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

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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

Study Description
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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.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Drug: BVD-523 Phase 1 Phase 2

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 136 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Arms and Interventions
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Arm Intervention/treatment
Experimental: BVD-523 Drug: BVD-523
Oral, multiple escalating doses, twice daily, for 21 days in each treatment cycle


Outcome Measures
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Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. 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.


Other Outcome Measures:
  1. 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.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

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


Locations
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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
Sponsors and Collaborators
BioMed Valley Discoveries, Inc
  Study Documents (Full-Text)

Documents provided by BioMed Valley Discoveries, Inc:
Study Protocol  [PDF] April 11, 2016
Statistical Analysis Plan  [PDF] June 23, 2017

More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: BioMed Valley Discoveries, Inc
ClinicalTrials.gov Identifier: NCT01781429    
Other Study ID Numbers: BVD-523-01
BVD-523-01 ( Other Identifier: BioMed Valley Discoveries, Inc. )
First Posted: February 1, 2013    Key Record Dates
Results First Posted: March 20, 2020
Last Update Posted: March 20, 2020
Last Verified: March 2020
Additional relevant MeSH terms:
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Neoplasms