A Phase 2 Trial of Lenvatinib for the Treatment of Anaplastic Thyroid Cancer (ATC)

ClinicalTrials.gov Identifier: NCT02657369

(Information correct August 22nd 2016)

Sponsor: Eisai Inc.

Primary Outcome Measures:
* Objective Response Rate (ORR)

Secondary Outcome Measures:
* Progression-Free Survival (PFS) at Week 12
* Overall Survival (OS) at Month 6
* Median PFS
* Median OS

Estimated Enrollment: 76
Study Start Date: July 2016
Estimated Study Completion Date: May 2018

Inclusion Criteria:
1. Participants must have histological diagnosis consistent of Anaplastic Thyroid Cancer (ATC). Cytologic diagnosis by fine needle aspiration alone is not sufficient. Histologic diagnosis may be made by core needle biopsy, incisional biopsy, thyroidectomy, or other surgical biopsy. Fresh tumor biopsies (re-biopsy) should be obtained whenever feasible. The central pathology review may take place prior to or after the participant starts treatment with lenvatinib.
a. Central review of pathology is required for study participation, but not required prior to enrollment or start of treatment in order to avoid delay. If the results of central pathology review are not available prior to the start of study treatment, the confirmation of diagnosis of ATC at the local laboratory is mandatory prior to scheduled start of treatment with lenvatinib.
b. If central pathology review indicates a diagnosis other than ATC, the participant may continue treatment with lenvatinib per standard of care, at the discretion of the treating investigator. Participants deemed to have another diagnosis (not ATC) will be taken off this study and replaced for the purpose of efficacy analyses.
c. Differentiated thyroid carcinoma (DTC) with focus loci of ATC is allowed. If a participant has pathology showing a small focus of ATC arising out of DTC and the measurable disease is not fully consistent with ATC, confirmation of ATC by biopsy is required.
d. An incidental focus of medullary thyroid cancer (MTC), DTC, and/or poorly differentiated thyroid cancer in a participant with ATC is allowed.
e. Histological diagnosis of ATC made through surgical resection is also acceptable.
2. Prior neoadjuvant, adjuvant, or palliative chemotherapy for ATC is allowed.
3. Measurable disease based on investigator's assessments meeting the following criteria:
a. At least 1 lesion of ? 10 millimeters (mm) in the longest diameter for a non-lymph node or
? 15 mm in the short-axis diameter for a lymph node which is serially measurable according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 using computerized tomography (CT) or magnetic resonance imaging (MRI).
b. Lesions that have had external beam radiotherapy or locoregional therapies such as radiofrequency ablation must show evidence of subsequent progressive disease (substantial size increase of ? 20%) to be deemed a target lesion.
4. Participants with known brain metastases who have completed whole brain radiotherapy, stereotactic radiosurgery, or complete surgical resection will be eligible if they have remained clinically stable, asymptomatic, and off steroids for 1 month prior to enrollment.
5. All previous chemotherapy or radiation therapy-related toxicities, except dry mouth, dysphagia, esophagitis, mucositis, alopecia, and irreversible late sequelae of radiation therapy, must have resolved to Grade 0 or 1 per Common Terminology Criteria for Adverse Events (CTCAE v 4.03), and all wounds from prior surgery must have adequately recovered.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
7. Blood pressure (BP) ? 150/90 millimeter of mercury (mmHg) at screening with or without antihypertensive medications and no change in antihypertensive medications within 1 week prior to Cycle 1/Day 1.
8. Adequate renal function as evidenced by calculated creatinine clearance ? 30 millimeter/ minute (mL/min) according to the Cockcroft and Gault formula.
9. Adequate bone marrow function:
a. Absolute neutrophil count (ANC) ? 1.5 x 10^9/liter (L) and
b. Hemoglobin ? 9.0 grams/deciliter (g/dL) (can be corrected by growth factor or transfusion) and
c. Platelet count ? 100 x 10^9/L.
10. Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) ? 1.5.
11. Adequate liver function:
a. Bilirubin ? 1.5 x upper limit of normal (ULN) except for unconjugated hyperbilirubinemia or Gilbert's syndrome;
b. Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ? 3 x ULN (? 5 x ULN if participant has liver metastases). If ALP is > 3 x ULN (in the absence of liver metastases) or > 5 x ULN (in the presence of liver metastases) AND participants are also known to have bone metastases, the liver-specific ALP must be separated from the total and used to assess the liver function instead of the total ALP.
12. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol.

Exclusion Criteria:
1. Differentiated thyroid cancer (DTC) or MTC. However, ATC arising out of DTC is allowed, as long as the measurable disease is clinically consistent with ATC i.e., rapidly progressive and/or 18F fluorodeoxyglucose (FDG)-avid.
2. Newly diagnosed participants who are considered appropriate candidates for comprehensive multimodality treatment (involving surgery and/or external beam radiotherapy or chemo radiotherapy).
3. Prior treatment with lenvatinib or any tyrosine kinase inhibitor.
4. Major surgery within 2 weeks prior to the first dose of lenvatinib.
5. Any anti-cancer treatment within 21 days or any investigational agent within 30 days before the first dose of study drug.
6. Radiotherapy within 3 weeks prior to the first dose of lenvatinib.
7. Participants having > 1 + proteinuria on urine dipstick testing will undergo 24 hour urine collection for quantitative assessment of proteinuria. Participants with urine protein ? 1 gram/24 hours will be ineligible.
8. Significant cardiovascular impairment: History of (a) congestive heart failure greater than New York Heart Association (NYHA) Class II, (b) unstable angina, (c) myocardial infarction, (d) stroke, or (e) cardiac arrhythmia associated with impairment within 6 months of the first dose of study drug.
9. A clinically significant electrocardiogram (ECG) abnormality, including a marked Baseline prolonged QT/QTc interval (e.g., a repeated demonstration of a QTc interval >500 milliseconds (msec)).
10. Active infection requiring systemic therapy.
11. Clinically significant hemoptysis or tumor bleeding within two weeks prior to first dose of lenvatinib.
12. Radiographic evidence of major blood vessel invasion/infiltration.
13. Other active malignancy (except definitively treated melanoma in-situ, basal or squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix or bladder) within past 24 months.
14. Scheduled for major surgery during the study.
15. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [ß-hCG] or human chorionic gonadotropin [hCG] test with a minimum sensitivity of 25 international units/liter (IU/L) or equivalent units of ß-hCG [or hCG]). A separate Baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
16. Females of childbearing potential who:
a. Had unprotected sexual intercourse within 30 days before study entry and who do not agree to use a highly effective method of contraception (e.g., total abstinence, an intrauterine device, a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period or for 30 days after study drug discontinuation. If a highly effective method of contraception is not appropriate or acceptable to the participant, then the participant must agree to use a medically acceptable method of contraception, e.g., a double-barrier method, such as a condom plus diaphragm with spermicide.
b. Are currently abstinent, and do not agree to use a double-barrier method (as described above) or refrain from sexually active during the study period or for 30 days after study drug discontinuation.
c. Are using hormonal contraceptives but are not on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and who do not agree to use the same contraceptive during the study or for 30 days after study drug discontinuation. It is currently unknown whether lenvatinib may reduce the effectiveness of hormonal contraceptives, and therefore women using oral hormonal contraceptives should add a barrier method.
(NOTE: All females will be considered to be of childbearing potential unless they are postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause] or have been sterilized surgically [i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing]).
17. Evidence of clinically significant disease (e.g., cardiovascular, respiratory, gastrointestinal, renal disease) that in the opinion of the investigator(s) could affect the participant's safety or interfere with the study assessments.
18. Known intolerance to the study drug or any of the excipients.
19. Any medical or other condition that in the opinion of the investigator(s) would preclude the participant's participation in a clinical study.

Contact: Eisai Medical Services 1-888-422-4743

 

Phase II Study Assessing the Efficacy and Safety of Lenvatinib for Anaplastic Thyroid Cancer

ClinicalTrials.gov Identifier: NCT02726503

(Information correct August 22nd 2016)

Sponsor: Translational Research Informatics Center, Kobe, Hyogo, Japan

 

The purpose of this phase ? study is to assess the efficacy and safety of lenvatinib for anaplastic thyroid cancer patients who are diagnosed as unresectable. The total duration of the study will be 30 months. All patients will start administration of lenvatinib within 1 week of enrollment and receive the study drug 24mg orally once daily at almost the same time. 1 cycle consists of 4 weeks. Treatment term starts on the day 1st of drug administration of cycle 1 and administration will be continued until patients meet withdrawal criteria. Safety and efficacy assesment will be conducted on a regular basis during the trial. Tumor evaluation will be conducted at 4weeks, 8 weeks, 12 weeks, 16 weeks and at every 8 weeks after the 16th week since initial administration. When study drug administration terminated,tests of the drug termination will be conducted within 7 days of withdrawal and final observation will be conducted at 30 days after the last dose. Survival survey will be conducted at follow-up term. After the termination of the study drug, survival follow up survey will be conducted every 12 weeks unless patients withdraw enrollment of this study.

Primary Outcome Measures:
* Overall Survival (OS)

Secondary Outcome Measures:
* Progression-Free Survival (PFS).
* Best Overall Response (BOR)
* Objective Response Rate (ORR)
* Disease Control Rate (DCR)
* Clinical Benefit Rate (CBR)
*
* Safety assessment on the incidence ratio of adverse events

Estimated Enrollment:39
Study Start Date: January 2016
Estimated Study Completion Date: July 2018

Inclusion Criteria:
1. Histologically confirmed as anaplastic thyroid cancer
2. Unresectable disease
3. Have measurable lesion defined by the RECIST version 1.1
4. Have adequate organ function and meet following laboratory value:
a. Bone marrow function test within 14 days prior to enrollment:
neutrophil count>=1.5 x 103/microL blood platelet count>=10.0 x 104/microL hemoglobin amount>=9.0 g/dL
b. Liver function test within 14 days prior to enrollment:
AST,ALT<=3.0 x ULN(without liver metastatic) AST,ALT<=5.0 x ULN(with liver metastatic) bilirubin<=2.0 mg/dL
c. Kidney function test within 14 days prior to enrollment:
GFR estimation>=50 ml/min/1.73 m2 GFR estimation calculated by following formula. Male:194 x(serum creatinine concentration)-1.094 x(Age)-0.287 Female:Male GFR estimation x 0.739
d. Cardiac function test within 28 days prior to enrollment: 12-lead electrocardiogram: no clinically important abnormality as shown below: heart disease, severe arrhythmia etc.
5. Regardless of usage of antihypertensive drug, systolic blood pressure <=140 mm Hg and diastolic blood pressure <=90 mm Hg (If already taking antihypertensive drug, must have capacity of further antihypertensive therapy.)
6. ECOG performance status 0-2
7. Ability to swallow oral medications
8. Life expectancy greater than 8 weeks
9. Have signed written informed consent to participate in this study

Exclusion Criteria:
1. Have complications or medical history of
a. Complication of brain metastasis (Exclude if cured and in clinically stable condition for more than 1 month prior to screening.)
b. Treatment required complication of systemic infectious disease
c. Complication of pulmonary fibrosis or interstitial pneumonitis
d. Medical history of clinically significant cardiovascular disease within 6 months of initial dose as: NYHA class above 2 leveled congestive heart failure, unstable angina, cardiac infarction or cardiac arrhythmia with paroxysmal or required treatment e) Uncontrollable complication of diabetes mellitus f) hemoptysis within 3 weeks of enrollment (blood volume of more than half of teaspoon) g) Medical history of hemorrhagic or thrombotic disease within 6 months of enrollment h) If proteinuria values above 2+ by urinary protein qualitative test, conduct 24-hour urine collection and the urine protein determined as 1g/24 hours or more. (can substitute to the ratio of proteinuria in morning urine/creatinine) i) Malabsorption at gastrointestinal tract and any of the complication diseases that investigator considers that will be affected to lenvatinib absorption j) Recent major surgery within 2 weeks (if needle biopsy within 1 week) of enrollment k) Drainage required celomic fluid stagnation
2. Have history of lenvatinib administration
3. Confirmed tumor invasion to the carotid arteries
4. Have history of high dose external radiation therapy to cervical region, and irradiated tumor location close to the carotid arteries.
5. Have any unresolved toxicity greater than 1 by CTCAE v4.0.
6. Have active double cancer
7. Female patients who are pregnant, lactating, breast feeding or have childbearing potential
8. Psychiatric disorder and regarded by the investigator as inadequate for this study enrollment
9. Confirmed as no resistance to any component of this drug
10. Currently receiving other interventional clinical study treatment

Contact: Iwao Sugitani, M.D., Ph.D
03-5814-6219
isugitani@nms.ac.jp

Contact: Makoto Tahara, M.D., Ph.D
04-7133-1111
matahara@east.ncc.go.jp

 

A Phase II Study of MLN0128 in Metastatic Anaplastic Thyroid Cancer

ClinicalTrials.gov identifier: NCT02244463
Information correct 17th Feb 2016

Sponsor: Dana-Farber Cancer Institute
Collaborator: Millennium Pharmaceuticals, Inc

This research study is studying a targeted therapy (ML0N128) as a possible treatment for anaplastic thyroid cancer.
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied. The FDA (the U.S. Food and Drug Administration) has not approved MLN0128 as a treatment for any disease.
MLN0128 prevents tumor cells from dividing and growing by selectively and potently inhibiting a chemical, mTOR kinase, which regulates cell growth and survival. Patients with anaplastic thyroid cancer have been observed to sometimes carry genetic alterations in their tumor cells which may make the cancer more sensitive to inhibition by MLN0128.
In this research study,the investigators are investigating usefulness of MLN0128 in metastatic anaplastic thyroid cancer cases.

Primary Outcome Measures:
* Progression Free Survival [ Time Frame: baseline, 4 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
* Overall All Response Rate
* Overall Survival Rate
* Number of Participants with Serious and Non-Serious Adverse Events
* Identification of biomarkers predictive of response to therapy with MLN0128

Estimated Enrollment: 25
Study Start Date: July 2015
Estimated Study Completion Date: January 2022

Eligibility:
Ages Eligible for Study: 18 Years and older
Genders Eligible for Study: Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:
* Male or female patients 18 years or older
* Any number of prior chemotherapy or targeted agents including rapamycin analogues allowed
* Newly diagnosed or refractory/metastatic anaplastic thyroid cancer confirmed by histology, incurable by surgery, radiotherapy or chemoradiotherapy alone or in combination
* Must have measurable disease
* ECOG performance status 0-2
* No active intracranial metastases
* Tissue for correlative studies must be available
* Ability to swallow oral medications
* Voluntary written consent must be given before performance of any study related procedure
* Adequate organ function, as specified below, within 21 days:
o Bone marrow reserve consistent with: absolute neutrophil count (ANC) ? 1.5 x 109/L; platelet count ? 100 x 109/L; hemoglobin ? 9 g/dL;
o Hepatic: total bilirubin ?1.5 x upper limit of normal (ULN), transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase-AST/SGOT and alanine aminotransferase/serum glutamic pyruvic transaminase-ALT/SGPT) ?2.5 x ULN (?5 x ULN if liver metastases are present);
o Renal: creatinine clearance ?50 mL/min
o Metabolic: fasting serum glucose (? 130 mg/dL) and fasting triglycerides ? 300 mg/dL
o Left ventricular ejection fraction (LVEF) within 5 absolute percentage points of institutional standard of normal as measured by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) within 4 weeks prior to first study drug administration (ie, if the institutional normal is 50%, subject's LVEF may be as low as 45% to be eligible for the study)
* Female patients who:
o Are postmenopausal for at least 1 year before the screening visit, OR
o Are surgically sterile, OR
o If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study drug, or agree to completely abstain from heterosexual intercourse
* Male patients, even if surgically sterilized (ie, status post-vasectomy), who:
o Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, or
o Agree to completely abstain from heterosexual intercourse
* Treatment with strong CYP2C19, CYP3A4, and CYP2C9 inhibitors and/or inducers must be discontinued

Exclusion Criteria:
* Female patients who are both lactating and breastfeeding or have a positive serum pregnancy test during the screening period
* Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment
* Treatment with any investigational products within 14 days
* Failed to recover from the reversible effects of prior anticancer therapies
* Manifestations of malabsorption due to prior gastrointestinal surgery or disease
* Poorly controlled diabetes mellitus
* History of any of the following within the last 6 months prior to study entry:
o Ischemic myocardial event
o Ischemic cerebrovascular event
o Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia
o Placement of a pacemaker for control of rhythm
o New York Heart Association Class III or IV heart failure
o Pulmonary embolism
* Significant active cardiovascular or pulmonary disease at the time of study entry, including:
o Uncontrolled high blood pressure
o Pulmonary hypertension
o Uncontrolled asthma or O2 saturation < 90%
o Significant valvular disease
o Medically significant (symptomatic) bradycardia
o History of arrhythmia requiring an implantable cardiac defibrillator
o Baseline prolongation of the rate-corrected QT interval (QTc)
* Treatment with hematopoietic growth factors, transfusions of blood and blood products, or systemic corticosteroids

Contact: Jochen Lorch, MD
617) 632-3090
JLORCH@partners.org

Locations

United States, Massachusetts
Dana-Farber Cancer Institute
Recruiting
Boston, Massachusetts, United States, 02115
Contact: Jochen Lorch, MD    617-632-3090    jlorch@partners.org   
Principal Investigator: Jochen Lorch, MD

Efatutazone With Paclitaxel Versus Paclitaxel Alone in Treating Patients With Advanced Anaplastic Thyroid Cancer

ClinicalTrials.gov identifier: NCT02152137

Information correct 17th Feb 2016
Sponsor: Alliance for Clinical Trials in Oncology
Collaborators: National Cancer Institute (NCI)
Daiichi Sankyo Inc.

This randomized phase II trial studies how well efatutazone with paclitaxel compared to paclitaxel alone works in treating patients with advanced anaplastic thyroid cancer. Drugs used in chemotherapy, such as efatutazone and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells by stopping them from dividing or by stopping them from spreading. It is not yet known whether efatutazone in combination with paclitaxel is more effective than paclitaxel alone in treating patients with advanced anaplastic thyroid cancer.

Primary Outcome Measures:
* Overall Survival

Secondary Outcome Measures:
* Confirmed response rate
* Progression Free Survival
* Incidence of adverse events, graded according to Common Terminology Criteria for Adverse Events version 4.0

 

Estimated Enrollment: 50
Study Start Date: September 2014
Estimated Primary Completion Date: October 2017

Detailed Description:
This is a Phase 2 randomized study of efatutazone with paclitaxel compared to paclitaxel alone. Patients are randomized to one of two treatment arms, efatutazone in combination with paclitaxel or paclitaxel alone. Protocol therapy will consist of continuous cycles administered every 21 days. Treatment will continue until disease progression, unacceptable adverse events, or a minimum of two cycles beyond a complete response. The primary and secondary objectives are listed below.
Primary objective:
To determine if the combination of paclitaxel and efatutazone improves overall survival (OS) compared to paclitaxel alone in patients with advanced anaplastic thyroid cancer.
Secondary objective:
To compare the confirmed response rate, duration of response, progression-free survival (PFS), and adverse event rates between the combination of paclitaxel and efatutazone vs. paclitaxel alone.
Patients will be followed for every 6 months until 5 years after registration.

 Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
1. Documentation of Disease - Patients must have histologically or cytologically diagnosed advanced anaplastic thyroid cancer (ATC).
2. Patients must have measurable disease as defined in the protocol.
3. Patients must have either metastatic (stage IVC) or locally advanced unresectable disease (stage IVB).
4. Prior Treatment:
o Patients should have resolution of any toxic effects of prior therapy (except alopecia) to NCI CTCAE, Version 4.0, grade 1.
o There is no limit to the number of prior lines of treatment a patient has received.
o No treatment with chemotherapy, radiation therapy, immunotherapy, biological therapy, hormonal therapy, or other thiazolidinediones (TZDs) ? 28 days before study registration.
o No prior taxane therapy ? 6 months, except as a radiosensitizer.
5. No history of the following:
o Class III or IV congestive heart failure (CHF)
o Grade 3 or 4 thromboembolic event ? 6 months
o Pericardial effusion ? 12 months (any grade)
o Pericardial involvement with tumor
o Grade 2 or higher pleural effusion ? 6 months
6. No current symptomatic, untreated, or uncontrolled brain metastases present
7. No major surgery ? 28 days prior to registration
8. No grade 2 or higher neuropathy
9. No known history of severe hypersensitivity reactions to any of the components of efatutazone or paclitaxel formulations
10. Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done ? 7 days prior to registration is required
11. Age ? 18 years
12. Concomitant Medications:
o Patients with diabetes mellitus requiring concurrent treatment with insulin or thiazolidinedione (TZD) oral agents are not eligible.
o Patients with known hypersensitivity to any TZD oral agents are not eligible.
13. Eastern Cooperative Oncology Group (ECOG) Performance Status ? 2
14. Required Initial Laboratory Values:
o Absolute Neutrophil Count (ANC) ? 1,500/mm3
o Platelet Count ? 100,000/mm3
o Creatinine ? 1.5 x ULN (Upper Limit of Normal) mg/dL OR
o Calculated Creatinine Clearance ? 60 mL/min
o Bilirubin ? 1.5 x ULN
o Aspartate aminotransferase (AST) ? 2.5 x ULN
o

