Trial of LBH589 in Metastatic Thyroid Cancer

• Sponsor: University of Wisconsin, Madison (Other)
• Overall Status: Completed
• CT.gov ID: NCT01013597
• Collaborator: Novartis Pharmaceuticals (Industry)
• Enrollment: 13
• Locations: 3
• Arm: 1
• Duration (Months): 73
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Thyroid Carcinoma	Drug: LBH589	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of LBH589 in Patients With Metastatic Medullary Thyroid Cancer and Radioactive Iodine Resistant Differentiated Thyroid Cancer
• Study Start Date: Jan 1, 2010
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: Feb 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LBH589	Drug: LBH589; LBH589 20mg by mouth three times weekly (Monday/Wednesday/Friday) for 28-day cycles.; Other Names: panobinostat

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. Protein Expression Patterns of Notch1 in Thyroid Tissue Samples. [End of study]

2. 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.

3. 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.

4. 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.

5. 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.

6. Tolerability of LBH589 [Every 4 weeks, up to 5 years]

   Tolerability and toxicity were not assessed separately, therefore tolerability is reported as toxicity.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St. Vincent Regional Cancer Center CCOP	Green Bay	Wisconsin	United States	54301
2	University of Wisconsin - Madison	Madison	Wisconsin	United States	53792
3	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• University of Wisconsin, Madison
• Novartis Pharmaceuticals

Investigators

• Principal Investigator: Anne Traynor, M.D., University of Wisconsin, Madison

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• University of Wisconsin Carbone Cancer Center

Publications

None provided.

• Responsible Party: University of Wisconsin, Madison
• ClinicalTrials.gov Identifier: NCT01013597
• Other Study ID Numbers: H-2009-0173; CO08322; H-2009-0173; NCI-2011-00715; A534260; SMPH\MEDICINE\HEM-ONC
• First Posted: Nov 13, 2009
• Last Update Posted: Nov 29, 2019
• Last Verified: Mar 1, 2017

• Keywords provided by University of Wisconsin, Madison: thyroid; medullary; differentiated; radioiodine-resistant; LBH589; panobinostat
• Additional relevant MeSH terms: Thyroid Neoplasms; Thyroid Diseases; Panobinostat

Study Results

Participant Flow

Arm/Group Title	LBH589
Arm/Group Description	LBH589: LBH589 20mg by mouth three times weekly (Monday/Wednesday/Friday) for 28-day cycles.
Period Title: Overall Study
STARTED	13
COMPLETED	12
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	LBH589
Arm/Group Description	LBH589: LBH589 20mg by mouth three times weekly (Monday/Wednesday/Friday) for 28-day cycles.
Overall Participants	13
Age, Customized (participants) [Number]
30-39 years	1 7.7%
40-49 years	2 15.4%
50-59 years	2 15.4%
60-69 years	6 46.2%
70-79 years	2 15.4%
Sex: Female, Male (Count of Participants)
Female	7 53.8%
Male	6 46.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	13 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 7.7%
White	12 92.3%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	13 100%

Outcome Measures

1. Primary Outcome

Title	Tumor Response Rate to LBH589.
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	LBH589
Arm/Group Description	LBH589: LBH589 20mg by mouth three times weekly (Monday/Wednesday/Friday) for 28-day cycles.
Measure Participants	13
No response	13 100%
Response	0 0%

2. Secondary Outcome

Title	Protein Expression Patterns of Notch1 in Thyroid Tissue Samples.
Time Frame	End of study

Outcome Measure Data

Analysis Population Description

Notch1 protein expression was not measured due to lack of efficiency of study intervention

Arm/Group Title	LBH589
Arm/Group Description	LBH589: LBH589 20mg by mouth three times weekly (Monday/Wednesday/Friday) for 28-day cycles.
Measure Participants	0

3. Secondary Outcome

Title	Time to Progression of Thyroid Cancer
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	LBH589
Arm/Group Description	LBH589: LBH589 20mg by mouth three times weekly (Monday/Wednesday/Friday) for 28-day cycles.
Measure Participants	13
Median (95% Confidence Interval) [months]	3.6

4. Secondary Outcome

Title	Overall Survival
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	LBH589
Arm/Group Description	LBH589: LBH589 20mg by mouth three times weekly (Monday/Wednesday/Friday) for 28-day cycles.
Measure Participants	13
Median (95% Confidence Interval) [months]	18.4

5. Secondary Outcome

Title	Impact of LBH589 on Tumor Markers for Thyroid Cancer
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	LBH589
Arm/Group Description	LBH589: LBH589 20mg by mouth three times weekly (Monday/Wednesday/Friday) for 28-day cycles.
Measure Participants	11
Mean (Standard Deviation) [ng/mL]	4.58 (716.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LBH589
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.98
	Comments
	Method	t-test, 2 sided
	Comments

6. Secondary Outcome

Title	Toxicity of LBH589
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	LBH589
Arm/Group Description	LBH589: LBH589 20mg by mouth three times weekly (Monday/Wednesday/Friday) for 28-day cycles.
Measure Participants	13
Anemia	3 23.1%
Leukopenia	7 53.8%
Neutropenia	7 53.8%
Lymphopenia	8 61.5%
Thrombocytopenia	8 61.5%
Hypoalbuminemia	3 23.1%
Fatigue	8 61.5%
Diarrhea	4 30.8%
Headache	1 7.7%
Bone Pain	1 7.7%
Hyperglycemia	1 7.7%
Hypocalcemia	2 15.4%
Asthenia	1 7.7%
Rash	1 7.7%
Anorexia	4 30.8%
Anxiety	1 7.7%
Elevated GGT	1 7.7%
Pulmonary embolism	1 7.7%

7. Secondary Outcome

Title	Tolerability of LBH589
Description	Tolerability and toxicity were not assessed separately, therefore tolerability is reported as toxicity.
Time Frame	Every 4 weeks, up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	LBH589
Arm/Group Description	LBH589: LBH589 20mg by mouth three times weekly (Monday/Wednesday/Friday) for 28-day cycles.
Measure Participants	0

Adverse Events

Arm/Group Title	LBH589
Arm/Group Description	LBH589: LBH589 20mg by mouth three times weekly (Monday/Wednesday/Friday) for 28-day cycles.
All Cause Mortality
	LBH589
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	LBH589
	Affected / at Risk (%)	# Events
Total	6/13 (46.2%)
Blood and lymphatic system disorders
Neutrophils/granulocytes (ANC/AGC)	1/13 (7.7%)
Platelets	1/13 (7.7%)
General disorders
Death, NOS	3/13 (23.1%)
Hemorrhage/bleeding	1/13 (7.7%)
Infections and infestations
Colitis, infectious	1/13 (7.7%)
Nervous system disorders
CNS cerebrovascular ischemia	1/13 (7.7%)
Other	1/13 (7.7%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion, non-malignant	1/13 (7.7%)
Vascular disorders
Thrombosis/thrombus/embolism	1/13 (7.7%)
Other (Not Including Serious) Adverse Events
	LBH589
	Affected / at Risk (%)	# Events
Total	0/13 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.