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A Phase I Trial of GSK2118436 (BRAFi) and Pazopanib in Patients With BRAF-mutated Advanced Malignant Tumors

Phase 1
18 Years
Open (Enrolling)
Unspecified Adult Solid Tumor, Protocol Specific

Thank you

Trial Information

A Phase I Trial of GSK2118436 (BRAFi) and Pazopanib in Patients With BRAF-mutated Advanced Malignant Tumors


I. To assess the safety and tolerability of GSK2118436 (dabrafenib) given with pazopanib
(pazopanib hydrochloride) as well as determining the maximum tolerated dosing regimen in
patients with BRAF mutated advanced malignant tumors.


I. Evaluate pharmacokinetics of the two study drugs and identify potential drug-drug

II. Determine pharmacogenomics with microarray testing. III. Perform genotyping of tumors
and if objective tumor response rates are identified.

IV. Assess objective tumor response rates.

OUTLINE: This is a dose-escalation study.

Patients receive dabrafenib orally (PO) twice daily (BID) on days 1-28 (once daily on day 1
and BID on days 3-28 of course 1), and pazopanib hydrochloride PO once daily (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.

After completion of study treatment, patients are followed up for 4 weeks.

Inclusion Criteria:

- 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 GSK2118436 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 entering study

- Adverse events related to prior tumor-specific therapy must have been resolved
to =< grade 1 prior to study entry 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

- ALT and AST =< 2.5 X ULN; concomitant elevations in bilirubin and AST/ALT above 1.0 x
ULN are not permitted

- Serum creatinine =< 1.5 x ULN (=< 133 umol/L)

- Urine protein to creatinine ratio (UPC; appropriate) < 1; if UPC >= 1, then a 24-hour
urine protein must be assessed; subjects must have a 24-hour urine protein value < 1
g to be eligible; use of urine dipstick for renal function assessment is not

- Left ventricular ejection fraction >= institutional lower limit of normal

- The effects of GSK2118436 on the developing human fetus are unknown; pazopanib
belongs to the pregnancy risk factor group D (adverse effects were observed in animal
studies); for these reasons, women of child-bearing potential and men must agree to
use adequate contraception (hormonal or 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 4 months after completion of
GSK2118436 and pazopanib administration

- Ability to understand and willingness to sign a written informed consent document

- Ability to swallow oral medication and keep a pill diary

Exclusion Criteria:

- 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 earlier

- 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 GSK2118436, 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 GSK2118436; 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 GSK2118436 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 GSK2118436 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 GSK2118436 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

- History of at least one of the following cardiovascular conditions within the past 6

- Cardiac angioplasty or stenting

- Myocardial infarction

- Unstable angina

- Symptomatic peripheral vascular disease

- Class III or IV congestive heart failure, as defined by the New York Heart

- History of valvular dysfunction on echocardiogram excluding mild valvular

- Known cardiac metastasis

- History of cerebrovascular accident including transient ischemic attack (TIA),
pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6
months; patients who are being treated for pulmonary embolism (PE) and/or DVT
diagnosed within the past 6 months with agents other than warfarin are allowed to
enter the study

- Prior major surgery or trauma within 28 days before first dose of study drug and/or
presence of any non-healing wound, fracture, or ulcer

- Evidence of active bleeding or bleeding diathesis

- Patient with hepatitis B and/or hepatitis C infection; patients with laboratory
evidence of hepatitis B virus (HBV) clearance are eligible for the trial

- Patient with history of malignancy other than completely resected non-melanomatous
skin carcinoma or successfully treated in situ carcinoma within 5 years of study

- Clinically significant gastrointestinal abnormalities that may affect absorption of
the study drugs including but not limited to:

- Malabsorption syndrome

- Major resection of the stomach or small bowel

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Outcome Description:

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.

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Manisha Shah, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Ohio State University


United States: Food and Drug Administration

Study ID:

OSU 12066



Start Date:

November 2012

Completion Date:

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific
  • BRAFi
  • BRAF-mutated
  • Neoplasms



Ohio State University Medical Center Columbus, Ohio  43210
University of Texas M.D. Anderson Cancer Center Houston, Texas  77030