Clinical trial NCT01781429: Phase I Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of BVD-523 in Patients With Advanced Malignancies
Official title: Phase I Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of BVD-523 in Patients With Advanced Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Advanced Solid Tumors
Lead sponsor: BioMed Valley Discoveries, Inc
Sponsor class: INDUSTRY
First posted: 2013-02-01
Enrollment: 136
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Detailed description: The study is being performed to assess the safety and tolerability of BVD-523

In Part 1 of the study, an accelerated dose escalation plan will be used to establish dose limiting toxicities, maximum tolerated dose, and the recommended Phase 2 dose.

In Part 2 of the study, additional patients with particular tumor types and/or cancers harboring specific genetic mutations will be recruited for treatment at the Recommended Phase 2 Dose. Patients may also be assessed pharmacodynamic measures in healthy or malignant tissues, using biomarker assays for phosphorylation, cytotoxic or cytostatic measures.

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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

Primary outcomes:
measure: Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT).
timeFrame: As indicated by safety and tolerability during study conduct; ~42 months
Secondary outcomes:
measure: Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites.
timeFrame: Samples will be collected on day 1 and day 15 of Cycle 1
measure: Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam.
timeFrame: 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:
measure: Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK)
timeFrame: Patients will be evaluated at baseline and on ~day 15 of Cycle 1
Locations:
city: Los Angeles
country: United States
facility: UCLA Med-Hematology & Oncology
state: California
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Sarasota
country: United States
facility: Florida Cancer Specialists and Research Group (Sarah Cannon Research Institute)
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital (MGH)
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Nashville
country: United States
facility: Sarah Cannon Research Institute Hospital at Vanderbilt
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Houston
country: United States
facility: UT M.D Anderson Cancer Center
state: Texas
Study officials:
References:
citation: 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.
citation: 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.
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.