Study of Targeted Therapy vs. Chemotherapy in Patients With Thyroid Cancer
Purpose
This phase III trial compares the effect of cabozantinib versus combination dabrafenib and trametinib for the treatment of patients with differentiated thyroid cancer that does not respond to treatment (refractory) and which expresses a BRAF V600E mutation. Cabozantinib is in a class of medications called receptor tyrosine kinase inhibitors. It binds to and blocks the action of several enzymes which are often over-expressed in a variety of tumor cell types. This may help stop or slow the growth of tumor cells and blood vessels the tumor needs to survive. Dabrafenib is an enzyme inhibitor that binds to and inhibits the activity of a protein called B-raf, which may inhibit the proliferation of tumor cells which contain a mutated BRAF gene. Trametinib is also an enzyme inhibitor. It binds to and inhibits the activity of proteins called MEK 1 and 2, which play a key role in activating pathways that regulate cell growth. This may inhibit the growth of tumor cells mediated by these pathways. The usual approach for patients with thyroid cancer is targeted therapy with dabrafenib and trametinib. This trial may help researchers decide which treatment option (cabozantinib alone or dabrafenib in combination with trametinib) is safer and/or more effective in treating patients with refractory BRAF V600E-mutated differentiated thyroid cancer.
Condition
- Refractory Differentiated Thyroid Gland Carcinoma
Eligibility
- Eligible Ages
- Over 18 Years
- Eligible Sex
- All
- Accepts Healthy Volunteers
- No
Criteria
Inclusion Criteria:
- Patient must be ≥ 18 years of age
- Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status
0-2
- Patient must have differentiated thyroid cancer (DTC) with BRAF V600E mutation as
determined by local testing, including the following subtypes (Note: results of a
previous biopsy will be accepted):
- Papillary thyroid carcinoma including histological variants of papillary
thyroid carcinoma (PTC) such as follicular variant, tall cell, columnar cell,
cribriform-morular, solid, oxyphil, Warthin-like, trabecular, tumor with
nodular fasciitis-like stroma, Hürthle cell variant of papillary carcinoma,
poorly differentiated.
- Follicular thyroid carcinoma including histological variants of follicular
thyroid carcinoma (FTC) such as Hürthle cell, clear cell, insular, and poorly
differentiated
- Patient must have been previously treated with or deemed ineligible for treatment
with Iodine-131 for DTC, and must be receiving thyroxine suppression therapy
- Patient must have had prior treatment with at least one of the following vascular
endothelial growth factor receptors (VEGFR)-targeting tyrosine kinase inhibitor
(TKI) agents for DTC: lenvatinib or sorafenib.
- NOTE: Up to two prior VEGFR-targeting TKI agents are allowed including, but not
limited to lenvatinib and sorafenib
- Patient must have measurable disease according to Response Evaluation Criteria in
Solid Tumors (RECIST) 1·1 on chest CT (computed tomography)/abdominal/pelvis CT/MRI
(magnetic resonance imaging) performed within 4 weeks prior to randomization
- Patient must have radiographic progression by Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1 over any time interval on or after most recent prior systemic
treatment
- Patient must not have any of the following cardiovascular and thromboembolic
disorders or medical conditions:
- Congestive heart failure class 3 or 4 as defined by the New York Heart
Association, unstable angina pectoris, or serious cardiac arrhythmias.
- Uncontrolled hypertension defined as sustained blood pressure > 150 mm Hg
systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment.
- Stroke, myocardial infarction, or thromboembolic event (e.g., deep venous
thrombosis, pulmonary embolism) within 6 months prior to randomization.
Patients with more recent diagnosis of deep venous thrombosis are allowed if
stable and treated with therapeutic anticoagulation for at least 6 weeks prior
to randomization
- Patient must not have any clinically significant hematemesis or haemoptysis of > 0·5
teaspoon (> 2·5 mL) of red blood or history of other significant bleeding within 3
months prior to randomization
- Patient must not have any cavitating pulmonary lesion(s) or lesions invading major
pulmonary blood vessels
- Patient must not be on any concomitant anticoagulation with oral anticoagulants or
platelet inhibitors, except for the following allowed agents:
- Low-dose aspirin for cardioprotection.
