Dabrafenib and Pazopanib Hydrochloride in Treating Patients With Advanced Malignant Tumors

NCT01713972 | Completed Phase 1 DMC

• 3 other identifiers: OSU 12066NCI-2012-01935NCCNGSK20014
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 2

Brief Summary

This phase I trial studies the side effects and best dose of dabrafenib and pazopanib hydrochloride when given together in treating patients with advanced malignant tumors. Dabrafenib and pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth

Conditions

Unspecified Adult Solid Tumor, Protocol Specific

Keywords

BRAFi; BRAF-mutated

Outcome Measures

Primary Outcomes (2)

• Incidence of adverse events using Common Terminology Criteria for Adverse Events (CTCAE) v4

  We will summarize observed adverse events and their grade and attribution for each dose level, and patterns reflecting tolerability of the regimen explored through graphical analysis and descriptive summaries.

  28 days

• Maximum tolerated dose, defined as the dose below the dose where at least 2 dose limiting toxicities (DLTs) are observed, graded using CTCAE v4

  28 days

Secondary Outcomes (4)

• Pharmacokinetics of the two study drugs (including Cmax, Css, clearance, t1/2 alpha, t1/2 beta, central volume of distribution, and steady state volume of distribution) and drug-drug interactions

  Pre-dose, .5, 1, 2, 3, 4, 8, 24 hours

• Pharmacogenomics determined with microarray testing on blood samples

  Day 1 of course 1

• Genotype of tumor tissue samples

  Baseline

• Objective tumor response rates with clinical assessment, tumor marker measurements and imaging studies as appropriate for each patient, as determined according to the Response Evaluation Criteria in Solid Tumors (RECIST), v1.1

  Up to 4 weeks after completion of study treatment

Study Arms (2)

Treatment (dabrafenib, pazopanib hydrochloride)

EXPERIMENTAL

Patients receive dabrafenib PO BID on days 1-28 (once daily on day 1 and BID on days 3-28 of course 1), and pazopanib hydrochloride PO QD on days 1-28 (days 2-28 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: dabrafenib; Drug: pazopanib hydrochloride; Other: Correlative studies

Correlative Studies

OTHER

Pharmacokinetic studies: Blood draw for various time points: Cycle 1 Days 1, 2, 3, 4 and 15; Cycle 2 Days 1, 2; and day 1 of Cycles 4, 6 and 12 * Pharmacogenomic studies: Blood draw on Cycle 1 Day 1 * Tumor genotyping: Archival tumor blocks or unstained slides * BRAF mutation quantification in circulating plasma DNA: Blood draw on Cycles 1-7 Day 1 and every other cycle thereafter; and at time of progression

Drug: dabrafenib; Drug: pazopanib hydrochloride; Other: Correlative studies

Interventions

dabrafenib DRUG

Given PO

Also known as: BRAF inhibitor GSK2118436, GSK2118436

Correlative Studies; Treatment (dabrafenib, pazopanib hydrochloride)

pazopanib hydrochloride DRUG

Given PO

Also known as: GW786034B, Votrient

Correlative Studies; Treatment (dabrafenib, pazopanib hydrochloride)

Correlative studies OTHER

Pharmacokinetic studies: Blood draw for various time points: Cycle 1 Days 1, 2, 3, 4 and 15; Cycle 2 Days 1, 2; and day 1 of Cycles 4, 6 and 12 * Pharmacogenomic studies: Blood draw on Cycle 1 Day 1 * Tumor genotyping: Archival tumor blocks or unstained slides * BRAF mutation quantification in circulating plasma DNA: Blood draw on Cycles 1-7 Day 1 and every other cycle thereafter; and at time of progression

Also known as: Pharmacokinetic studies, Pharmacogenomic studies, Tumor genotyping, BRAF mutation quantification

Correlative Studies; Treatment (dabrafenib, pazopanib hydrochloride)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Must have a histologically or cytologically confirmed malignant tumor that is advanced, metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective
• Tumors must carry the BRAF mutation
• Prior therapies:
• There is no limit to prior cytotoxic regimens
• No more than three prior regimens of tyrosine kinase inhibitors are allowed; prior use of pazopanib and/or inhibitor dabrafenib is not allowed; prior use of vemurafenib and sorafenib is allowed
• Patients must not have received systemic chemotherapy, immunotherapy, biologic therapy or radiation therapy within 4 weeks of study
• Adverse events related to prior tumor-specific therapy must have been resolved to =\< grade 1 prior to study enrollment except for alopecia
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
• Life expectancy greater than 12 weeks
• Absolute neutrophil count (ANC) \>= 1.5 X 10\^9/L; for patients (pts) with hairy cell leukemia, ANC \>= 1 X 10\^9/L is required
• Hemoglobin \>= 9 g/dL (5.6 mmol/L); for pts with hairy cell leukemia, hemoglobin \>= 8 g/dL is required
• Platelets \>= 100 X 10\^9/L; for pts with hairy cell leukemia, platelets \>= 75 X 10\^9/L is required
• International normalized ratio (INR) =\< 1.2 X upper limit of normal (ULN); subjects receiving anticoagulant therapy with warfarin are not eligible
• Activated partial thromboplastin time (aPTT) =\< 1.2 X ULN
• Total bilirubin =\< 1.5 X ULN; concomitant elevations in bilirubin and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) above 1.0 x ULN are not permitted

You may not qualify if:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks prior to study enrollment
• Patients who are receiving any other investigational agents
• Patients with symptomatic, untreated brain metastases; patients who are on a stable dose of corticosteroids for more than 1 month or off corticosteroids for 2 weeks can be enrolled; enzyme-inducing anti-epileptic drugs are not permitted; screening with central nervous system (CNS) imaging (computerized tomography \[CT\] or magnetic resonance imaging \[MRI\]) is required only if clinically indicated
• Patients with a known history of glucose-6-phosphate dehydrogenase (G6PD) deficiency; patients with G6PD deficiency are excluded from clinical trials because they may develop nonimmune hemolytic anemia in response to dabafenib, which contains a sulfonamide, a potential risk factor for subjects with this deficiency
• Patients taking prohibited medications within 7 days of entering study will be excluded due to potential serious interactions with dabafenib; patients taking therapeutic doses of warfarin will not be allowed on the study due to potential drug interactions (patient on prophylactic low dose warfarin are allowed)
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study because dabrafenib is an investigational agent with unknown teratogenicity and because pazopanib belongs to pregnancy risk factor group D (adverse effects were observed in animal studies); because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with dabrafenib and pazopanib, breastfeeding should be discontinued if the mother is treated with these agents
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are excluded because of possible pharmacokinetic interactions of highly active anti-retroviral therapy (HAART) with dabrafenib and pazopanib; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
• Poorly controlled hypertension (defined as systolic blood pressure \[BP\] \>= 140 and/or diastolic BP \>= 90) measured on more than one occasion and not responsive to antihypertensives; Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry and during study if required; BP must be re-assessed on two occasions separated by a minimum of 1 hour; on each of these occasions, the mean systolic (S)BP/diastolic (D)BP values (of 3 readings) must be \< 140/90 mmHg in order for a subject to be eligible for the study
• Prolongation of heart rate-corrected QT interval (QTc) \> 480 msecs (using Bazett's formula)
• History of at least one of the following cardiovascular conditions within the past 6 months:
• Cardiac angioplasty or stenting
• Myocardial infarction
• Unstable angina
• Symptomatic peripheral vascular disease

Sponsors & Collaborators

• Manisha Shah: lead
• National Comprehensive Cancer Network: collaborator

Study Sites (2)

Ohio State University Medical Center

Columbus, Ohio, 43210, United States

Location

University of Texas M.D. Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Burkart J, Owen D, Shah MH, Abdel-Misih SRZ, Roychowdhury S, Wesolowski R, Haraldsdottir S, Reeser JW, Samorodnitsky E, Smith A, Konda B. Targeting BRAF Mutations in High-Grade Neuroendocrine Carcinoma of the Colon. J Natl Compr Canc Netw. 2018 Sep;16(9):1035-1040. doi: 10.6004/jnccn.2018.7043.

  PMID: 30181415 DERIVED

Related Links

• Jamesline

MeSH Terms

Interventions

dabrafenib; pazopanib; Pharmacogenomic Testing

Intervention Hierarchy (Ancestors)

Genetic Testing; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques; Genetic Techniques; Genetic Services; Health Services; Health Care Facilities Workforce and Services; Diagnostic Services; Preventive Health Services

Study Officials

• Manisha Shah, MD

  Ohio State University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: October 22, 2012
• First Posted: October 25, 2012
• Study Start: November 19, 2012
• Primary Completion: July 30, 2016
• Study Completion: December 26, 2018
• Last Updated: March 1, 2019

Record last verified: 2019-02

Locations

US (2)