Contact: Robert Smallridge, MD
904 953-2392

Ceritinib (LDK378) in Mutation,Oncogene Directed Therapy in Metastatic or Locally Advanced Anaplastic/Undifferentiated Thyroid Cancer

ClinicalTrials.gov identifier: NCT02289144

Information correct 17th Feb 2016

Sponsor: University of Texas Southwestern Medical Center
Collaborator: Novartis

Purpose
This is an, open-label, protocol designed to evaluate the activity of targeted therapy in anaplastic/undifferentiated thyroid cancer. Arm A will evaluate ATC/UTC with mutations or rearrangements detected in the ALK gene.
There is no effective treatment for anaplastic thyroid cancer in the locally recurrent or metastatic setting. Ceritinib will be administered to the patient until disease progression by RECIST 1.1, unacceptable toxicity, withdrawal of consent, or discontinuation of the trial for any other reason.
The primary focus of this arm of the protocol is identifying ceritinib's activity in anaplastic or undifferentiated thyroid cancer patients. Those patients with mutations identified in their ALK gene by sequencing their tumor samples, or with the established ALK abnormalities will be treated with ALK-inhibitors. These include the Ventana assay and Vysis FISH probe, and patients with tumors positive by this assay will also be considered eligible for therapy on the trial.

Therapeutic Portion:
ARM A: ALK Abnormality IND Ceritinib 750 mg orally daily on Day 1 Continue q4 weeks x 2 cycles

Primary Endpoint: The development of progression; new recurrence or distant metastasis, as well as enlargement of an existing metastasis on radiographic imaging.

Secondary Endpoints:
1. Overall response rate for patients treated with ceritinib as part of the study.
2. Death of study participant due to any cause.

 

Estimated Enrollment: 10
Study Start Date: June 2015
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: December 2017

Detailed Description:
This is an, open-label, protocol designed to evaluate the activity of targeted therapy in anaplastic/undifferentiated thyroid cancer. Arm A will evaluate ATC/UTC with mutations or rearrangements detected in the ALK gene.
There is no effective treatment for anaplastic thyroid cancer in the locally recurrent or metastatic setting. Ceritinib will be administered to the patient until disease progression by RECIST 1.1, unacceptable toxicity, withdrawal of consent, or discontinuation of the trial for any other reason.
The primary focus of this arm of the protocol is identifying ceritinib's activity in anaplastic or undifferentiated thyroid cancer patients. Those patients with mutations identified in their ALK gene by sequencing their tumor samples, or with the established ALK abnormalities will be treated with ALK-inhibitors. These include the Ventana assay and Vysis FISH probe, and patients with tumors positive by this assay will also be considered eligible for therapy on the trial.
The goal of this multi-center, multi-arm trial is to measure the impact of treating metastatic anaplastic thyroid cancer patients with targeted therapy selected for these patients due the presence of a genetic mutation or other aberration. This trial will serve as a framework by which new biomarker-drug combinations can be identified and added as new arms.

Therapeutic Portion:
ARM A: ALK Abnormality IND Ceritinib 750 mg orally daily on Day 1 Continue q4 weeks x 2 cycles

Primary Endpoint: The development of progression; new recurrence or distant metastasis, as well as enlargement of an existing metastasis on radiographic imaging. CT scans of the neck, chest, abdomen and pelvis will be performed at baseline and every two cycles (cycles are 28 days long) according to standard of care. Other imaging of these areas such as PET/MRI will be allowed if CT cannot be performed. MRI of the brain will be performed at baseline and as clinically indicated. Wherever it can be safely given, radiographic contrast agents should be given for the imaging studies.

Secondary Endpoints:
1. Overall response rate for patients treated with ceritinib as part of the study.
2. Death of study participant due to any cause.
 
Ages Eligible for Study:  18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:
1. Histologically or cytologically confirmed diagnosis of anaplastic thyroid cancer or undifferentiated thyroid cancer that demonstrates mutation in the ALK gene as assessed by sequencing of the tumor specimen for Arm A. Other ALK abnormalities as detected by the approved FISH test (Abbott Molecular Inc), using Vysis breakapart probes (defined as 15% or more positive tumor cells); or the Ventana IHC test will also be seen as evidence of ALK abnormality and meeting eligibility requirement.
2. Patients will not have any other curative therapeutic option, such as radiation or surgery.
3. WHO performance status 0-2.
4. Age greater then or equal to 18 years.
5. Patients must have recovered from all toxicities related to prior anticancer therapies to ? Grade 2 (CTCAE v 4.03), provided that any concomitant medication is given prior to initiation of treatment with ceritinib. Exception to this criterion: patients with any grade of alopecia are allowed to enter the treatment.
6. Adequate organ function: the following laboratory criteria have been met:
o Absolute neutrophil count (ANC) greater then or equal to 1.5 x 109/L
o Hemoglobin (Hgb) ? 8 g/dL
o Platelets greater then or equal to 75 x 109/L
o Serum total bilirubin ? 1.5 x upper limit of normal (ULN), except for patients with Gilbert's syndrome who may be included if total bilirubin ? 3.0 x ULN and direct bilirubin ? 1.5 x ULN
o Aspartate transaminase (AST) < 2.0 x ULN, except for patients with liver metastasis, who are only included if AST < 3 x ULN; alanine transaminase (ALT) < 2.0 x ULN, except for patients with liver metastasis, who are only included if ALT < 3 x ULN
o Calculated or measured creatinine clearance (CrCL) less then or equal to 30 mL/min
7. Patient must have the following laboratory values or have the following laboratory values corrected with supplements to be within normal limits at screening:
o Potassium ? LLN
o Magnesium ? LLN
o Phosphorus ? LLN
o Total calcium (corrected for serum albumin) ? LLN
8. Written informed consent for the protocol must be obtained prior to any screening procedures.
9. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other procedures.

