Study of Panobinostat in Patients With Neuroendocrine Tumors

• Sponsor: University of Wisconsin, Madison (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00985946
• Collaborator: Novartis Pharmaceuticals (Industry)
• Enrollment: 15
• Location: 1
• Arm: 1
• Duration (Months): 59
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This summary will use Panobinostat (LBH589) in patients with neuroendocrine tumors to see how the patient's tumor responds to panobinostat. Additionally, this study will examine how long it takes neuroendocrine tumor patient's cancer to progress while taking the drug and examine the overall survival of patients using panobinostat. Also, the study will examine the toxicity and tolerability of panobinostat in the patient population. Finally, this study will look at the effect of panobinostat on Notch 1 signaling before and after treatment with panobinostat.

Condition or Disease	Intervention/Treatment	Phase
Neuroendocrine Tumors	Drug: panobinostat (LBH589)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Panobinostat in Patients With Neuroendocrine Tumors
• Study Start Date: May 1, 2010
• Actual Primary Completion Date: Apr 1, 2015
• Actual Study Completion Date: Apr 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: panobinostat This is a single arm trial. All patients will take panobinostat	Drug: panobinostat (LBH589); Panobinostat will be taken once daily at 20 mg three times a week (every Monday, Wednesday, Friday). It will be taken as long as patients are benefiting from treatment.

Outcome Measures

Primary Outcome Measures

1. Tumor Response Rate of Patients With Gastrointestinal Neuroendocrine Tumors Using Response Evaluation Criteria in Solid Tumors (RECIST) Criteria. [every 8 weeks, up to 5 years]

   Confirmed anti-tumor response rate will be validated by the Response Evaluation Criteria in Solid Tumors (RECIST). All participants included in the study will be assessed for response to the proposed panobinostat treatment, even if there are protocol treatment deviations. Each participant will be assigned one of the following categories: complete response, partial response, stable disease, progressive disease, early death from malignant disease, early death from toxicity, early death because of other cause, or unknown.

Secondary Outcome Measures

1. Number of Participants With Toxicities [up to 5 years]

   Evaluate the toxicity and tolerability of panobinostat in the patient population

2. Evaluate the Time to Progression for Patients With Gastrointestinal Neuroendocrine Tumors Treated With Panobinostat [Up to 5 years]

3. Delineate the Expression of Notch 1 in Neuroendocrine Tumor Samples Before and During Treatment With Panobinostat [Pre-treatment and up to week 12]

   The expression of Notch 1 in neuroendocrine tumor samples will be evaluated prior to Cycle 1 Day 1 dose and at the end of Cycle 2 of treatment of treatment.

4. Evaluate the Overall Survival of Patients With Gastrointestinal Neuroendocrine Tumors Treated With Panobinostat [Up to 5 years]

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, low grade neuroendocrine neoplasms. Small cell lung cancers, paragangliomas, and pheochromocytomas are excluded

• Must have measurable disease as defined by RECIST

• 4 weeks from completion of major surgery, chemotherapy, or other systemic therapy or local liver therapy to study registration. Concurrent octreotide is allowed.

• Not allowed to be on concurrent chemotherapy or radiation

• 18 years of age or older

• ECOG Performance status of equal to or less than 2

• Able to sign and date a written informed consent prior to participation in the study

• Baseline MUGA or ECHO must demonstrate LVEF greater than or equal to the lower limit of the institutional normal

• Must have the following laboratory criteria: Neutrophil count greater than 1500/mm3, platelet count greater than 100,000/mm3L, hemoglobin greater than or equal to 9 g/dL, AST/SGOT and ALT/SGPT less than or equal to 2.5 x ULN, serum bilirubin less than or equal to 1.5 x ULN, serum creatinine less than or equal to 1.5 x ULN, total serum calcium greater than or equal to LLN, serum potassium greater than or equal to LLN, serum sodium greater than or equal to LLN, serum albumin greater than or equal to LLN or 3g/dl,

• Women of child bearing potential must have a negative urine pregnancy test within 72 hours of first administration of study treatment and must be willing to use two methods of contraception

• Patients with a history of 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 the first panobinostat treatment

• Impaired cardiac function including any of the following: Screening ECG with a QTc greater than 450 msec, patients with congenital long QT syndrome, history of unsustained ventricular tachycardia, any history of ventricular fibrillation or torsades de pointes, bradycardia defined as heart rate less than 50 beats per minutes, patients with a myocardial infarction or unstable angina within 6 months of study entry, congestive heart failure, right bundle branch block or left anterior hemiblock

• Uncontrolled hypertension

• Unresolved diarrhea greater than CTCAE grade 1

• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral panobinostat

• Other concurrent sever and/or uncontrolled medical conditions

• Patients with a history of another primary malignancy that, in the opinion of the investigator, would interfere with the assessment of the primary endpoint of the study

• Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C, baseline testing is not required

• Any significant history of non-compliance to medical regimens or with inability to grant a reliable informed consent

• Any medication which may cause QTc prolongation or inducing torsades de pointes

• Use of concomitant medications that may interact with panobinostat

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Wisconsin, Madison	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• University of Wisconsin, Madison
• Novartis Pharmaceuticals

Investigators

• Principal Investigator: Noelle LoConte, MD, 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: NCT00985946
• Other Study ID Numbers: CO08209; CLBH589BUS38T; 2010-0050; 2014-1298; A534260; SMPH\MEDICINE\HEM-ONC; NCI-2011-00320
• First Posted: Sep 29, 2009
• Last Update Posted: Dec 9, 2019
• Last Verified: Jun 1, 2017

• Additional relevant MeSH terms: Neuroendocrine Tumors; Panobinostat

Study Results

Participant Flow

Recruitment Details	This study actively recruited from April 2010 through May 2011 at a large cancer center in Wisconsin.

Arm/Group Title	Panobinostat
Arm/Group Description	Adult patients with histologically confirmed, metastatic, low-grade NETs and an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 were treated with oral panobinostat 20 mg once daily three times per week. Treatment was continued until patients experienced unacceptable toxicities or disease progression. The study was stopped at planned interim analysis based on a Simon two-stage design.
Period Title: Overall Study
STARTED	15
COMPLETED	8
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	Panobinostat
Arm/Group Description	Adult patients with histologically confirmed, metastatic, low-grade NETs and an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 were treated with oral panobinostat 20 mg once daily three times per week. Treatment was continued until patients experienced unacceptable toxicities or disease progression. The study was stopped at planned interim analysis based on a Simon two-stage design.
Overall Participants	15
Age, Customized (participants) [Number]
40-49 years of age	3 20%
50-59 years of age	5 33.3%
60-69 years of age	4 26.7%
70-79 years of age	2 13.3%
>= 80 years of age	1 6.7%
Sex: Female, Male (Count of Participants)
Female	5 33.3%
Male	10 66.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	13 86.7%
Unknown or Not Reported	2 13.3%
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	0 0%
White	15 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	15 100%

Outcome Measures

1. Primary Outcome

Title	Tumor Response Rate of Patients With Gastrointestinal Neuroendocrine Tumors Using Response Evaluation Criteria in Solid Tumors (RECIST) Criteria.
Description	Confirmed anti-tumor response rate will be validated by the Response Evaluation Criteria in Solid Tumors (RECIST). All participants included in the study will be assessed for response to the proposed panobinostat treatment, even if there are protocol treatment deviations. Each participant will be assigned one of the following categories: complete response, partial response, stable disease, progressive disease, early death from malignant disease, early death from toxicity, early death because of other cause, or unknown.
Time Frame	every 8 weeks, up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Panobinostat
Arm/Group Description	Adult patients with histologically confirmed, metastatic, low-grade NETs and an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 were treated with oral panobinostat 20 mg once daily three times per week. Treatment was continued until patients experienced unacceptable toxicities or disease progression. The study was stopped at planned interim analysis based on a Simon two-stage design.
Measure Participants	15
Stable Disease	15 100%
Complete Response	0 0%
Partial Response	0 0%
Progressive Disease	0 0%
Early death from malignant disease	0 0%
Early death from toxicity	0 0%
Early death because of other cause	0 0%
Unknown	0 0%

2. Secondary Outcome

Title	Number of Participants With Toxicities
Description	Evaluate the toxicity and tolerability of panobinostat in the patient population
Time Frame	up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Panobinostat
Arm/Group Description	Adult patients with histologically confirmed, metastatic, low-grade NETs and an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 were treated with oral panobinostat 20 mg once daily three times per week. Treatment was continued until patients experienced unacceptable toxicities or disease progression. The study was stopped at planned interim analysis based on a Simon two-stage design.
Measure Participants	15
Number [participants]	5 33.3%

3. Secondary Outcome

Title	Evaluate the Time to Progression for Patients With Gastrointestinal Neuroendocrine Tumors Treated With Panobinostat
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Panobinostat
Arm/Group Description	Adult patients with histologically confirmed, metastatic, low-grade NETs and an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 were treated with oral panobinostat 20 mg once daily three times per week. Treatment was continued until patients experienced unacceptable toxicities or disease progression. The study was stopped at planned interim analysis based on a Simon two-stage design.
Measure Participants	15
Median (90% Confidence Interval) [months]	9.9

4. Secondary Outcome

Title	Delineate the Expression of Notch 1 in Neuroendocrine Tumor Samples Before and During Treatment With Panobinostat
Description	The expression of Notch 1 in neuroendocrine tumor samples will be evaluated prior to Cycle 1 Day 1 dose and at the end of Cycle 2 of treatment of treatment.
Time Frame	Pre-treatment and up to week 12

Outcome Measure Data

Analysis Population Description

Data to delineate the expression of Notch 1 in neuroendocrine tumor samples was not collected. The question regarding the role of Notch1 in well-differentiated NET remains unanswered.

Arm/Group Title	Panobinostat
Arm/Group Description	Adult patients with histologically confirmed, metastatic, low-grade NETs and an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 were treated with oral panobinostat 20 mg once daily three times per week. Treatment was continued until patients experienced unacceptable toxicities or disease progression. The study was stopped at planned interim analysis based on a Simon two-stage design.
Measure Participants	0

5. Secondary Outcome

Title	Evaluate the Overall Survival of Patients With Gastrointestinal Neuroendocrine Tumors Treated With Panobinostat
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Panobinostat
Arm/Group Description	Adult patients with histologically confirmed, metastatic, low-grade NETs and an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 were treated with oral panobinostat 20 mg once daily three times per week. Treatment was continued until patients experienced unacceptable toxicities or disease progression. The study was stopped at planned interim analysis based on a Simon two-stage design.
Measure Participants	15
Median (90% Confidence Interval) [months]	47.27

Adverse Events

Time Frame	Adverse events were collected for 5 years.
Adverse Event Reporting Description	Grade refers to the severity of the Adverse Event (AE) from grades 1 through 5, where 1 is a mild AE, and 5 is death related to an adverse AE. Systematic Adverse Event assessment included regular assessment of subjects by the treating investigator, including physical exam, ECOG performance status, ECG, and lab assessments.
Arm/Group Title	Panobinostat
Arm/Group Description	Adult patients with histologically confirmed, metastatic, low-grade NETs and an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 were treated with oral panobinostat 20 mg once daily three times per week. Treatment was continued until patients experienced unacceptable toxicities or disease progression. The study was stopped at planned interim analysis based on a Simon two-stage design. Fifteen patients were accrued, and 13 were evaluable for response. No responses were seen, but the stable disease rate was 100%. The median progression-free survival (PFS) was 9.9 months, and the median overall survival was 47.3 months. Fatigue (27%), thrombocytopenia (20%), diarrhea (13%), and nausea (13%) were the most common related grade 3 toxicities. There was one grade 4 thrombocytopenia (7%). These results did not meet the prespecified criteria to open the study to full accrual.
All Cause Mortality
	Panobinostat
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Panobinostat
	Affected / at Risk (%)	# Events
Total	6/15 (40%)
Blood and lymphatic system disorders
Grade 2 hemoglobin	1/15 (6.7%)	1
Grade 4 platelets (thrombocytopenia)	1/15 (6.7%)	1
Cardiac disorders
Grade 3 hypotension	1/15 (6.7%)	1
Grade 5 hypotension (death)	1/15 (6.7%)	1
Gastrointestinal disorders
Grade 3 diarrhea	2/15 (13.3%)	2
Grade 3 Pneumotosis Coli	1/15 (6.7%)	1
Grade 3 small bowel NOS	1/15 (6.7%)	1
General disorders
Grade 3 pain	2/15 (13.3%)	2
Grade 4 pain	1/15 (6.7%)	1
Hepatobiliary disorders
Grade 2 pancreatitis	1/15 (6.7%)	1
Infections and infestations
Grade 3 febrile neutropenia	1/15 (6.7%)	1
Grade 3 infection	1/15 (6.7%)	1
Metabolism and nutrition disorders
Grade 3 albumin, serum low	1/15 (6.7%)	1
Grade 1 creatinine	1/15 (6.7%)	1
Grade 1 glucose, serum-high (hyperglycemia)	1/15 (6.7%)	1
Grade 3 lipase	1/15 (6.7%)	1
Grade 4 lipase	1/15 (6.7%)	1
Grade 1 magnesium, serum-low (hypomagnesemia)	1/15 (6.7%)	1
Grade 1 potassium, serum-low (hypokalemia)	1/15 (6.7%)	1
Grade 1 sodium, serum-low (hyponatremia)	1/15 (6.7%)	1
Other (Not Including Serious) Adverse Events
	Panobinostat
	Affected / at Risk (%)	# Events
Total	15/15 (100%)
Blood and lymphatic system disorders
Edema: limb	2/15 (13.3%)	3
Hemorrhage/Bleeding	1/15 (6.7%)	1
Leukocytes (total WBC)	3/15 (20%)	18
Lymphopenia	3/15 (20%)	8
Platelets	13/15 (86.7%)	73
Thrombotic microangiopathy	1/15 (6.7%)	1
Ear and labyrinth disorders
Auditory/Ear	1/15 (6.7%)	1
Tinnitus	1/15 (6.7%)	1
Endocrine disorders
Thyroid function, high (hyperthyroidism, thyrotoxicosis)	4/15 (26.7%)	6
Thyroid function, low (hypothyroidism)	8/15 (53.3%)	26
Gastrointestinal disorders
Anorexia	6/15 (40%)	18
Constipation	1/15 (6.7%)	1
Diarrhea	13/15 (86.7%)	52
Dysphagia (difficulty swallowing)	1/15 (6.7%)	1
Flatulence	4/15 (26.7%)	9
Gastritis (including bile reflux gastritis)	1/15 (6.7%)	2
Gastrointestinal	3/15 (20%)	3
Heartburn/dyspepsia	2/15 (13.3%)	2
Mucositis/stomatitis (clinical exam) - Oral cavity	3/15 (20%)	3
Nausea	13/15 (86.7%)	39
Taste alteration (dysgeusia)	4/15 (26.7%)	5
Vomiting	8/15 (53.3%)	17
General disorders
Fatigue (asthenia, lethargy, malaise)	15/15 (100%)	68
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	1/15 (6.7%)	1
Pain	11/15 (73.3%)	40
Sweating (diaphoresis)	1/15 (6.7%)	1
Immune system disorders
Allergic rhinitis	1/15 (6.7%)	1
Allergy/Immunology	1/15 (6.7%)	1
Infections and infestations
Gingivitis	1/15 (6.7%)	1
Infection	2/15 (13.3%)	3
Injury, poisoning and procedural complications
Bruising (in absence of Grade 3 or 4 thrombocytopenia)	3/15 (20%)	6
Investigations
Alkaline phosphatase	8/15 (53.3%)	15
AST, SGOT(serum glutamic oxaloacetic transaminase)	1/15 (6.7%)	1
Cholesterol, serum-high (hypercholesteremia)	5/15 (33.3%)	26
Creatinine	8/15 (53.3%)	43
GGT (gamma-Glutamyl transpeptidase)	8/15 (53.3%)	21
Hemoglobin	10/15 (66.7%)	42
INR (International Normalized Ratio of prothrombin time)	2/15 (13.3%)	9
Lipase	1/15 (6.7%)	1
Potassium, serum-high (hyperkalemia)	3/15 (20%)	9
Potassium, serum-low (hypokalemia)	1/15 (6.7%)	1
Weight loss	9/15 (60%)	37
Metabolism and nutrition disorders
Albumin, serum-low (hypoalbuminemia)	8/15 (53.3%)	27
Calcium, serum-high (hypercalcemia)	1/15 (6.7%)	1
Calcium, serum-low (hypocalcemia)	2/15 (13.3%)	4
Dehydration	4/15 (26.7%)	4
Elevated Triglycerides	1/15 (6.7%)	1
Glucose, serum-high (hyperglycemia)	13/15 (86.7%)	61
Magnesium, serum-high (hypermagnesemia)	4/15 (26.7%)	8
Magnesium, serum-low (hypomagnesemia)	1/15 (6.7%)	1
Phosphate, serum-low (hypophosphatemia)	2/15 (13.3%)	8
Sodium, serum-high (hypernatremia)	1/15 (6.7%)	1
Sodium, serum-low (hyponatremia)	5/15 (33.3%)	18
Triglyceride, serum-high (hypertriglyceridemia)	8/15 (53.3%)	51
Musculoskeletal and connective tissue disorders
Cervical spine-range of motion	1/15 (6.7%)	1
Joint-function	1/15 (6.7%)	1
Muscle weakness, generalized or specific area (not due to neuropathy) - Whole body/generalized	2/15 (13.3%)	3
Musculoskeletal/Soft Tissue	1/15 (6.7%)	1
Nervous system disorders
Memory impairment	1/15 (6.7%)	1
Neuropathy: sensory	2/15 (13.3%)	8
Neutrophils/granulocytes (ANC/AGC)	4/15 (26.7%)	16
Tremor	1/15 (6.7%)	4
Renal and urinary disorders
Glomerular filtration rate	5/15 (33.3%)	12
Urinary frequency/urgency	1/15 (6.7%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/15 (6.7%)	1
Dyspnea (shortness of breath)	3/15 (20%)	4
Skin and subcutaneous tissue disorders
Dermatology/Skin	2/15 (13.3%)	2
Dry skin	2/15 (13.3%)	3
Hair loss/alopecia (scalp or body)	1/15 (6.7%)	1
Nail changes	2/15 (13.3%)	3
Rash/desquamation	1/15 (6.7%)	1
Vascular disorders
Flushing	5/15 (33.3%)	20
Hypertension	2/15 (13.3%)	3
Hypotension	3/15 (20%)	5
Thrombosis/thrombus/embolism	1/15 (6.7%)	1

Limitations/Caveats

This study was terminated early because of the use of objective response rate as the primary outcome measure, which is a shortcoming of this study.

More Information

Certain Agreements

Principal Investigators are NOT 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.