Phase I Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of BVD-523 in Patients With Advanced Malignancies

NCT01781429 | Completed Phase 1 Results DMC

• 1 other identifier: BVD-523-01
• Study Type: interventional
• Target: 136
• Locations: 1 country
• Sites: 9

Brief Summary

This open-label, multi-center Phase 1/2 study will assess the safety, pharmacokinetics, and pharmacodynamics of escalating doses of BVD-523 in patients with advanced malignancies. The study also seeks to demonstrate target modulation and early signs of clinical response in select patient populations.

Conditions

Advanced Solid Tumors

Outcome Measures

Primary Outcomes (1)

• Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT).

  DLT is defined as any BVD-523 related toxicity in the first 21 days of treatment that results in: 1. ≥Grade 4 hematologic toxicity for \>1 day; 2. Grade 3 hematologic toxicity with complications e.g., thrombocytopenia with bleeding; 3. ≥Grade 3 non-hematologic toxicity, except untreated nausea, vomiting, constipation, pain and rash (these become DLTs if the adverse event (AE) persists despite adequate treatment), a doubling of aspartate transaminase (AST)/alanine transaminase (ALT) in patients with grade 2 ALT/AST at baseline; 4. A treatment interruption exceeding 5 days (or an interruption exceeding 7 days for rash, despite adequate treatment) in Cycle 1 (or inability to begin Cycle 2 for \> 7 days) due to BVD-523-related toxicity.

  As indicated by safety and tolerability during study conduct; ~42 months

Secondary Outcomes (2)

• Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites.

  Samples will be collected on day 1 and day 15 of Cycle 1

• Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam.

  Patients will be evaluated at baseline & at periodic follow-up visits through the time their participation in the study is completion. The best responses presented occurred at different time points for each patient.

Other Outcomes (1)

• Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK)

  Patients will be evaluated at baseline and on ~day 15 of Cycle 1

Study Arms (1)

BVD-523

EXPERIMENTAL

Drug: BVD-523

Interventions

BVD-523 DRUG

Oral, multiple escalating doses, twice daily, for 21 days in each treatment cycle

BVD-523

Eligibility Criteria

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

You may qualify if:

• Patients with metastatic or advanced-stage malignant tumor. Patients may have received up to 2 prior lines of chemotherapy for their metastatic disease
• ECOG score of 0 or 1
• Predicted life expectancy of ≥ 3 months
• Adequate bone marrow, liver and renal function renal function
• Adequate cardiac function
• For women: Negative pregnancy test for females of child-bearing potential; must be surgically sterile, postmenopausal, or compliant with a contraceptive regimen during and for 3 months after the treatment period
• For men: Must be surgically sterile, or compliant with a contraceptive regimen during and for 3 months after the treatment period
• For Part 2 of the Study only, patients must have measurable disease by RECIST 1.1 and be in one of the the groups below. Patients in groups 1, 2, 4, 5 and 6 may not have been previously treated with BRAF and/or MEK inhibitors
• Group 1: Patients with BRAF mutated cancer, except those with colorectal or non-small cell lung cancers
• Group 2: Patients with BRAF mutated colorectal cancer
• Group 3: Patients with BRAF mutated melanoma who have progressed on, or are refractory to BRAF and/or MEK inhibitors
• Group 4: Patients with NRAS mutated melanoma
• Group 5: Patients with MEK mutated cancer
• Group 6: Patients with BRAF mutated non-small cell lung cancer
• Group 7: Patients with ERK mutated cancer

You may not qualify if:

• Gastrointestinal condition which could impair absorption of 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
• Any cancer-directed therapy (chemotherapy, radiotherapy, hormonal therapy, biologic or immunotherapy, etc.) within 28 days or 5 half-lives, whichever is shorter
• 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 BVD-523.
• Pregnant or breast-feeding women
• Any evidence of serious active infections
• Any important medical illness or abnormal laboratory finding that would increase the risk of participating in this study
• A history or current evidence/risk of retinal vein occlusion or central serous retinopathy
• Concurrent therapy with any other investigational agent
• Concomitant malignancies or previous malignancies with less than 2 years disease-free interval at the time of enrollment

Sponsors & Collaborators

• BioMed Valley Discoveries, Inc: lead

Study Sites (9)

UCLA Med-Hematology & Oncology

Los Angeles, California, 90095, United States

Location

Yale Cancer Center

New Haven, Connecticut, 06520, United States

Location

Florida Cancer Specialists and Research Group (Sarah Cannon Research Institute)

Sarasota, Florida, 34232, United States

Location

Massachusetts General Hospital (MGH)

Boston, Massachusetts, 02114, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

Sarah Cannon Research Institute Hospital at Vanderbilt

Nashville, Tennessee, 37203, United States

Location

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, 37212, United States

Location

UT M.D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (3)

• Wu J, Liu D, Offin M, Lezcano C, Torrisi JM, Brownstein S, Hyman DM, Gounder MM, Abida W, Drilon A, Harding JJ, Sullivan RJ, Janku F, Welsch D, Varterasian M, Groover A, Li BT, Lacouture ME. Characterization and management of ERK inhibitor associated dermatologic adverse events: analysis from a nonrandomized trial of ulixertinib for advanced cancers. Invest New Drugs. 2021 Jun;39(3):785-795. doi: 10.1007/s10637-020-01035-9. Epub 2021 Jan 3.

  PMID: 33389388 DERIVED

• Mendzelevski B, Ferber G, Janku F, Li BT, Sullivan RJ, Welsch D, Chi W, Jackson J, Weng O, Sager PT. Effect of ulixertinib, a novel ERK1/2 inhibitor, on the QT/QTc interval in patients with advanced solid tumor malignancies. Cancer Chemother Pharmacol. 2018 Jun;81(6):1129-1141. doi: 10.1007/s00280-018-3564-1. Epub 2018 Mar 30.

  PMID: 29603015 DERIVED

• 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 DERIVED

MeSH Terms

Interventions

ulixertinib

Results Point of Contact

• Title: Brent Kreider, PhD
• Organization: BioMed Valley Discoveries

bkreider@biomed-valley.com

816-960-4644

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 28, 2013
• First Posted: February 1, 2013
• Study Start: March 1, 2013
• Primary Completion: February 1, 2018
• Study Completion: September 1, 2018
• Last Updated: March 20, 2020
• Results First Posted: March 20, 2020

Record last verified: 2020-03

Locations

US (9)