Exclusion Criteria:
* Patients eligible must not meet any of the following criteria:
a. Patients with known hypersensitivity to any of the excipients of ceritinib (microcrystalline cellulose, mannitol, crospovidone, colloidal silicon dioxide and magnesium stearate).
b. Patients with symptomatic CNS metastases who are neurologically unstable or have required increasing doses of steroids within the 1 week prior to study entry to manage CNS symptoms.
c. Prior therapy with ceritinib.
d. Presence or history of a malignant disease other than thyroid cancer that has been diagnosed and/or required therapy within the past year and is undergoing active anticancer treatment. Exceptions to this exclusion include the following: completely resected basal cell and squamous cell skin cancers, and completely resected carcinoma in situ of any type.
e. Patients with known history of extensive disseminated bilateral interstitial fibrosis or interstitial lung disease, including a history of pneumonitis, hypersensitivity pneumonitis, interstitial pneumonia, obliterative bronchiolitis, and clinically significant radiation pneumonitis (i.e. affecting activities of daily living or requiring therapeutic intervention).
f. Patient has clinically significant, uncontrolled heart disease and/or recent cardiac event (within 6 months), such as:
* unstable angina within 6 months prior to screening;
* myocardial infarction within 6 months prior to screening;
* history of documented congestive heart failure (New York Heart Association functional classification III-IV);
* uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ? 160 mm Hg and/or Diastolic Blood Pressure (DBP) ? 100 mm Hg, with or without antihypertensive medication
* initiation or adjustment of antihypertensive medication(s) is allowed prior to screening;
* ventricular arrhythmias; supraventricular and nodal arrhythmias not controlled with medication;
* other cardiac arrhythmia not controlled with medication;
* corrected QTc > 450 msec using Fridericia correction on the screening ECG
g. Impaired GI function or GI disease that may alter absorption of ceritinib or inability to swallow up to five ceritinib capsules daily.
h. Ongoing GI adverse events > grade 2 (e.g. nausea, vomiting, or diarrhea) at the start of the study.
i. Receiving medications that meet one of the following criteria and that cannot be discontinued at least 1 week prior to the start of treatment with ceritinib and for the duration of participation (see Appendix 1 Tables):
* Medication with a known risk of prolonging the QT interval or inducing Torsades de Pointes (please refer to http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm)
* Strong inhibitors or strong inducers of CYP3A4/5 (please refer to http://medicine.iupui.edu/flockhart/table.htm or http://www.druginteractioninfo.org)
* Medications with a low therapeutic index that are primarily metabolized by CYP3A4/5, CYP2C8 and/or CYP2C9 (please refer to http://medicine.iupui.edu/flockhart/table.htm or http://www.druginteractioninfo.org)
* Therapeutic doses of warfarin sodium (Coumadin) or any other coumadin-derived anti-coagulant. Anticoagulants not derived from warfarin are allowed (eg, dabigatran, rivaroxaban, apixaban).
* Unstable or increasing doses of corticosteroids
* enzyme-inducing anticonvulsive agents
* herbal supplements
j. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
k. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and agree to continue for 3 months after the last dose of study treatment. Highly effective contraception methods include:
* Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
* Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
* Male sterilization (at least 6 months prior to screening) with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate. For female subjects on the study the vasectomized male partner should be the sole partner for that subject.
* Combination of any two of the following (a+b or a+c or b+c):
a. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception.
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS).
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository.
In case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to screening. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
l. Sexually active males unless they agree to use a condom during intercourse while taking drug and agree to continue for 3 months after the last dose of study treatment. Male patients for 3 months should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.

Contact: Pamela Kurian
214-648-5874
Pamela.Kurian@UTSouthwestern.edu

UT Southwestern Medical Center

Dallas, Texas, United States, 75390
Contact: Pamela Kurian    214-648-5874    Pamela.Kurian@UTSouthwestern.edu   
Principal Investigator: Saad A Khan, MD         

 

Intensity-Modulated Radiation Therapy and Paclitaxel With or Without Pazopanib Hydrochloride in Treating Patients With Anaplastic Thyroid Cancer

ClinicalTrials.gov identifier: NCT01236547

Information correct 17th Feb 2016
Sponsor: National Cancer Institute (NCI)

This randomized phase II trial studies the side effects and how well intensity-modulated radiation therapy (IMRT) and paclitaxel with or without pazopanib hydrochloride works in treating patients with anaplastic thyroid cancer. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs used in chemotherapy, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Pazopanib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether radiation therapy and paclitaxel are more effective when given with pazopanib hydrochloride in treating thyroid cancer.

