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Unspecified Adult Solid Tumor, Protocol SpecificPhase 1NCT01713972

Dabrafenib and Pazopanib Hydrochloride in Treating Patients With Advanced Malignant Tumors

A Phase 1 study testing dabrafenib, pazopanib hydrochloride and Correlative studies in people with Unspecified Adult Solid Tumor, Protocol Specific, run by Manisha Shah at 2 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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 Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
dabrafenib, pazopanib hydrochloride and Correlative studies
Could I receive a placebo?
No, everyone receives an active treatment
How many people
23 participants
Where
2 sitesUnited States
Study dates
19 Nov 2012to 26 Dec 2018
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

  • 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
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  • 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
  • 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 acceptable
  • Left ventricular ejection fraction >= institutional lower limit of normal
  • The effects of dabrafenib 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 dabrafenib 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

Who cannot join

  • 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
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  • 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
  • Class III or IV congestive heart failure, as defined by the New York Heart Association
  • History of valvular dysfunction on echocardiogram excluding mild valvular dysfunction
  • 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 enrollment
  • 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

Trial locations and contacts

2 sites in 1 country.

United States2 sites

  • Ohio State University Medical Center

    Columbus, Ohio, 43210

  • University of Texas M.D. Anderson Cancer Center

    Houston, Texas, 77030

Other trials in United States

About this study

Official title: A Phase I Trial of Dabrafenib (BRAFi) and Pazopanib in Patients With BRAF-mutated Advanced Malignant Tumors

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

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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.

SECONDARY OBJECTIVES:

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

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.

Being tested
dabrafenib, pazopanib hydrochloride, Correlative studies
Keywords
BRAFi, BRAF-mutated

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, GSK2118436

    Given PO

  • pazopanib hydrochlorideDrug

    Also called GW786034B, Votrient

    Given PO

  • Correlative studiesOther

    Also called Pharmacokinetic studies, Pharmacogenomic studies, Tumor genotyping, BRAF mutation quantification

    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
Study groups in NCT01713972
Study groupRoleWhat they receive
Treatment (dabrafenib, pazopanib hydrochloride)ExperimentalPatients 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.
Receives: Drug: dabrafenib; Drug: pazopanib hydrochloride; Other: Correlative studies
Correlative StudiesOtherPharmacokinetic 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
Receives: Drug: dabrafenib; Drug: pazopanib hydrochloride; Other: Correlative studies

What is being measured

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

  1. 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.

    Measured: 28 days

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

    Measured: 28 days

Secondary outcomes (4)

  1. 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

    Comparisons of groups of patients based on clinical response or toxicity will involve the use of analysis of variance for continuous data and categorical methods such as Fisher's exact test and chi-square tests for discrete data.

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

  2. Pharmacogenomics determined with microarray testing on blood samples

    Descriptive data will be computed and compared using analysis of variance and nonparametric rank equivalents for continuous data and chi-square or Fisher's exact test for discrete data.

    Measured: Day 1 of course 1

  3. Genotype of tumor tissue samples

    Descriptive data will be computed and compared using analysis of variance and nonparametric rank equivalents for continuous data and chi-square or Fisher's exact test for discrete data.

    Measured: Baseline

  4. 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

    Descriptive data will be computed and compared using analysis of variance and nonparametric rank equivalents for continuous data and chi-square or Fisher's exact test for discrete data.

    Measured: Up to 4 weeks 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 Oct 2012 (estimated)
  2. Study start19 Nov 2012
  3. Primary completion30 Jul 2016
  4. Study completion26 Dec 2018

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
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
23 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01713972
Sponsor's protocol ID
OSU 12066
Other IDs
NCI-2012-01935, NCCNGSK20014
Status last verified
Feb 2019
First submitted
22 Oct 2012
Last updated
1 Mar 2019
Results posted
No
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 30181415

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing dabrafenib, pazopanib hydrochloride and Correlative studies in people with Unspecified Adult Solid Tumor, Protocol Specific, run by Manisha Shah at 2 sites in United States.

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 22 inclusion and 26 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: finished, as of the sponsor's last update on 1 Mar 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. 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 is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

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 adverse events using Common Terminology Criteria for Adverse Events (CTCAE) v4 (time frame: 28 days). 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 NCT01713972, which also lists 1 linked publication.

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 1 Mar 2019.

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