Thyroid Carcinoma
Conditions
Keywords
thyroid, medullary, differentiated, radioiodine-resistant, LBH589, panobinostat
Brief summary
The purpose of this study is to evaluate the tumor response rate in patients with metastatic medullary thyroid cancer (MTC) or radioiodine resistant differentiated thyroid cancer (DTC) after receiving treatment with LBH589 20 mg by mouth, three times weekly. Time to progression, overall survival, toxicity, tolerability, and Notch1 protein expression patterns will also be evaluated.
Detailed description
Medullary thyroid cancer (MTC) is a neuroendocrine tumor and accounts for 3-5% of cases of thyroid cancer. The majority of patients with MTC do not present with early stage disease. Differentiated thyroid cancer (DTC) accounts for \>90% of all thyroid cancers. In a sub-set of patients, thyroid cells become resistant to I-131 radioiodine therapy and subsequently develop distant metastases. In both MTC and DTC, systemic chemotherapy for metastatic disease is largely ineffective. LBH589 is a histone deacetylase (HDAC) with recently demonstrated activity to inhibit the Notch1 signaling pathway in MTC cancer cells and suppress tumor cell proliferation in DTC cancer cells. This clinical trial will evaluate the tumor response rate of LBH589 in patients with metastatic MTC or radioactive iodine resistant DTC.
Interventions
DRUGLBH589
LBH589 20mg by mouth three times weekly (Monday/Wednesday/Friday) for 28-day cycles.
Sponsors
Novartis Pharmaceuticals
University of Wisconsin, Madison
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed metastatic medullary or differentiated thyroid cancer. Diagnosis must be confirmed at University of Wisconsin * Patients must have measurable disease as defined by RECIST. * At least 3 weeks from the completion of major surgery, chemotherapy, or other systemic therapy or local liver therapy to study registration * No concurrent chemotherapy or radiation therapy * ECOG Performance Status of ≤ 2 * Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed * Adequate bone marrow, kidney, liver function * Left ventricular ejection fraction ≥ the lower limit of the institutional normal * Those with differentiated thyroid cancer must have radioactive iodine resistant disease, defined by failure to incorporate 131-Iodine after therapy, FDG-avidity on a PET scan, or progression of measurable disease after 131-Iodine therapy or an allergy to radioactive iodine * Hypertension must be well controlled (to less than 150/90 mmHg) on a stable regimen of anti-hypertensive therapy
Exclusion criteria
* Prior HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer * Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first LBH589 treatment * Impaired cardiac function * Concomitant use of drugs with a risk of causing torsades de pointes * Patients with unresolved diarrhea \> CTCAE grade 1 * Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LBH589 * Other concurrent severe and/or uncontrolled medical conditions * Women who are pregnant or breast feeding or women of childbearing potential (WOCBP) not willing to use a double barrier method of contraception during the study and 3 months after last study drug administration. Women of childbearing potential must have a negative serum pregnancy test within 7 days of the first administration of oral LBH589. * Male patients whose sexual partners are WOCBP not using a double method of contraception during the study and 3 months after the end of treatment * Patients with a history of another primary malignancy that, in the opinion of the investigator, would interfere with the assessment of the primary endpoints of the study * Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C * Patients with any significant history of non-compliance to medical regimens or with inability to grant a reliable informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Response Rate to LBH589. | Every 8 weeks. | per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v.1.0) for target lesions and assessed by CT/MRI: Response includes Complete Response (CR, disappearance of all target lesions), or Partial Response (PR, \>=30% decrease in the sum of the longest diameter of target lesions). No Response includes Stable Disease (SD, neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease), and Progressive Disease (PD, at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s).) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression of Thyroid Cancer | Every 3 months until progression up to 5 years | Progression is defined using the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Time to progression is defined as the number of days from the day of first LBH589 administration to the day the patient experienced an event of disease progression or death, whichever came first. Progression was assessed every 3 months until death or up to 5 years, whichever occurred first. |
| Overall Survival | Every 3 months up to 5 years | For a given patient, overall survival (OS) is defined as the number of days from the day of first LBH589 administration until the patient's death. If a patient was alive at the time of analysis, then the patient's data is censored at the date of the last available evaluation.Survival was assessed every three months until death or final data analysis, whichever occurred first. |
| Protein Expression Patterns of Notch1 in Thyroid Tissue Samples. | End of study | — |
| Toxicity of LBH589 | Every 4 weeks, up to 5 years | Most frequent toxicities at least possibly related to panobinostat, grades 2-4 (grading based on NCI common terminology criteria for adverse events CTCAE version 3). Toxicities were collected from the time the patient provided informed consent until 4 weeks after the patient stopped LBH589. |
| Tolerability of LBH589 | Every 4 weeks, up to 5 years | Tolerability and toxicity were not assessed separately, therefore tolerability is reported as toxicity. |
| Impact of LBH589 on Tumor Markers for Thyroid Cancer | Baseline and end of treatment, up to 1 year | Change in serum Thyroglobulin level from baseline to end of treatment. Treatment continued until either extraordinary medical circumstances, disease progression, toxicity, subject withdrawal, or death. At the time subjects came off of study treatment for one of the reasons already listed, a sample was collected for tumor markers. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LBH589 LBH589: LBH589 20mg by mouth three times weekly (Monday/Wednesday/Friday) for 28-day cycles. | 13 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | LBH589 |
|---|---|
| Age, Customized 30-39 years | 1 participants |
| Age, Customized 40-49 years | 2 participants |
| Age, Customized 50-59 years | 2 participants |
| Age, Customized 60-69 years | 6 participants |
| Age, Customized 70-79 years | 2 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 13 |
| serious Total, serious adverse events | 6 / 13 |
Outcome results
Primary
Tumor Response Rate to LBH589.
per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v.1.0) for target lesions and assessed by CT/MRI: Response includes Complete Response (CR, disappearance of all target lesions), or Partial Response (PR, \>=30% decrease in the sum of the longest diameter of target lesions). No Response includes Stable Disease (SD, neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease), and Progressive Disease (PD, at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s).)
Time frame: Every 8 weeks.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LBH589 | Tumor Response Rate to LBH589. | No response | 13 participants |
| LBH589 | Tumor Response Rate to LBH589. | Response | 0 participants |
Secondary
Impact of LBH589 on Tumor Markers for Thyroid Cancer
Change in serum Thyroglobulin level from baseline to end of treatment. Treatment continued until either extraordinary medical circumstances, disease progression, toxicity, subject withdrawal, or death. At the time subjects came off of study treatment for one of the reasons already listed, a sample was collected for tumor markers.
Time frame: Baseline and end of treatment, up to 1 year
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LBH589 | Impact of LBH589 on Tumor Markers for Thyroid Cancer | 4.58 ng/mL | Standard Deviation 716.65 |
p-value: 0.98t-test, 2 sided
Secondary
Overall Survival
For a given patient, overall survival (OS) is defined as the number of days from the day of first LBH589 administration until the patient's death. If a patient was alive at the time of analysis, then the patient's data is censored at the date of the last available evaluation.Survival was assessed every three months until death or final data analysis, whichever occurred first.
Time frame: Every 3 months up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LBH589 | Overall Survival | 18.4 months |
Secondary
Protein Expression Patterns of Notch1 in Thyroid Tissue Samples.
Time frame: End of study
Population: Notch1 protein expression was not measured due to lack of efficiency of study intervention
Secondary
Time to Progression of Thyroid Cancer
Progression is defined using the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Time to progression is defined as the number of days from the day of first LBH589 administration to the day the patient experienced an event of disease progression or death, whichever came first. Progression was assessed every 3 months until death or up to 5 years, whichever occurred first.
Time frame: Every 3 months until progression up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LBH589 | Time to Progression of Thyroid Cancer | 3.6 months |
Secondary
Tolerability of LBH589
Tolerability and toxicity were not assessed separately, therefore tolerability is reported as toxicity.
Time frame: Every 4 weeks, up to 5 years
Secondary
Toxicity of LBH589
Most frequent toxicities at least possibly related to panobinostat, grades 2-4 (grading based on NCI common terminology criteria for adverse events CTCAE version 3). Toxicities were collected from the time the patient provided informed consent until 4 weeks after the patient stopped LBH589.
Time frame: Every 4 weeks, up to 5 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LBH589 | Toxicity of LBH589 | Rash | 1 participants |
| LBH589 | Toxicity of LBH589 | Pulmonary embolism | 1 participants |
| LBH589 | Toxicity of LBH589 | Anemia | 3 participants |
| LBH589 | Toxicity of LBH589 | Leukopenia | 7 participants |
| LBH589 | Toxicity of LBH589 | Neutropenia | 7 participants |
| LBH589 | Toxicity of LBH589 | Lymphopenia | 8 participants |
| LBH589 | Toxicity of LBH589 | Thrombocytopenia | 8 participants |
| LBH589 | Toxicity of LBH589 | Hypoalbuminemia | 3 participants |
| LBH589 | Toxicity of LBH589 | Fatigue | 8 participants |
| LBH589 | Toxicity of LBH589 | Diarrhea | 4 participants |
| LBH589 | Toxicity of LBH589 | Headache | 1 participants |
| LBH589 | Toxicity of LBH589 | Bone Pain | 1 participants |
| LBH589 | Toxicity of LBH589 | Hyperglycemia | 1 participants |
| LBH589 | Toxicity of LBH589 | Hypocalcemia | 2 participants |
| LBH589 | Toxicity of LBH589 | Asthenia | 1 participants |
| LBH589 | Toxicity of LBH589 | Anorexia | 4 participants |
| LBH589 | Toxicity of LBH589 | Anxiety | 1 participants |
| LBH589 | Toxicity of LBH589 | Elevated GGT | 1 participants |