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

Advanced Solid Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01781429
• Other study ID #: BVD-523-01
• Secondary ID: BVD-523-01
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: March 2013
• Est. completion date: September 2018

Study information

• Verified date: March 2020
• Source: BioMed Valley Discoveries, Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 136
• Est. completion date: September 2018
• Est. primary completion date: February 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Advanced Solid Tumors
• Neoplasms

Intervention

Drug:
• BVD-523
Oral, multiple escalating doses, twice daily, for 21 days in each treatment cycle

Locations

Country	Name	City	State
United States	Massachusetts General Hospital (MGH)	Boston	Massachusetts
United States	UT M.D Anderson Cancer Center	Houston	Texas
United States	UCLA Med-Hematology & Oncology	Los Angeles	California
United States	Sarah Cannon Research Institute Hospital at Vanderbilt	Nashville	Tennessee
United States	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee
United States	Yale Cancer Center	New Haven	Connecticut
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Florida Cancer Specialists and Research Group (Sarah Cannon Research Institute)	Sarasota	Florida

Sponsors (1)

Lead Sponsor	Collaborator
BioMed Valley Discoveries, Inc

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Pharmacodynamic (PD) Response Measured as Percentage Enzyme Inhibition of RSK1 Ser 380 (pRSK)	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.	Patients will be evaluated at baseline and on ~day 15 of Cycle 1
Primary	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: =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.	As indicated by safety and tolerability during study conduct; ~42 months
Secondary	Characterization of the Time Versus Plasma Concentration Profiles of BVD-523 and Selected Metabolites.	Data provided is for BVD-523.	Samples will be collected on day 1 and day 15 of Cycle 1
Secondary	Clinical Evidence of Tumor Response Assessed by Physical or Radiological Exam.	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.	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.