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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
Sponsor:
Information provided by (Responsible Party):
BioMed Valley Discoveries, Inc

Tracking Information
First Submitted Date  ICMJE January 28, 2013
First Posted Date  ICMJE February 1, 2013
Results First Submitted Date  ICMJE October 15, 2019
Results First Posted Date  ICMJE March 20, 2020
Last Update Posted Date March 20, 2020
Actual Study Start Date  ICMJE March 2013
Actual Primary Completion Date February 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 18, 2020)
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:
  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.
Original Primary Outcome Measures  ICMJE
 (submitted: January 30, 2013)
Determination of recommended phase 2 dose (RP2D) of BVD-523 determined by dose-limiting toxicities. [ Time Frame: Until safety and tolerability limit further dose escalation; up to ~18 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 18, 2020)
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 30, 2013)
  • 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 ]
  • Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam. [ Time Frame: Patients will be evaluated at baseline and at 60 days ]
Current Other Pre-specified Outcome Measures
 (submitted: March 18, 2020)
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.
Original Other Pre-specified Outcome Measures
 (submitted: January 30, 2013)
  • Pharmacodynamic response assessed by blood and tissue analyses. [ Time Frame: Patients will be evaluated at baseline and on ~day 15 of Cycle 1 ]
    To evaluate pharmacodynamic measures in healthy or malignant tissues, using biomarker assays for phosphorylation, cytotoxic or cytostatic measures.
  • Radiographic response assessed using using F-fluorodeoxyglucose-positron-emission tomography (FDG-PET) scans. [ Time Frame: Patients will be evaluated at baseline and day 22 (end of 1st cycle) to identify early response. ]
 
Descriptive Information
Brief Title  ICMJE Phase I Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of BVD-523 in Patients With Advanced Malignancies
Official Title  ICMJE Phase I Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of BVD-523 in Patients With Advanced Malignancies
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Advanced Solid Tumors
Intervention  ICMJE Drug: BVD-523
Oral, multiple escalating doses, twice daily, for 21 days in each treatment cycle
Study Arms  ICMJE Experimental: BVD-523
Intervention: Drug: BVD-523
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 19, 2018)
136
Original Estimated Enrollment  ICMJE
 (submitted: January 30, 2013)
120
Actual Study Completion Date  ICMJE September 2018
Actual Primary Completion Date February 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01781429
Other Study ID Numbers  ICMJE BVD-523-01
BVD-523-01 ( Other Identifier: BioMed Valley Discoveries, Inc. )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party BioMed Valley Discoveries, Inc
Study Sponsor  ICMJE BioMed Valley Discoveries, Inc
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account BioMed Valley Discoveries, Inc
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP