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BRAF Gene MutationPhase 1NCT01907802

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

A Phase 1 study testing Dabrafenib, Laboratory Biomarker Analysis and Pharmacogenomic Study in people with BRAF Gene Mutation and Hepatic Complication, run by National Cancer Institute (NCI) at 18 sites in 2 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Dabrafenib, Laboratory Biomarker Analysis and Pharmacogenomic Study
Could I receive a placebo?
No, everyone receives an active treatment
How many people
8 participants
Where
18 sitesin 2 countries
Study dates
23 Aug 2013to 16 Dec 2015
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • Ability to understand and willingness to sign written informed consent
  • Life expectancy of > 3 months
  • REGISTRATION ELIGIBILITY CRITERIA
  • Patients with known BRAF^V600X 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
  • NOTE: this applies to patient in the normal and renal dysfunction cohorts (N, R3 and R4); abnormal albumin is allowed for patients in the liver dysfunction cohorts
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional upper limit of normal (ULN)
  • NOTE: this applies to patient in the normal and renal dysfunction cohorts (N, R3 and R4); patients with elevated AST and/or ALT may be assigned to liver dysfunction cohorts
  • 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
  • NOTE: this applies to patient in the normal and renal dysfunction cohorts (N, R3 and R4); elevated PT/INR is allowed for patients in the liver dysfunction cohorts
  • 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

Who cannot join

  • 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
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  • 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

Trial locations and contacts

18 sites in 2 countries.

18 sites in 2 countries

United States17 sites

  • University of Colorado Hospital

    Aurora, Colorado, 80045

  • Johns Hopkins University/Sidney Kimmel Cancer Center

    Baltimore, Maryland, 21287

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02215

  • University of Chicago Comprehensive Cancer Center

    Chicago, Illinois, 60637

  • Case Western Reserve University

    Cleveland, Ohio, 44106

  • Ohio State University Comprehensive Cancer Center

    Columbus, Ohio, 43210

  • Wayne State University/Karmanos Cancer Institute

    Detroit, Michigan, 48201

  • City of Hope Comprehensive Cancer Center

    Duarte, California, 91010

  • Mayo Clinic in Florida

    Jacksonville, Florida, 32224-9980

  • USC / Norris Comprehensive Cancer Center

    Los Angeles, California, 90033

  • University of Wisconsin Hospital and Clinics

    Madison, Wisconsin, 53792

  • Rutgers Cancer Institute of New Jersey

    New Brunswick, New Jersey, 08903

  • University of Pittsburgh Cancer Institute (UPCI)

    Pittsburgh, Pennsylvania, 15232

  • Mayo Clinic

    Rochester, Minnesota, 55905

  • University of California Davis Comprehensive Cancer Center

    Sacramento, California, 95817

  • City of Hope South Pasadena

    South Pasadena, California, 91030

  • Washington University School of Medicine

    St Louis, Missouri, 63110

Other trials in United States

Canada1 site

  • University Health Network-Princess Margaret Hospital

    Toronto, Ontario, M5G 2M9

Other trials in Canada

About this study

Official title: A Phase 1 and Pharmacokinetic Study of Dabrafenib (GSK2118436B) in Patients With BRAFV600X Mutations and Renal or Hepatic Dysfunction

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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:

  1. 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:

  1. 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.

Being tested
Dabrafenib, Laboratory Biomarker Analysis, Pharmacogenomic Study, Pharmacological Study
Medical subject headings
Renal Insufficiency

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DabrafenibDrug

    Also called BRAF Inhibitor GSK2118436, GSK-2118436A, GSK2118436

    Given PO

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • Pharmacogenomic StudyOther

    Also called PHARMACOGENOMIC

    Correlative studies

  • Pharmacological StudyOther

    Correlative studies

Study groups in NCT01907802
Study groupRoleWhat they receive
Treatment (dabrafenib)ExperimentalPatients 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.
Receives: Drug: Dabrafenib; Other: Laboratory Biomarker Analysis; Other: Pharmacogenomic Study; Other: Pharmacological Study

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Incidence of toxicities graded according to NCI CTCAE v4.0

    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.

    Measured: Up to 30 days after completion of study treatment

  2. MTD of dabrafenib, defined as the highest dose level that is estimated to induce a dose-limiting toxicity rate less than 33.3% by the two-way isotonic regression, graded according to NCI CTCAE v4.0

    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.

    Measured: Up to 28 days

Secondary outcomes (7)

  1. Incidence of adverse events graded according to NCI CTCAE v4.0

    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.

    Measured: Up to 30 days after completion of study treatment

  2. 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

    Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease.

    Measured: Up to 30 days after completion of study treatment

  3. Time until any treatment-related toxicity

    The data on time-related variables will be summarized descriptively.

    Measured: Up to 30 days after completion of study treatment

  4. Time until treatment related grade 3+ toxicity

    The data on time-related variables will be summarized descriptively.

    Measured: Up to 30 days after completion of study treatment

  5. Time until hematologic nadirs (white blood cells, ANC, platelets)

    The data on time-related variables will be summarized descriptively.

    Measured: Up to 30 days after completion of study treatment

  6. Time to progression

    The data on time-related variables will be summarized descriptively.

    Measured: Up to 30 days after completion of study treatment

  7. Time to treatment failure

    The data on time-related variables will be summarized descriptively.

    Measured: 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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted25 Jul 2013 (estimated)
  2. Study start23 Aug 2013
  3. Primary completion16 Dec 2015
  4. Study completion16 Dec 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
8 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01907802
Sponsor's protocol ID
NCI-2013-01338
Other IDs
NCI-2013-01338, MC1211, 9343, 9343, P30CA015083, U01CA132123, U01CA062490, U01CA069912
Status last verified
Aug 2018
First submitted
22 Jul 2013
Last updated
14 Aug 2018
Results posted
No
Data monitoring committee
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Dabrafenib, Laboratory Biomarker Analysis and Pharmacogenomic Study in people with BRAF Gene Mutation and Hepatic Complication, run by National Cancer Institute (NCI) at 18 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 43 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 14 Aug 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 18 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early. Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of toxicities graded according to NCI CTCAE v4.0 (time frame: Up to 30 days after completion of study treatment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01907802.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Aug 2018.

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