Dabrafenib in Treating Patients With Solid Tumors and Kidney or Liver Dysfunction

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01907802
First received: July 22, 2013
Last updated: September 23, 2014
Last verified: September 2014
  Purpose

This phase I trial studies the side effects and best dose of dabrafenib in treating patients with solid tumors and kidney or liver dysfunction. Dabrafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.


Condition Intervention Phase
Hepatic Complications
Renal Failure
Unspecified Adult Solid Tumor, Protocol Specific
Drug: dabrafenib
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1 and Pharmacokinetic Study of Dabrafenib (GSK2118436B) in Patients With BRAFV600X Mutations and Renal or Hepatic Dysfunction

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Incidence of toxicities graded according to NCI CTCAE v4.0 [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: Yes ]
    Overall toxicity incidence as well as toxicity profiles by dose level and patient will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses.

  • MTD of dabrafenib, defined as the highest dose level that is estimated to induce a dose-limiting toxicity (DLT) rate less than 33.3% by the two-way isotonic regression, graded according to NCI CTCAE v4.0 [ Time Frame: Up to 28 days ] [ Designated as safety issue: Yes ]
    Overall toxicity incidence as well as toxicity profiles by dose level and patient will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses.


Secondary Outcome Measures:
  • Incidence of adverse events graded according to NCI CTCAE v4.0 [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: Yes ]
    The number and severity of all adverse events (overall, by dose level, and by tumor group) will be tabulated and summarized for the three patient groups. The grade 3+ adverse events will also be described and summarized in a similar fashion.

  • Best response, defined as the best objective status recorded from the start of treatment until disease progression/recurrence, measured by modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: No ]
    Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease.

  • Time until any treatment-related toxicity [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: Yes ]
    The data on time-related variables will be summarized descriptively.

  • Time until treatment related grade 3+ toxicity [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: Yes ]
    The data on time-related variables will be summarized descriptively.

  • Time until hematologic nadirs (white blood cells [WBC], ANC, platelets) [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: No ]
    The data on time-related variables will be summarized descriptively.

  • Time to progression [ Time Frame: Up to 30 days after completion of study treatment ] [ Designated as safety issue: No ]
    The data on time-related variables will be summarized descriptively.

  • Time to treatment failure [ Time Frame: Time from registration to documentation of progression, unacceptable toxicity, or refusal to continue participation by the patient, assessed up to 30 days after completion of study treatment ] [ Designated as safety issue: No ]
    The data on time-related variables will be summarized descriptively.


Other Outcome Measures:
  • Pharmacokinetic profile of dabrafenib [ Time Frame: Days 1 and 15 of course 1, and day 1 of all subsequent courses ] [ Designated as safety issue: No ]
    Descriptive statistics and statistical plots will form the basis of presentation of biomarker, pharmacokinetic and pharmacogenetic studies. Clinical response and toxicity profile for patients will be correlated with the pharmacokinetic (PK) parameters and key polymorphisms in gene.

  • Pharmacogenetic profile of dabrafenib [ Time Frame: Day 1 prior to treatment ] [ Designated as safety issue: No ]
    Descriptive statistics and statistical plots will form the basis of presentation of biomarker, pharmacokinetic and pharmacogenetic studies. Clinical response and toxicity profile for patients will be correlated with the PK parameters and key polymorphisms in gene.


Estimated Enrollment: 122
Study Start Date: August 2013
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (dabrafenib)
Patients receive dabrafenib PO BID on days 1-28 (QD on day 1 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: dabrafenib
Given PO
Other Names:
  • BRAF inhibitor GSK2118436
  • GSK-2118436A
  • GSK2118436
  • Tafinlar
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the toxicity profile and the maximum tolerated doses (MTDs) of dabrafenib in patients with v-raf murine sarcoma viral oncogene homolog B1 (BRAF)^V600X mutations and renal or hepatic dysfunction.

SECONDARY OBJECTIVES:

I. To assess for tumor response and various times to clinical event. II. To provide dosing recommendations for dabrafenib in patients with varying degrees of hepatic and renal dysfunction for possible inclusion in the label.

TERTIARY OBJECTIVES:

I. To assess the pharmacokinetic and pharmacogenetic profile of dabrafenib and active metabolites.

OUTLINE: This is a dose-escalation study.

