Clinical trial NCT06475989: Study of Targeted Therapy vs. Chemotherapy in Patients With Thyroid Cancer
Official title: A Randomized Phase III Study of BRAF-Targeted Therapy vs Cabozantinib in RAI-Refractory Differentiated Thyroid Cancer With BRAF V600Em
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Refractory Differentiated Thyroid Gland Carcinoma
Lead sponsor: Eastern Cooperative Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2024-06-26
Enrollment: 264
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility 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

Primary outcomes:
measure: Progression free survival (PFS)
timeFrame: From randomization to radiographic progression of disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or death from any cause, up to 5 years
Secondary outcomes:
measure: Objective response
timeFrame: Up to 5 years
measure: Overall survival
timeFrame: From randomization to death from any cause, up to 5 years
measure: Duration of response
timeFrame: From confirmed response (complete response or partial response) to progression among patients who achieve a response, up to 5 years
measure: PFS2 - the time from randomization to progression on subsequent therapy or death from any cause (whichever occurs first)
timeFrame: From randomization to progression on subsequent therapy or death from any cause, up to 5 years
measure: Incidence of adverse events
timeFrame: at 2 weeks, 4 weeks, 8 weeks, 16 weeks, and then every 12 weeks after the 16-week confirmatory scan
Other outcomes:
measure: Patient tolerability
timeFrame: At baseline, 4, 8, 16, and 28 weeks
Locations:
city: Fort Smith
country: United States
facility: Mercy Hospital Fort Smith
state: Arkansas
city: Little Rock
country: United States
facility: CARTI Cancer Center
state: Arkansas
city: Derby
country: United States
facility: Smilow Cancer Hospital-Derby Care Center
state: Connecticut
city: Fairfield
country: United States
facility: Smilow Cancer Hospital Care Center-Fairfield
state: Connecticut
city: Glastonbury
country: United States
facility: Smilow Cancer Hospital Care Center at Glastonbury
state: Connecticut
city: Greenwich
country: United States
facility: Smilow Cancer Hospital Care Center at Greenwich
state: Connecticut
city: Guilford
country: United States
facility: Smilow Cancer Hospital Care Center - Guilford
state: Connecticut
city: Hartford
country: United States
facility: Smilow Cancer Hospital Care Center at Saint Francis
state: Connecticut
city: New Haven
country: United States
facility: Smilow Cancer Center/Yale-New Haven Hospital
state: Connecticut
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: North Haven
country: United States
facility: Yale-New Haven Hospital North Haven Medical Center
state: Connecticut
city: Stamford
country: United States
facility: Smilow Cancer Hospital Care Center at Long Ridge
state: Connecticut
city: Torrington
country: United States
facility: Smilow Cancer Hospital-Torrington Care Center
state: Connecticut
city: Trumbull
country: United States
facility: Smilow Cancer Hospital Care Center-Trumbull
state: Connecticut
city: Waterbury
country: United States
facility: Smilow Cancer Hospital-Waterbury Care Center
state: Connecticut
city: Waterford
country: United States
facility: Smilow Cancer Hospital Care Center - Waterford
state: Connecticut
city: Boise
country: United States
facility: Saint Alphonsus Cancer Care Center-Boise
state: Idaho
city: Caldwell
country: United States
facility: Saint Alphonsus Cancer Care Center-Caldwell
state: Idaho
city: Coeur d'Alene
country: United States
facility: Kootenai Health - Coeur d'Alene
state: Idaho
city: Emmett
country: United States
facility: Walter Knox Memorial Hospital
state: Idaho
city: Meridian
country: United States
facility: Idaho Urologic Institute-Meridian
state: Idaho
city: Nampa
country: United States
facility: Saint Alphonsus Cancer Care Center-Nampa
state: Idaho
city: Post Falls
country: United States
facility: Kootenai Clinic Cancer Services - Post Falls
state: Idaho
city: Sandpoint
country: United States
facility: Kootenai Clinic Cancer Services - Sandpoint
state: Idaho
city: Alton
country: United States
facility: OSF Saint Anthony's Health Center
state: Illinois
city: Centralia
country: United States
facility: Saint Mary's Hospital
state: Illinois
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: University of Illinois
state: Illinois
city: DeKalb
country: United States
facility: Northwestern Medicine Cancer Center Kishwaukee
state: Illinois
city: Geneva
country: United States
facility: Northwestern Medicine Cancer Center Delnor
state: Illinois
city: Glenview
country: United States
facility: Northwestern Medicine Glenview Outpatient Center
state: Illinois
city: Grayslake
country: United States
facility: Northwestern Medicine Grayslake Outpatient Center
state: Illinois
city: Lake Forest
country: United States
facility: Northwestern Medicine Lake Forest Hospital
state: Illinois
city: Mount Vernon
country: United States
facility: Good Samaritan Regional Health Center
state: Illinois
city: Orland Park
country: United States
facility: Northwestern Medicine Orland Park
state: Illinois
city: Warrenville
country: United States
facility: Northwestern Medicine Cancer Center Warrenville
state: Illinois
city: Cedar Rapids
country: United States
facility: Mercy Hospital
state: Iowa
city: Cedar Rapids
country: United States
facility: Oncology Associates at Mercy Medical Center
state: Iowa
city: Garden City
country: United States
facility: Central Care Cancer Center - Garden City
state: Kansas
city: Great Bend
country: United States
facility: Central Care Cancer Center - Great Bend
state: Kansas
city: Bemidji
country: United States
facility: Sanford Joe Lueken Cancer Center
state: Minnesota
city: Burnsville
country: United States
facility: Minnesota Oncology - Burnsville
state: Minnesota
city: Cambridge
country: United States
facility: Cambridge Medical Center
state: Minnesota
city: Coon Rapids
country: United States
facility: Mercy Hospital
state: Minnesota
city: Edina
country: United States
facility: Fairview Southdale Hospital
state: Minnesota
city: Maple Grove
country: United States
facility: Fairview Clinics and Surgery Center Maple Grove
state: Minnesota
city: Maplewood
country: United States
facility: Minnesota Oncology Hematology PA-Maplewood
state: Minnesota
city: Maplewood
country: United States
facility: Saint John's Hospital - Healtheast
state: Minnesota
city: Minneapolis
country: United States
facility: Abbott-Northwestern Hospital
state: Minnesota
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Minneapolis
country: United States
facility: Health Partners Inc
state: Minnesota
city: Monticello
country: United States
facility: Monticello Cancer Center
state: Minnesota
city: New Ulm
country: United States
facility: New Ulm Medical Center
state: Minnesota
city: Princeton
country: United States
facility: Fairview Northland Medical Center
state: Minnesota
city: Robbinsdale
country: United States
facility: North Memorial Medical Health Center
state: Minnesota
city: Saint Louis Park
country: United States
facility: Park Nicollet Clinic - Saint Louis Park
state: Minnesota
city: Saint Paul
country: United States
facility: Regions Hospital
state: Minnesota
city: Saint Paul
country: United States
facility: United Hospital
state: Minnesota
city: Shakopee
country: United States
facility: Saint Francis Regional Medical Center
state: Minnesota
city: Stillwater
country: United States
facility: Lakeview Hospital
state: Minnesota
city: Thief River Falls
country: United States
facility: Sanford Thief River Falls Medical Center
state: Minnesota
city: Waconia
country: United States
facility: Ridgeview Medical Center
state: Minnesota
city: Willmar
country: United States
facility: Rice Memorial Hospital
state: Minnesota
city: Woodbury
country: United States
facility: Minnesota Oncology Hematology PA-Woodbury
state: Minnesota
city: Worthington
country: United States
facility: Sanford Cancer Center Worthington
state: Minnesota
city: Wyoming
country: United States
facility: Fairview Lakes Medical Center
state: Minnesota
city: Ballwin
country: United States
facility: Saint Louis Cancer and Breast Institute-Ballwin
state: Missouri
city: Bolivar
country: United States
facility: Central Care Cancer Center - Bolivar
state: Missouri
city: Branson
country: United States
facility: Cox Cancer Center Branson
state: Missouri
city: Cape Girardeau
country: United States
