Phase I Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of BVD-523 in Patients With Advanced Malignancies
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT01781429|
Recruitment Status : Completed
First Posted : February 1, 2013
Results First Posted : March 20, 2020
Last Update Posted : March 20, 2020
|Condition or disease||Intervention/treatment||Phase|
|Advanced Solid Tumors||Drug: BVD-523||Phase 1 Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||136 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of BVD-523 in Patients With Advanced Malignancies|
|Actual Study Start Date :||March 2013|
|Actual Primary Completion Date :||February 2018|
|Actual Study Completion Date :||September 2018|
Oral, multiple escalating doses, twice daily, for 21 days in each treatment cycle
- Determination of Recommended Phase 2 Dose (RP2D) of BVD-523 by Dose-limiting Toxicities (DLT). [ Time Frame: As indicated by safety and tolerability during study conduct; ~42 months ]
DLT is defined as any BVD-523 related toxicity in the first 21 days of treatment that results in:
- ≥Grade 4 hematologic toxicity for >1 day;
- Grade 3 hematologic toxicity with complications e.g., thrombocytopenia with bleeding;
- ≥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;
- 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.
- Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites. [ Time Frame: Samples will be collected on day 1 and day 15 of Cycle 1 ]Data provided is for BVD-523.
- Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. [ Time Frame: 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. ]At enrollment, all study patients had metastatic or advanced-stage malignant tumor for which no curative therapy was known to exist. Patients entering Part 2 additionally had to have measurable disease by RECIST version 1.1. Data shown is best response.
- Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK) [ Time Frame: Patients will be evaluated at baseline and on ~day 15 of Cycle 1 ]RSK1, a member of the RSK serine/threonine kinase family, is a direct substrate of the MAP Kinases ERK1 & ERK2. RSK1 and ERK1/2 form an inactive complex in unstimulated cells. Upon activation of the mitogenic pathway, ERK1/2 phosphorylates Thr573, Thr359 and Ser363 on RSK1. Thr573 resides in the activation loop of the carboxy terminal kinase domain of RSK1 and once phosphorylated, enables RSK1 to autophosphorylate Ser380. Phosphorylation of Ser380 on RSK1 can therefore be used as a target biomarker for ERK1 and ERK2 activity. BVD-523 inhibits the activity of ERK. In this study, phosphorylation of RSK1 Ser 380 (pRSK) was used as a target biomarker for assessment of ERK inhibition by BVD-523 in human whole blood samples.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01781429
|United States, California|
|UCLA Med-Hematology & Oncology|
|Los Angeles, California, United States, 90095|
|United States, Connecticut|
|Yale Cancer Center|
|New Haven, Connecticut, United States, 06520|
|United States, Florida|
|Florida Cancer Specialists and Research Group (Sarah Cannon Research Institute)|
|Sarasota, Florida, United States, 34232|
|United States, Massachusetts|
|Massachusetts General Hospital (MGH)|
|Boston, Massachusetts, United States, 02114|
|United States, Missouri|
|Washington University School of Medicine|
|Saint Louis, Missouri, United States, 63110|
|United States, New York|
|Memorial Sloan-Kettering Cancer Center|
|New York, New York, United States, 10065|
|United States, Tennessee|
|Sarah Cannon Research Institute Hospital at Vanderbilt|
|Nashville, Tennessee, United States, 37203|
|Vanderbilt-Ingram Cancer Center|
|Nashville, Tennessee, United States, 37212|
|United States, Texas|
|UT M.D Anderson Cancer Center|
|Houston, Texas, United States, 77030|