer Center
state: Missouri
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center / Duke Cancer Institute
state: North Carolina
city: Kettering
country: United States
facility: Kettering Cancer Center
state: Ohio
city: Pittsburgh
country: United States
facility: UPMC Hillman Cancer Center
state: Pennsylvania
city: Sioux Falls
country: United States
facility: Avera Cancer Institute
state: South Dakota
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC - Sarah Cannon (SCRI)
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Seattle
country: United States
facility: University of Washington/Seattle Cancer Care Alliance
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Clinical Science Center
state: Wisconsin
city: Marshfield
country: United States
facility: Marshfield Medical Center
state: Wisconsin
Study officials:
References:
citation: 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.
citation: 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.