Patients receive dabrafenib orally (PO) twice daily (BID) on days 1-28 (once daily [QD] on day 1 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • PRE-REGISTRATION ELIGIBILITY CRITERIA
  • Willing to provide tissue as required per protocol for central BRAF^V600X mutation testing

    • NOTE: patients with prior BRAF^600X testing that demonstrate a mutation at V600X will be allowed to enroll prior to central testing if the assay was performed at a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory assay; this includes THxID, BRAF Detection Kit, Cobas 4800 BRAF600 mutation test and other CLIA-certified assays available at participating institutions
  • Patients with unknown BRAF^600X status: histologically confirmed melanoma, papillary thyroid, cholangiocarcinoma or testicular cancer that is metastatic or unresectable and for which the investigator feels a BRAF^600X targeted agent is a reasonable treatment

    • NOTE: patient must be screened by central BRAF testing and must demonstrate a V600 mutation prior to start of study agent
    • Note: other tumor types without known BRAF^600X mutations will not be eligible for central testing
  • Ability to understand and willingness to sign written informed consent
  • Life expectancy of > 3 months
  • REGISTRATION ELIGIBILITY CRITERIA
  • Patients with known BRAF^V600X0 mutation: patients must have BRAF^V600X mutated, histologically confirmed cancer that is metastatic or unresectable and for which curative or standard therapies do not exist or are no longer effective

    • NOTE: colorectal cancers with BRAF mutations ARE NOT allowed
    • NOTE: any mutation at the V600 position that results in a change from V (valine) is allowed; this includes E, D, K, R or other mutations not noted here at the V600 position
  • Any number of the following prior therapies is allowed:

    • Chemotherapy >= 28 days prior to registration
    • Mitomycin C/nitrosoureas >= 42 days prior to registration
    • Immunotherapy >= 28 days prior to registration
    • Biologic therapy >= 28 days prior to registration
    • Radiation therapy >= 28 days prior to registration
    • Radiation to < 25% of bone marrow
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Karnofsky >= 70%)
  • Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels
  • Absolute neutrophil count (ANC) >= 1.2 x 10^9/L
  • Hemoglobin >= 9 g/dL
  • Platelets >= 100 x 10^9/L
  • Albumin >= 2.5 g/dL
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional upper limit of normal (ULN)
  • Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN; subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to randomization
  • Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO)
  • Hepatic and renal function meeting the strata below:

    • Group N: Hepatic: normal function (bilirubin =< ULN; AST =< ULN); renal: normal function (creatinine clearance [CrCl] >= 60 mL/min as estimated by the Cockcroft and Gault equation)
    • Group R3: Hepatic: normal function (bilirubin =< ULN; AST =< ULN); renal: severe dysfunction (CrCl >= 15 and < 30 mL/min as estimated by the Cockcroft and Gault equation)
    • Group R4: Hepatic: normal function (bilirubin =< ULN; AST =< ULN; renal: renal failure (hemodialysis)
    • Group H1: Hepatic: mild dysfunction (bilirubin =< ULN; AST > ULN); renal: acceptable function (CrCl >= 60 mL/min as estimated by the Cockcroft and Gault equation)
    • Group H2: Hepatic: moderate dysfunction (bilirubin > ULN and =< 3 x ULN; AST > ULN); renal: acceptable function (CrCl>=≥ 60 mL/min as estimated by the Cockcroft and Gault equation)
    • Group H3: Hepatic: severe dysfunction (bilirubin > 3 x ULN and up to investigators discretion; AST > ULN); renal: acceptable function (CrCl >= 60 mL/min as estimated by the Cockcroft and Gault equation)
  • Women of childbearing potential must have a negative serum pregnancy test =< 7 days prior to registration
  • Women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 1 month after completion of dabrafenib administration
  • Ability to understand and the willingness to sign a written informed consent document
  • Willingness to provide blood and tissue samples as required per protocol
  • Patients with a history of clinical benefit from prior RAF inhibitor therapy, as judged by the investigator, will be allowed

Exclusion Criteria:

  • Patients with active biliary obstruction; NOTE: patients for which a shunt has been in place for at least 10 days prior to the first dose of dabrafenib are allowed
  • Reduced left ventricular ejection fraction (< 50%) or other evidence of cardiac dysfunction as determined by the investigator
  • Use of an investigational anti-cancer drug within 28 days preceding the first dose of dabrafenib
  • Patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or cytochrome P450 family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible

    • For patients on intermediate inducers or inhibitors, attempts should be made to switch to an alternative agent or delay enrollment until treatment course with concomitant agent completed; if not possible, patient may be enrolled if it is felt to be in the patients best interest as decided by the investigator
    • Weak inhibitors of CYP3A or CYP2C8 should be used with caution and attempts made to limit their use or find alternative agents, if possible
  • Warfarin use is provisionally allowed
  • Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0) grade 2 or higher from previous anti-cancer therapy, except alopecia
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible; Note: patients not on antiretroviral therapies are eligible for this study
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, diabetes mellitus, hypertension, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
  • Presence of malignancy other than the study indication under this trial within 5 years of study enrollment
  • History or evidence of cardiovascular risks including any of the following:

    • QT interval corrected for heart rate using the Bazett's formula QTcB >= 480 msec
    • History of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within the past 24 weeks prior to randomization
    • History or evidence of current class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system
    • Intra-cardiac defibrillators
    • Abnormal cardiac valve morphology (>= grade 2) documented by ECHO; (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study
    • History or evidence of current clinically significant uncontrolled cardiac arrhythmias; clarification: subjects with atrial fibrillation controlled for > 30 days prior to dosing are eligible
    • Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti- hypertensive therapy
  • Brain metastases that are symptomatic or untreated or not stable for >= 3 months (must be documented by imaging) or requiring corticosteroids; subjects on a stable dose of corticosteroids > 1 month or who have been off corticosteroids for at least 2 weeks can be enrolled with approval of the Cancer Therapy Evaluation Program (CTEP) medical monitor; subjects must also be off enzyme-inducing anticonvulsants for > 4 weeks
  • History of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks; class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system; or history of known cardiac arrhythmias unless it has been stably controlled
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to dabrafenib or other agents used in this study
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with dabrafenib
  • Any condition or medical problem in addition to the underlying malignancy and organ dysfunction which the investigator feels would pose unacceptable risk
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01907802

Locations
United States, California
City of Hope Recruiting
Duarte, California, United States, 91010
Contact: Vincent Chung    626-471-9200    vchung@coh.org   
Principal Investigator: Vincent Chung         
University of Southern California/Norris Cancer Center Recruiting
Los Angeles, California, United States, 90033
Contact: Anthony El-Khoueiry    323-865-3595    elkhouei@med.usc.edu   
Principal Investigator: Anthony El-Khoueiry         
University of California at Davis Cancer Center Recruiting
Sacramento, California, United States, 95817
Contact: Karen L. Kelly    916-734-3735    karen.kelly@ucdmc.ucdavis.edu   
Principal Investigator: Karen L. Kelly         
City of Hope South Pasadena Recruiting
South Pasadena, California, United States, 91030
Contact: Stephen C. Koehler    626-396-2900    skoehler@cohmg.com   
Principal Investigator: Stephen C. Koehler         
United States, Colorado
University of Colorado Cancer Center - Anschutz Cancer Pavilion Recruiting
Aurora, Colorado, United States, 80045
Contact: Cindy O'Bryant    303-724-2625    cindy.obryant@ucdenver.edu   
Principal Investigator: Cindy O'Bryant         
United States, Florida
Mayo Clinic in Florida Recruiting
Jacksonville, Florida, United States, 32224-9980
Contact: George P. Kim    904-953-6460    kim.george@mayo.edu   
Principal Investigator: George P. Kim         
United States, Maryland
Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center Recruiting
Baltimore, Maryland, United States, 21287
Contact: Michelle A. Rudek    410-614-6321    mrudek2@jhmi.edu   
Principal Investigator: Michelle A. Rudek         
United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02115
Contact: Geoffrey I. Shapiro    617-632-4942    geoffrey_shapiro@dfci.harvard.edu   
Principal Investigator: Geoffrey I. Shapiro         
United States, Michigan
Barbara Ann Karmanos Cancer Institute Recruiting
Detroit, Michigan, United States, 48201
Contact: Patricia M. LoRusso    313-576-8716    lorussop@karmanos.org   
Principal Investigator: Patricia M. LoRusso         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Paul Haluska    507-284-2511    haluska.paul@mayo.edu   
Principal Investigator: Paul Haluska         
United States, Ohio
Case Western Reserve University Recruiting
Cleveland, Ohio, United States, 44106
Contact: Jennifer R. Eads    216-844-6031    jennifer.eads@uhhospitals.org   
Principal Investigator: Jennifer R. Eads         
United States, Pennsylvania
University of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Hussein A. Tawbi    412-648-6578    tawbhx@upmc.edu   
Principal Investigator: Hussein A. Tawbi         
United States, Wisconsin
University of Wisconsin Hospital and Clinics Recruiting
Madison, Wisconsin, United States, 53792
Contact: William R. Schelman    608-263-6222    wrs@medicine.wisc.edu   
Principal Investigator: William R. Schelman         
Canada, Ontario
University Health Network-Princess Margaret Hospital Recruiting
Toronto, Ontario, Canada, M5G 2M9
Contact: Philippe L. Bedard    416-946-4534    philippe.bedard@unh.ca   
Principal Investigator: Philippe L. Bedard         
Sponsors and Collaborators
Investigators
Principal Investigator: Paul Haluska Mayo Clinic
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01907802     History of Changes
Other Study ID Numbers: NCI-2013-01338, NCI-2013-01338, MC1211, 9343, U01CA062490, UM1CA186644, U01CA069912, P30CA015083, U01CA132123, UM1CA186686, UM1CA186709
Study First Received: July 22, 2013
Last Updated: September 23, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Renal Insufficiency
Kidney Diseases
Urologic Diseases
Dabrafenib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 30, 2014