- Therapeutic anticoagulation with any agent in patients (1) without known brain
metastases, (2) on a stable dose for at least 6 weeks prior to randomization,
and (3) with no clinically significant hemorrhagic complications from the
anticoagulation regimen or the tumor
- Patient must not have any gastrointestinal (GI) disorders associated with a high
risk of perforation or fistula formation:
- Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel
disease, ulcerative colitis, diverticulitis, cholecystitis, symptomatic
cholangitis or appendicitis, acute pancreatitis, or acute obstruction of the
pancreatic or biliary duct, or gastric outlet obstruction
- Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal
abscess within 6 months prior to randomization
- Patient must have completed any prior local therapy (e.g., surgery, radiation,
ablation) at least 4 weeks prior to randomization, with complete wound healing and
resolution of clinically relevant complications from prior local therapy
- Patient must not have had major surgery (e.g., GI surgery, removal or biopsy of
brain metastasis) within 8 weeks prior to randomization. Complete wound healing from
major surgery must have occurred 4 weeks prior to randomization and from minor
surgery (e.g., simple excision, tooth extraction) at least 10 days prior to
randomization
- Patient must not have any lesion(s) with ≥ 2cm growth within 3 months or ≥ 1.5cm
growth within 2 months prior to randomization, and must not have documented
anaplastic histology at or following cancer recurrence
- Patient must not have had prior treatment with cabozantinib or any prior BRAF
targeted therapy for thyroid cancer
- Patient must not be pregnant or breast-feeding due to the potential harm to an
unborn fetus and possible risk for adverse events in nursing infants with the
treatment regimens being used.
All patients of childbearing potential must have a blood test or urine study within 14
days prior to randomization to rule out pregnancy.
A patient of childbearing potential is defined as anyone, regardless of sexual
orientation or whether they have undergone tubal ligation, who meets the following
criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or
bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following
cancer therapy does not rule out childbearing potential) for at least 24 consecutive
months (i.e., has had menses at any time in the preceding 24 consecutive months).
- Patients must not expect to conceive or father children by using accepted and
effective method(s) of contraception or by abstaining from sexual intercourse for
the duration of their participation in the study and for 2 weeks after the last dose
of dabrafenib and 4 months after the last dose of trametinib or cabozantinib.
Patients must also not breastfeed while on study treatment and for 2 weeks after the
last dose of dabrafenib and for 4 months after the last dose of trametinib or
cabozantinib.
- NOTE: Patients of childbearing potential who are on hormonal contraceptives may
be at risks because dabrafenib may decrease the efficacy of hormonal
contraceptives. An effective non-hormonal contraception should be used during
therapy and for 2 weeks following discontinuation of dabrafenib and at least 4
months following the last dose of trametinib and cabozantinib
- Patient must have the ability to understand and the willingness to sign a written
informed consent document. Patients with impaired decision-making capacity (IDMC)
who have a legally authorized representative (LAR) or caregiver and/or family member
available will also be considered eligible
- Hemoglobulin (Hgb) ≥ 8 g/dL obtained ≤ 28 days prior to protocol randomization
- Leukocytes ≥ 3,000/mcL obtained ≤ 28 days prior to protocol randomization
- Absolute neutrophil count (ANC) ≥ 1,500/mcL obtained ≤ 28 days prior to protocol
randomization
- Platelets ≥ 100,000/mcL obtained ≤ 28 days prior to protocol randomization
- Total bilirubin ≤ 2.0 x institutional upper limit of normal (ULN) obtained ≤ 28 days
prior to protocol randomization
- Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT])
≤ 3.0 × institutional ULN or < 5.0 x ULN with the presence of hepatic metastasis
obtained ≤ 28 days prior to protocol randomization
- Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m² obtained ≤ 28 days
prior to protocol randomization
- Urine protein/creatinine (UPC) ratio ≥ 1 obtained ≤ 28 days prior to protocol
randomization
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months of randomization are eligible
for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV
viral load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load
- Patients with treated brain metastases are eligible if follow-up brain imaging
obtained after central nervous system (CNS)-directed therapy (radiotherapy and/or
surgery) shows no evidence of progression. CNS disease must be stable for at least 4
weeks prior to randomization; patients must be neurologically asymptomatic and
without corticosteroid treatment at time of randomization
- Patients with a prior or concurrent malignancy whose natural history or treatment
does not have the potential to interfere with the safety or efficacy assessment of
the investigational regimen are eligible for this trial
- Patients must have corrected QT interval calculated by the Fridericia formula (QTcF)
≤ 500 ms obtained within 28 days prior to randomization.
- NOTE: If a single electrocardiogram (ECG) shows a QTcF with an absolute value >
500 ms, two additional ECGs at intervals of approximately 3 minutes (min) must
be performed within 30 min after the initial ECG, and the average of these 3
consecutive results for QTcF will be used to determine eligibility
- Patient must be English or Spanish speaking to be eligible for the quality of life
(QOL) component of the study.
- NOTE: Sites cannot translate the associated QOL forms
Study Design
- Phase
- Phase 3
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel Assignment
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
| Arm | Description | Assigned Intervention |
|---|---|---|
|
Active Comparator Arm A (Dabrafenib and trametinib) |
Patients receive dabrafenib PO BID and trametinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, blood sample collection and may undergo MRI throughout the study. |
|
|
Experimental Arm B (Cabozantinib) |
Patients receive cabozantinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, blood sample collection and may undergo MRI throughout the study. |
|
Recruiting Locations
Anchorage, Alaska 98508
Anchorage, Alaska 99508
Anchorage, Alaska 99508
Anchorage, Alaska 99508
Anchorage, Alaska 99508
Anchorage, Alaska 99508
Fairbanks, Alaska 99701
Fort Smith, Arkansas 72903
Site Public Contact
800-378-9373
Little Rock, Arkansas 72205
Burbank, California 91505
Irvine, California 92612
Napa, California 94558
Site Public Contact
707-521-3830
Orange, California 92868
Palo Alto, California 94304
Santa Rosa, California 95403
Site Public Contact
707-521-3830
Santa Rosa, California 95405
Site Public Contact
707-521-3830
Aurora, Colorado 80045
Site Public Contact
720-848-0650
Highlands Ranch, Colorado 80129
Site Public Contact
720-848-0650
Derby, Connecticut 06418
Fairfield, Connecticut 06824
Glastonbury, Connecticut 06033
Greenwich, Connecticut 06830
Guilford, Connecticut 06437
Hartford, Connecticut 06105
New Haven, Connecticut 06510
New Haven, Connecticut 06520
North Haven, Connecticut 06473
Stamford, Connecticut 06902
Torrington, Connecticut 06790
Trumbull, Connecticut 06611
Waterbury, Connecticut 06708
Waterford, Connecticut 06385
Fort Lauderdale, Florida 33308
Atlanta, Georgia 30308
Site Public Contact
888-946-7447
Boise, Idaho 83706
Boise, Idaho 83712
Caldwell, Idaho 83605
Coeur d'Alene, Idaho 83814
Fruitland, Idaho 83619
Meridian, Idaho 83642
Meridian, Idaho 83642
Nampa, Idaho 83687
Nampa, Idaho 83687
Post Falls, Idaho 83854
Sandpoint, Idaho 83864
Twin Falls, Idaho 83301
Alton, Illinois 62002
Site Public Contact
618-463-5623
Aurora, Illinois 60506
Barrington, Illinois 60010
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847-842-4847
Chicago, Illinois 60611
Chicago, Illinois 60612
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312-355-3046
Chicago, Illinois 60637
Chicago, Illinois 60657
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773-296-5360
Crystal Lake, Illinois 60014
DeKalb, Illinois 60115
Downers Grove, Illinois 60515
Elgin, Illinois 60123
Site Public Contact
847-429-2907
Geneva, Illinois 60134
Glenview, Illinois 60026
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312-695-1102
Grayslake, Illinois 60030
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312-695-1102
Hazel Crest, Illinois 60429
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708-799-9995
Lake Forest, Illinois 60045
Libertyville, Illinois 60048
Libertyville, Illinois 60048
Mount Vernon, Illinois 62864
New Lenox, Illinois 60451
Oak Lawn, Illinois 60453-2699
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800-323-8622
Oak Lawn, Illinois 60453
Orland Park, Illinois 60462
Orland Park, Illinois 60462
Palos Heights, Illinois 60463
Park Ridge, Illinois 60068
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847-384-3621
Shiloh, Illinois 62269
Warrenville, Illinois 60555
Crown Point, Indiana 46307
Ankeny, Iowa 50023
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515-241-3305
Bettendorf, Iowa 52722
Carroll, Iowa 51401
Cedar Rapids, Iowa 52403
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319-365-4673
Cedar Rapids, Iowa 52403
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319-363-2690
Clive, Iowa 50325
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515-241-3305
Clive, Iowa 50325
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515-241-3305
Council Bluffs, Iowa 51503
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712-322-4136
Council Bluffs, Iowa 51503
Council Bluffs, Iowa 51503
Creston, Iowa 50801
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515-241-3305
Des Moines, Iowa 50309
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515-241-6727
Des Moines, Iowa 50309
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515-241-3305
Des Moines, Iowa 50314
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515-282-2200
Des Moines, Iowa 50314
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515-241-3305
Des Moines, Iowa 50314
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515-241-3305
Fort Dodge, Iowa 50501
Iowa City, Iowa 52242
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800-237-1225
Pella, Iowa 50219
Waukee, Iowa 50263
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515-241-3305
West Des Moines, Iowa 50266
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515-241-3305
West Des Moines, Iowa 50266
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515-875-9815
Garden City, Kansas 67846
Great Bend, Kansas 67530
Pittsburg, Kansas 66762
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888-446-3729
Lexington, Kentucky 40536
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859-257-3379
Baltimore, Maryland 21201
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800-888-8823
Alma, Michigan 48801
Alpena, Michigan 49707
Ann Arbor, Michigan 48103
Ann Arbor, Michigan 48106
Ann Arbor, Michigan 48109
Brighton, Michigan 48114
Brighton, Michigan 48114
Brighton, Michigan 48116
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800-865-1125
Canton, Michigan 48188
Canton, Michigan 48188
Chelsea, Michigan 48118
Chelsea, Michigan 48118
Clarkston, Michigan 48346
Detroit, Michigan 48236
East China, Michigan 48054
Flint, Michigan 48503
Flint, Michigan 48503
Flint, Michigan 48503
Flint, Michigan 48503
Gladwin, Michigan 48624
Grosse Pointe Woods, Michigan 48236
Grosse Pointe Woods, Michigan 48236
Grosse Pointe Woods, Michigan 48236
Lansing, Michigan 48912
Livonia, Michigan 48154
Macomb, Michigan 48044
Macomb, Michigan 48044
Midland, Michigan 48670
Mount Pleasant, Michigan 48858
Pontiac, Michigan 48341
Pontiac, Michigan 48341
Pontiac, Michigan 48341
Saginaw, Michigan 48601
Tawas City, Michigan 48764
Warren, Michigan 48093
Warren, Michigan 48093
Warren, Michigan 48093
Ypsilanti, Michigan 48106
Ypsilanti, Michigan 48197
Bemidji, Minnesota 56601
Burnsville, Minnesota 55337
Cambridge, Minnesota 55008
Chaska, Minnesota 55318
Coon Rapids, Minnesota 55433
Coon Rapids, Minnesota 55433
Edina, Minnesota 55435
Edina, Minnesota 55435
Maple Grove, Minnesota 55369
Maple Grove, Minnesota 55369
Maplewood, Minnesota 55109
Maplewood, Minnesota 55109
Minneapolis, Minnesota 55407
Minneapolis, Minnesota 55415
Minneapolis, Minnesota 55454
Monticello, Minnesota 55362
New Ulm, Minnesota 56073
Princeton, Minnesota 55371
Robbinsdale, Minnesota 55422
Saint Louis Park, Minnesota 55416
Saint Paul, Minnesota 55101
Saint Paul, Minnesota 55102
Shakopee, Minnesota 55379
Stillwater, Minnesota 55082
Thief River Falls, Minnesota 56701
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605-312-3320
Waconia, Minnesota 55387
Willmar, Minnesota 56201
Woodbury, Minnesota 55125
Worthington, Minnesota 56187
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605-312-3320
Wyoming, Minnesota 55092
Ballwin, Missouri 63011
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888-446-3729
Bolivar, Missouri 65613
Branson, Missouri 65616
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417-269-4520
Cape Girardeau, Missouri 63703
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888-446-3729
City of Saint Peters, Missouri 63376
Creve Coeur, Missouri 63141
Joplin, Missouri 64804
Joplin, Missouri 64804
Osage Beach, Missouri 65065
Rolla, Missouri 65401
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573-458-6379
Rolla, Missouri 65401
Saint Joseph, Missouri 64506
Springfield, Missouri 65804
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417-269-4520
Springfield, Missouri 65807
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417-269-4520
St Louis, Missouri 63109
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888-446-3729
St Louis, Missouri 63110
St Louis, Missouri 63128
St Louis, Missouri 63129
St Louis, Missouri 63136
St Louis, Missouri 63141
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314-251-7066
Washington, Missouri 63090
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636-390-1600
Anaconda, Montana 59711
Billings, Montana 59101
Bozeman, Montana 59715
Great Falls, Montana 59405
Great Falls, Montana 59405
Havre, Montana 59501
Helena, Montana 59601
Kalispell, Montana 59901
Missoula, Montana 59802
Missoula, Montana 59804
Omaha, Nebraska 68114
Site Public Contact
402-334-4773
Omaha, Nebraska 68114
Site Public Contact
402-354-5144
Chapel Hill, North Carolina 27599
Durham, North Carolina 27710
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888-275-3853
Bismarck, North Dakota 58501
Fargo, North Dakota 58103
Site Public Contact
701-234-6161
Fargo, North Dakota 58103
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605-312-3320
Fargo, North Dakota 58104
Site Public Contact
800-437-4010
Fargo, North Dakota 58122
Fargo, North Dakota 58122
Lawton, Oklahoma 73505
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877-231-4440
Oklahoma City, Oklahoma 73104
Oklahoma City, Oklahoma 73120
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405-752-3402
Baker City, Oregon 97814
Bend, Oregon 97701
Clackamas, Oregon 97015
Coos Bay, Oregon 97420
Hood River, Oregon 97031
Newberg, Oregon 97132
Ontario, Oregon 97914
Oregon City, Oregon 97045
Portland, Oregon 97213
Portland, Oregon 97225
Portland, Oregon 97239
Redmond, Oregon 97756
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541-706-2909
Allentown, Pennsylvania 18103
Bethlehem, Pennsylvania 18017
East Stroudsburg, Pennsylvania 18301
Erie, Pennsylvania 16505
Hazleton, Pennsylvania 18201
Philadelphia, Pennsylvania 19104
Pittsburgh, Pennsylvania 15232
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412-647-8073
Westerly, Rhode Island 02891
Charleston, South Carolina 29425
Sioux Falls, South Dakota 57104
Sioux Falls, South Dakota 57117-5134
Nashville, Tennessee 37204
Site Public Contact
800-811-8480
Nashville, Tennessee 37232
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800-811-8480
Salt Lake City, Utah 84112
Aberdeen, Washington 98520
Bellingham, Washington 98225
Centralia, Washington 98531
Edmonds, Washington 98026
Everett, Washington 98201
Issaquah, Washington 98029
Kennewick, Washington 99336
Lacey, Washington 98503
Longview, Washington 98632
Mount Vernon, Washington 98274
Seattle, Washington 98107
Seattle, Washington 98122-5711
Seattle, Washington 98122
Sedro-Woolley, Washington 98284
Spokane, Washington 99202
Spokane, Washington 99216
Spokane, Washington 99218
Vancouver, Washington 98664
Walla Walla, Washington 99362
Burlington, Wisconsin 53105
Cudahy, Wisconsin 53110
Eau Claire, Wisconsin 54701
Germantown, Wisconsin 53022
Grafton, Wisconsin 53024
Green Bay, Wisconsin 54311
Kenosha, Wisconsin 53142
Marinette, Wisconsin 54143
Marshfield, Wisconsin 54449
Milwaukee, Wisconsin 53209
Milwaukee, Wisconsin 53215
Milwaukee, Wisconsin 53233
Minocqua, Wisconsin 54548
New Richmond, Wisconsin 54017
Oshkosh, Wisconsin 54904
Racine, Wisconsin 53406
Rice Lake, Wisconsin 54868
Sheboygan, Wisconsin 53081
Stevens Point, Wisconsin 54482
Summit, Wisconsin 53066
Two Rivers, Wisconsin 54241
Wauwatosa, Wisconsin 53226
West Allis, Wisconsin 53227
Weston, Wisconsin 54476
Cheyenne, Wyoming 82001
Cody, Wyoming 82414
More Details
- Status
- Recruiting
- Sponsor
- ECOG-ACRIN Cancer Research Group
Study Contact
Detailed Description
PRIMARY OBJECTIVE: I. To compare progression-free survival (PFS) in patients with BRAF V600Em differentiated thyroid cancer who progressed on frontline multikinase inhibitor treated with dabrafenib/trametinib or cabozantinib. SECONDARY OBJECTIVES: I. To compare the objective response rate in patients with BRAF V600Em differentiated thyroid cancer that progressed on frontline multikinase inhibitor treated with dabrafenib/trametinib or cabozantinib. II. To compare the duration of response in patients with BRAF V600Em differentiated thyroid cancer that progressed on frontline multikinase inhibitor treated with dabrafenib/trametinib or cabozantinib. III. To compare the overall survival in patients with BRAF V600Em differentiated thyroid cancer that progressed on frontline multikinase inhibitor treated with dabrafenib/trametinib or cabozantinib. IV. To compare the PFS2 in patients with BRAF V600Em differentiated thyroid cancer that progressed on frontline multikinase inhibitor treated with dabrafenib/trametinib or cabozantinib. V. To compare the safety/tolerability in patients with BRAF V600Em differentiated thyroid cancer that progressed on frontline multikinase inhibitor treated with dabrafenib/trametinib or cabozantinib. QUALITY OF LIFE OBJECTIVE: I. To assess patient tolerability of treatment using the Functional Assessment Cancer Therapy General (FACT G)P5 and general quality of life using the FACT-G7. OUTLINE: Patients are randomized to 1 of 2 arms. Patients may crossover to other treatment arm at the time of progression. ARM A: Patients receive dabrafenib orally (PO) twice per day (BID) and trametinib PO once per day (QD) on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan, blood sample collection and may undergo magnetic resonance imaging (MRI) throughout the study. ARM B: Patients receive cabozantinib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, blood sample collection and may undergo MRI throughout the study. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months thereafter up to 5 years.