Primary Outcome Measures:
* Discontinuation of treatment due to toxicity, grade 4 (CTCAE v. 4.0) hemorrhage, grade 4 febrile neutropenia, or any grade 5 adverse event that is assessed to be definitely, probably, or possibly related to the induction or concurrent treatment [ Time Frame: Up to 8 years ] [ Designated as safety issue: Yes ]
* Overall survival (Phase II) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
Estimated using the Kaplan-Meier method. The distributions of the overall survival times will be compared between treatment arms with a one sided log rank test.

 

Secondary Outcome Measures:
* Grade 4 (CTCAE, v. 4.0) hemorrhage, grade 4 febrile neutropenia, discontinuation of treatment due to toxicity, or any grade 5 adverse event (Phase II) [ Time Frame: Up to 8 years ] [ Designated as safety issue: Yes ]
Only adverse events (AEs) assessed to be definitely, probably, or possibly related to protocol treatment will be considered. The rates of adverse events, discontinuation of treatment, and response will be estimated using a binomial distribution along with their associated 95% confidence intervals and will be compared using Fisher's exact test.

* Local-regional control (Phase II) [ Time Frame: Up to 12 months ] [ Designated as safety issue: No ]
Estimated by the cumulative incidence method at 6 and 12 months.

* Other adverse events (CTCAE, v. 4.0) assessed to be definitely, probably, or possibly related to adjuvant paclitaxel or pazopanib/placebo after concurrent treatment (Phase II) [ Time Frame: Up to 8 years ] [ Designated as safety issue: Yes ]
Only AEs assessed to be definitely, probably, or possibly related to protocol treatment will be considered. The rates of adverse events, discontinuation of treatment, and response will be estimated using a binomial distribution along with their associated 95% confidence intervals and will be compared using Fisher's exact test.

* Response of the primary site in patients with measurable disease following chemoradiation as per RECIST version 1.1 (Phase II) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
Estimated using a binomial distribution along with their associated 95% confidence intervals and will be compared using Fisher's exact test.

Estimated Enrollment: 121
Study Start Date: October 2010
Estimated Primary Completion Date: October 2018

Experimental: Arm I (paclitaxel, pazopanib hydrochloride, IMRT)
Patients receive paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD for 2-3 weeks. Patients then receive concurrent paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD for 6-7 weeks (or until radiation treatment is completed) and IMRT 5 days per week for 6.5 weeks (total of 66 Gy in 33 fractions). Beginning 25-31 days after the completion of IMRT, patients receive paclitaxel IV over 1 hour once weekly and pazopanib hydrochloride PO QD. Treatment repeats every 3 weeks for 4 courses (for patients with no measurable disease) or continues in the absence of disease progression or unacceptable toxicity (for patients with measurable disease).

Active Comparator: Arm II (paclitaxel, placebo, IMRT)
Patients receive paclitaxel IV over 1 hour once weekly and placebo PO QD for 2-3 weeks. Patients then receive concurrent paclitaxel IV over 1 hour once weekly and placebo PO QD for 6-7 weeks (or until radiation treatment is completed) and IMRT 5 days per week for 6.5 weeks (total of 66 Gy in 33 fractions). Beginning 25-31 days after the completion of IMRT, patients receive paclitaxel IV over 1 hour once weekly and placebo PO QD. Treatment repeats every 3 weeks for 4 courses (for patients with no measurable disease) or continues in the absence of disease progression or unacceptable toxicity (for patients with measurable disease).

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:
* Pathologically (histologically or cytologically) proven diagnosis of anaplastic thyroid cancer (a diagnosis that is noted to be "consistent with anaplastic thyroid cancer" with the presence of a thyroid mass is acceptable)
o Note: Tissue collection for central review is mandatory, but central review is not required for eligibility; treatment will be started prior to central review
* If there was a total or partial thyroidectomy completed within 3 months of enrollment, the surgical specimen must show the area of anaplastic thyroid cancer to be at least 1 cm in greatest dimension
* The following minimum diagnostic workup is required:
o History/physical examination within 2 weeks prior to registration
o Imaging of neck and brain (computed tomography [CT] scan or magnetic resonance imaging [MRI]) and chest/abdominal imaging (chest x-ray or chest CT scan, or full body positron emission tomography [PET]/CT are acceptable) within 4 weeks prior to registration
o Note: The CT scan of the neck must be done with contrast or if an MRI is done, with gadolinium; therefore, the CT portion of a full body PET/CT has to be a high resolution CT to be acceptable for eligibility
o Abdominal imaging must cover the liver and adrenal glands; therefore, separate imaging is not required if these areas are covered by a chest CT scan
* Electrocardiogram within 10 days prior to registration
* Zubrod performance status 0-2
* Absolute neutrophil count (ANC) >= 1,500 cells/mm^3
* Platelets >= 100,000 cells/mm^3
* Hemoglobin (Hgb) >= 9.0 g/dL (note: the use of transfusion or other intervention to achieve Hgb >= 9.0 g/dL is acceptable)
* Total bilirubin < 1.5 x institutional upper limit of normal (ULN) (except for patients with Gilbert's syndrome and elevations of indirect bilirubin)
* Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 2.5 x institutional ULN ; note: patients who have both bilirubin > ULN and AST/ALT > ULN are not eligible (unless they have Gilbert's syndrome and elevations of indirect bilirubin)
* Spot urine protein to creatinine ratio (UPCR) < 1 or a 24-hour urine protein collection < 1 gm) within 10 days prior to registration
* Creatinine < 1.5 mg/dL or within normal institutional limits; Note: if neither criteria is met, the creatinine clearance must be > 50 mL/min^2 per either the Cockcroft-Gault equation, Jeliffe method, or 12- or 24-hour urine collection
* Serum electrolytes including sodium, potassium, blood urea nitrogen (BUN), creatinine, glucose, magnesium, phosphate, and calcium within 10 days prior to registration
* Documentation of the patient's history of corrected QT interval (QTc) prolongation, family history of prolonged QTc, and relevant cardiac disease within 10 days prior to registration
* Evaluation of the patient's medications within 10 days prior to registration with attempt to change any medication that affects cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)
* Blood pressure =< 140/90 within 10 days of registration (must be taken and recorded by a health care professional); Note: if the systolic blood pressure is > 140 and/or diastolic blood pressure is > 90 at the time of registration, the patient's blood pressure must be controlled; systolic blood pressure must be < 140 and diastolic blood pressure must be < 90 on at least 2 separate measurements prior to the start of treatment, and the treating physician must believe that this is feasible in order to enroll the patient
* Prothrombin time (PT)/international normalized ratio (INR)/partial thromboplastin time (PTT) within 1.2 x the upper limit of normal within 10 days prior to registration unless the patient is receiving Coumadin and has a stable INR that is in range for the desired level of anticoagulation
* Negative pregnancy test (serum or urine) within 10 days of registration in women of child-bearing potential
* Women of childbearing potential and male participants who are sexually active must agree to practice adequate contraception during treatment and for 6 months post-treatment
* The patient must provide study specific informed consent prior to study entry

Exclusion Criteria:
* Known active invasive malignancy (except for non-melanomatous skin cancer or anaplastic thyroid cancer; the presence of prostate cancer confined to the prostate with a prostate-specific antigen [PSA] =< 1 ng/mL for more than 6 months also is allowed)
* Prior systemic chemotherapy for anaplastic thyroid cancer
o Patients who have had chemotherapy or radiotherapy within 4 weeks of registration (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 > 4 weeks previously
o Patients receiving other investigational agents
* Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields
* Patients with any of the following cardiovascular conditions within the past 6 months:
o Cerebrovascular accident (CVA) or transient ischemic attack (TIA)
o Admission for unstable angina
o Myocardial Infarction
o Cardiac angioplasty or stenting
o Coronary artery bypass graft surgery
o Pulmonary embolism, untreated deep venous thrombosis (DVT), or DVT which has been treated with therapeutic anticoagulation for less than 6 weeks
o Arterial thrombosis
o Symptomatic peripheral vascular disease
o Class II or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system; Note: a patient who has a history of class II heart failure and is asymptomatic on treatment may be considered eligible for the study
* Certain medications that are associated with a risk for QTc prolongation and/or Torsades de Pointes, although not prohibited, should be avoided or replaced with medications that do not carry these risks, if possible
* Patients who require heparin (other than low-molecular weight heparin)
* Patients with any condition that may impair the ability to absorb oral medications/investigational product including:
o Prior surgical procedures affecting absorption including, but not limited to, major resection of stomach or small bowel
o Active peptic ulcer disease
o Malabsorption syndrome
* Patients with any condition that may increase the risk of gastrointestinal bleeding or gastrointestinal perforation, including:
o Active peptic ulcer disease
o Known intraluminal metastatic lesions
o Inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease) or other gastrointestinal conditions which increase the risk of perforation
o History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment
* History of hemoptysis within 30 days of registration; Note: patients who have minimal bleeding from the mouth which is clearly not related to a source in the lungs i.e., surgery such as a non-lung biopsy are eligible only after good hemostasis has been documented
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection or psychiatric illness/social situations that would limit compliance with study requirements
* Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception
* Prior allergic reaction to the study drug(s) involved in this protocol
* QTc prolongation defined as a QTc interval >= 480 msecs or other significant electrocardiogram (EKG) abnormalities are ineligible; Note: if unsure about EKG abnormality, the treating physician should discuss this with Drs. Sherman or Bible
* Known brain metastasis
* Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy
* Certain medications that act through the cytochrome P450 (CYP450) system are specifically prohibited in patients receiving pazopanib and others should be avoided or administered with extreme caution
o Strong inhibitors of CYP3A4 such as ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole may increase pazopanib concentrations and are prohibited; although, in exceptional circumstances, they may be administered in conjunction with lowering the dose of pazopanib by 50% of what would otherwise be administered; grapefruit juice is also an inhibitor of CYP450 and should not be taken with pazopanib
o Strong inducers of CYP3A4, such as rifampin, may decrease pazopanib concentrations, are strictly prohibited
o Medications that have narrow therapeutic windows and are substrates of CYP3A4, cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6), or cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) should be avoided and, if necessary, administered with caution

Sponsors and Collaborators
National Cancer Institute (NCI)

Principal Investigator: Eric Sherman
NRG Oncology