facility: Southeast Cancer Center
state: Missouri
city: Joplin
country: United States
facility: Freeman Health System
state: Missouri
city: Joplin
country: United States
facility: Mercy Hospital Joplin
state: Missouri
city: Osage Beach
country: United States
facility: Lake Regional Hospital
state: Missouri
city: Rolla
country: United States
facility: Delbert Day Cancer Institute at PCRMC
state: Missouri
city: Rolla
country: United States
facility: Mercy Clinic-Rolla-Cancer and Hematology
state: Missouri
city: Saint Joseph
country: United States
facility: Heartland Regional Medical Center
state: Missouri
city: Saint Louis
country: United States
facility: Saint Louis Cancer and Breast Institute-South City
state: Missouri
city: Saint Louis
country: United States
facility: Mercy Hospital South
state: Missouri
city: Saint Louis
country: United States
facility: Mercy Hospital Saint Louis
state: Missouri
city: Springfield
country: United States
facility: Mercy Hospital Springfield
state: Missouri
city: Springfield
country: United States
facility: CoxHealth South Hospital
state: Missouri
city: Washington
country: United States
facility: Mercy Hospital Washington
state: Missouri
city: Anaconda
country: United States
facility: Community Hospital of Anaconda
state: Montana
city: Billings
country: United States
facility: Billings Clinic Cancer Center
state: Montana
city: Bozeman
country: United States
facility: Bozeman Health Deaconess Hospital
state: Montana
city: Great Falls
country: United States
facility: Benefis Sletten Cancer Institute
state: Montana
city: Great Falls
country: United States
facility: Great Falls Clinic
state: Montana
city: Kalispell
country: United States
facility: Logan Health Medical Center
state: Montana
city: Missoula
country: United States
facility: Community Medical Center
state: Montana
city: Bismarck
country: United States
facility: Sanford Bismarck Medical Center
state: North Dakota
city: Fargo
country: United States
facility: Sanford South University Medical Center
state: North Dakota
city: Fargo
country: United States
facility: Southpointe-Sanford Medical Center Fargo
state: North Dakota
city: Fargo
country: United States
facility: Sanford Medical Center Fargo
state: North Dakota
city: Fargo
country: United States
facility: Sanford Broadway Medical Center
state: North Dakota
city: Fargo
country: United States
facility: Sanford Roger Maris Cancer Center
state: North Dakota
city: Oklahoma City
country: United States
facility: Mercy Hospital Oklahoma City
state: Oklahoma
city: Baker City
country: United States
facility: Saint Alphonsus Cancer Care Center-Baker City
state: Oregon
city: Ontario
country: United States
facility: Saint Alphonsus Cancer Care Center-Ontario
state: Oregon
city: Erie
country: United States
facility: UPMC Hillman Cancer Center Erie
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute (UPCI)
state: Pennsylvania
city: Westerly
country: United States
facility: Smilow Cancer Hospital Care Center - Westerly
state: Rhode Island
city: Sioux Falls
country: United States
facility: Sanford Cancer Center Oncology Clinic
state: South Dakota
city: Sioux Falls
country: United States
facility: Sanford USD Medical Center - Sioux Falls
state: South Dakota
city: Eau Claire
country: United States
facility: Marshfield Medical Center-EC Cancer Center
state: Wisconsin
city: Marshfield
country: United States
facility: Marshfield Medical Center-Marshfield
state: Wisconsin
city: Minocqua
country: United States
facility: Marshfield Medical Center - Minocqua
state: Wisconsin
city: New Richmond
country: United States
facility: Cancer Center of Western Wisconsin
state: Wisconsin
city: Rice Lake
country: United States
facility: Marshfield Medical Center-Rice Lake
state: Wisconsin
city: Stevens Point
country: United States
facility: Marshfield Medical Center-River Region at Stevens Point
state: Wisconsin
city: Weston
country: United States
facility: Marshfield Medical Center - Weston
state: Wisconsin
city: Cody
country: United States
facility: Billings Clinic-Cody
state: Wyoming
city: Sheridan
country: United States
facility: Welch Cancer Center
state: Wyoming
Study officials:
affiliation: ECOG-ACRIN Cancer Research Group
name: Lova Sun
role: PRINCIPAL_INVESTIGATOR
References: