Dabrafenib and Lapatinib Ditosylate in Treating Patients With Refractory Thyroid Cancer That Cannot Be Removed By Surgery

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01947023
First received: September 16, 2013
Last updated: July 28, 2014
Last verified: March 2014

September 16, 2013
July 28, 2014
August 2013
September 2015   (final data collection date for primary outcome measure)
Maximum tolerated dose of lapatinib ditosylate, in combination with the established dose of dabrafenib, defined as the highest dose at which not more than 1/6 of the patients experience dose limiting toxicity [ Time Frame: First 42 days of treatment ] [ Designated as safety issue: Yes ]
Maximum tolerated dose (MTD) of lapatinib ditosylate, in combination with the established dose of dabrafenib, defined as the highest dose at which not more than 1/6 of the patients experience dose limiting toxicity [ Time Frame: First 42 days of treatment ] [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT01947023 on ClinicalTrials.gov Archive Site
  • Mean percent change in the post-treatment tissues relative to pre-treatment tissues for the phosphorylated protein targets examined [ Time Frame: Baseline to day 7 of course 1 ] [ Designated as safety issue: No ]
    Tissues such as phosphorylated mitogen-activated protein kinase 1 (ERK), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian) (HER2), v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian) (HER3), epidermal growth factor receptor (EGFR), platelet derived growth factor (PDGF), or v-akt murine thymoma viral oncogene homolog 1 (AKT) will be examined. Mean percent change will be calculated and compared.
  • Mean percentage change in transcript levels in the post-treatment tissues relative to pre-treatment tissues for several genes analyzed by reverse-transcriptase-polymerase chain reaction [ Time Frame: Baseline to day 7 of course 1 ] [ Designated as safety issue: No ]
    Genes including sodium/iodide symporter (NIS), dual-specificity phosphatase 5 (DUSP5), and plasminogen activator (PLAT) will be examined. Mean percentage change is calculated and compared with respect to each genotype.
  • Mean percent change in the post-treatment tissues relative to pre-treatment tissues for the phosphorylated protein targets examined (such as phosphorylated ERK, HER2, HER3, EGFR, PDGF, or AKT) [ Time Frame: Baseline to day 7 of course 1 ] [ Designated as safety issue: No ]
    Mean percent change will be calculated and compared.
  • Mean percentage change in transcript levels in the post-treatment tissues relative to pre-treatment tissues for several genes (including NIS, DUSP5, and PLAT) analyzed by reverse-transcriptase-polymerase chain reaction (RT-PCR) [ Time Frame: Baseline to day 7 of course 1 ] [ Designated as safety issue: No ]
    Mean percentage change is calculated and compared with respect to each genotype.
Not Provided
Not Provided
 
Dabrafenib and Lapatinib Ditosylate in Treating Patients With Refractory Thyroid Cancer That Cannot Be Removed By Surgery
A Phase 1 Study of Dabrafenib in Combination With Lapatinib in BRAF Mutant Thyroid Cancer

This phase I trial studies the side effects and best dose of lapatinib ditosylate when given together with dabrafenib in treating patients with refractory thyroid cancer that cannot be removed by surgery. Dabrafenib and lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of lapatinib (lapatinib ditosylate) that can be used in combination of dabrafenib.

SECONDARY OBJECTIVES:

I. Evaluate potential mechanisms of primary resistance of v-raf murine sarcoma viral oncogene homolog B (BRAF) mutant thyroid cancer to dabrafenib by performing pathway profiling of tumor biopsies before and while on therapy.

II. Obtain preliminary data on the activity of the combination of lapatinib and dabrafenib in BRAF mutant thyroid cancer through imaging.

OUTLINE: This is a dose-escalation study of lapatinib ditosylate.

Patients receive dabrafenib* orally (PO) on days 1-28 and lapatinib ditosylate PO on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

NOTE: *Patients also receive dabrafenib PO for 2 weeks prior to beginning treatment with lenalidomide.

After completion of study treatment, patients are followed up for 4 weeks and then annually thereafter.

Interventional
Phase 1
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Recurrent Thyroid Cancer
  • Drug: lapatinib ditosylate
    Given PO
    Other Names:
    • GSK572016
    • GW-572016
    • GW2016
    • Lapatinib
    • Tykerb
  • 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
Experimental: Treatment (lapatinib ditosylate, dabrafenib)

Patients receive dabrafenib* PO on days 1-28 and lapatinib ditosylate PO on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

NOTE: *Patients also receive dabrafenib PO for 2 weeks prior to beginning treatment with lenalidomide.

Interventions:
  • Drug: lapatinib ditosylate
  • Drug: dabrafenib
  • Other: pharmacological study
  • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
18
Not Provided
September 2015   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Patients must have measurable and histologically or cytologically confirmed thyroid cancer with a BRAF V600E (c. 1799 T to A and c.1799_1800TG>AA) mutation that is not considered curable by surgery; confirmation will be done at Memorial Sloan Kettering Cancer Center (MSKCC); only tumors with a BRAFV600E mutation will be eligible for the clinical study; BRAF status will be assessed in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory using mass spectroscopy or amplification of the corresponding exons by polymerase chain reaction (PCR); the PCR product is sequenced on a MiSeq instrument; if there is an equivocal case, Sanger sequencing is used; sensitivity and specificity were both measured at 100%
  • The tumor is considered to be radioactive-iodine refractory by any of the following criteria:

    • Total lifetime dose of radioactive iodine > 600 mCi
    • Absent or insufficient radioactive iodine uptake in either all lesions or an index lesion which has never been resected or received external beam radiation therapy as documented on a radioactive iodine scan (insufficient uptake must be confirmed by either an endocrinologist or nuclear medicine physician)
    • Progression of disease (by imaging or serum thyroglobulin) within 6 months of radioactive iodine treatment
    • Fludeoxyglucose F 18 (FDG)-avid lesion (standard uptake variable maximum [SUVmax] >= 3) on a FDG-positron emission tomography (PET) scan
  • No recent treatment for thyroid cancer as defined as:

    • No radioactive iodine therapy is allowed if given < 3 months prior to initiation of this protocol therapy; a diagnostic study using < 10 mCi of radioactive iodine (RAI) is not considered radioactive iodine therapy
    • No external beam radiation therapy < 4 weeks prior to initiation of therapy on this protocol
    • No chemotherapy or targeted therapy (e.g., tyrosine kinase inhibitor) is allowed < 4 weeks prior to the initiation of therapy
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or Karnofsky >= 60%
  • Life expectancy of greater than 2 months
  • Able to swallow and retain oral medication
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
  • Hemoglobin >= 9 g/dL
  • Platelets >= 75 x 10^9/L
  • Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN
  • Serum creatinine =< 1.5 mg/dL (if serum creatinine is > 1.5 mg/dL, calculate creatinine clearance using standard Cockcroft and Gault method or using a 24 hour urine collection for creatinine; creatinine clearance must be > 50 mL/min)
  • Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.3 x institutional ULN unless patient is on anticoagulation therapy
  • Left ventricular ejection fraction >= institutional lower limit of normal (LLN)
  • Women of childbearing potential must have a negative serum pregnancy test within 7 days of the first dose of study treatment
  • Women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control, or abstinence; hormonal contraception is not allowed due to drug-drug interactions) 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 or lapatinib administration
  • Therapeutic level dosing of warfarin can be used with approval by principal investigator and close monitoring of PT/INR by the site; exposure may be decreased due to enzyme induction when on treatment, thus warfarin dosing may need to be adjusted based upon PT/INR; consequently, when discontinuing dabrafenib or lapatinib, warfarin exposure may be increased and thus close monitoring via PT/INR and warfarin dose adjustments must be made as clinically appropriate; prophylactic low dose warfarin may be given to maintain central catheter patency
  • Ability to understand and the willingness to sign a written informed consent document
  • Patient must agree to allow 3 separate biopsies of any malignant lesion; biopsies do not need to be done if:

    • Tumor is not considered accessible by either the investigator or the person performing the biopsy (it is determined the risk is too high due to location near vital organs or too great of a risk of an adverse event)
    • Patient is on anticoagulation and it would be unsafe to temporarily hold the anticoagulation
    • A minimum of 8 subjects must participate in the biopsy part of the study; if at any time there is a total of 10 out of the 18 evaluable subjects who have not had biopsies due to either of the first 2 reasons above, all further subjects who are registered to the study must be included in the biopsy part (i.e., subjects who would have been excluded from having biopsies done due to the above reasons would be excluded from participating in the study)

Exclusion Criteria:

  • Patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A (CYP3A) or CYP family 2, subfamily C, polypeptide 8 (CYP2C8) are ineligible; current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 1 (Bcrp1) should also be excluded

    • Strong CYP3A/2C8/Pgp/Bcrp inhibitor/inducer: clarithromycin, telithromycin, rifamycin class agents (e.g., rifampin, rifabutin, rifapentine), troleandomycin; therapeutic area: antibiotics
    • Strong CYP3A/2C8/Pgp/Bcrp inhibitor/inducer: itraconazole, ketoconazole, posaconazole, voriconazole; therapeutic area: antifungals
    • Strong CYP3A/2C8/Pgp/Bcrp inhibitor/inducer: nefazodone; therapeutic area: antidepressants
    • Strong CYP3A/2C8/Pgp/Bcrp inhibitor/inducer: gemfibrozil; therapeutic area: hyperlipidemia
    • Strong CYP3A/2C8/Pgp/Bcrp inhibitor/inducer: carbamazepine, Phenobarbital, amiodarone, phenytoin, S- mephenytoin; therapeutic area: miscellaneous
    • Strong CYP3A/2C8/Pgp/Bcrp inhibitor/inducer: cyclosporine ; therapeutic area: immunosuppressive agents
  • 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 antiviral drugs and/or cluster of differentiation (CD)4 count is inadequate (< 500); if neither condition exists, HIV-positive patients are eligible
  • 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
  • Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
  • A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency
  • Presence of an invasive malignancy other than the study indication under this trial within 3 years of study enrollment
  • Brain metastases that are symptomatic or requiring corticosteroids (except inhaled); subjects must also be off of enzyme-inducing anticonvulsants for > 4 weeks
  • Corrected QT (QTc) interval >= 480 msecs; 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 lapatinib
  • Medical or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with dabrafenib
Both
18 Years and older
No
United States
 
NCT01947023
NCI-2013-01748, NCI-2013-01748, 9354, 13-061, 9354, P30CA008748, U01CA069856
Yes
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Eric Sherman Memorial Sloan-Kettering Cancer Center
National Cancer Institute (NCI)
March 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP