Lithium for Low-Grade Neuroendocrine Tumors

• ClinicalTrials.gov Identifier: NCT00501540
• Recruitment Status: Completed
• First Posted: July 16, 2007
• Results First Posted: May 3, 2017
• Last Update Posted: November 26, 2019
• Sponsor: University of Wisconsin, Madison
• Collaborators: National Institutes of Health (NIH); National Cancer Institute (NCI)
• Information provided by (Responsible Party): University of Wisconsin, Madison

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Neuroendocrine Tumors
• Intervention: Drug: Lithium Carbonate
• Enrollment: 15

Participant Flow

Recruitment Details	This study enrolled participants with low grade neuroendocrine tumors (NETs) from July 2007 through May 2009.
Pre-assignment Details

Arm/Group Title	Lithium
Arm/Group Description	Lithium carbonate was dosed on a flat scale of mg/day and not by weight or body surface area (BSA). Lithium carbonate was provided as a 300mg tablet and was taken daily without breaks in treatment. Lithium Carbonate: Lithium 300mg PO TID escalating to a lithium level of 0.8-1.2. Lithium carbonate was administered the first week at 300 mg flat dose three times each day. A serum lithium level was checked after 4-5 days of treatment by drawing a blood sample prior to the morning dose of lithium. Evaluated every 8 weeks.
Period Title: Overall Study
Started	15
Completed	10
Not Completed	5
Reason Not Completed
Death	5

Baseline Characteristics

Arm/Group Title		Lithium
Arm/Group Description		Lithium carbonate was dosed on a flat scale of mg/day and not by weight or body surface area (BSA). Lithium carbonate was provided as a 300mg tablet and was taken daily without breaks in treatment. Lithium Carbonate: Lithium 300mg PO TID escalating to a lithium level of 0.8-1.2. Lithium carbonate was administered the first week at 300 mg flat dose three times each day. A serum lithium level was checked after 4-5 days of treatment by drawing a blood sample prior to the morning dose of lithium. Evaluated every 8 weeks.
Overall Number of Baseline Participants		15
Baseline Analysis Population Description		Participants with histologically confirmed metastatic low-grade neuroendocrine neoplasms were enrolled.
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	15 participants
	<=18 years	0 0.0%
	Between 18 and 65 years	11 73.3%
	>=65 years	4 26.7%
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	15 participants
	<=18 years	0 0.0%
	Between 18 and 65 years	11 73.3%
	>=65 years	4 26.7%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	15 participants
	Female	9 60.0%
	Male	6 40.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	15 participants
	Hispanic or Latino	0 0.0%
	Not Hispanic or Latino	15 100.0%
	Unknown or Not Reported	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	15 participants
	American Indian or Alaska Native	0 0.0%
	Asian	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%
	Black or African American	0 0.0%
	White	15 100.0%
	More than one race	0 0.0%
	Unknown or Not Reported	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	15 participants
		15

Outcome Measures

1. Primary Outcome

Title	Tumor Response Rate Measured by the Response Evaluation Criteria in Solid Tumors (RECIST)
Description	Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR) >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) >=20% increase in the sum of the longest diameter of target lesions; Stable Disease (SD), small changes that do not meet the above criteria.
Time Frame	Up to 4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lithium
Arm/Group Description:	Lithium carbonate was dosed on a flat scale of mg/day and not by weight or body surface area (BSA). Lithium carbonate was provided as a 300mg tablet and was taken daily without breaks in treatment. Lithium Carbonate: Lithium 300mg PO TID escalating to a lithium level of 0.8-1.2. Lithium carbonate was administered the first week at 300 mg flat dose three times each day. A serum lithium level was checked after 4-5 days of treatment by drawing a blood sample prior to the morning dose of lithium. Evaluated every 8 weeks.
Overall Number of Participants Analyzed	15
Measure Type: Number; Unit of Measure: participants
Complete Response (CR)	0
Partial Response (PR)	0
Progressive Disease (PD)	0
Stable Disease (SD)	8

2. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	Progression is defined using 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. Progression free survival is measured from the date of entry on the study to the appearance of new metastatic lesions or objective tumor progression. If a participant did not experience an event of disease progression or death at the time of analysis (03/10/2011), then the patient's data was censored at the date of the last available evaluation.
Time Frame	Up to 4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lithium
Arm/Group Description:	Lithium carbonate was dosed on a flat scale of mg/day and not by weight or body surface area (BSA). Lithium carbonate was provided as a 300mg tablet and was taken daily without breaks in treatment. Lithium Carbonate: Lithium 300mg PO TID escalating to a lithium level of 0.8-1.2. Lithium carbonate was administered the first week at 300 mg flat dose three times each day. A serum lithium level was checked after 4-5 days of treatment by drawing a blood sample prior to the morning dose of lithium. Evaluated every 8 weeks.
Overall Number of Participants Analyzed	15
Median (95% Confidence Interval); Unit of Measure: months
	4.50; (2.99 to 4.50)

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival for a participant is defined as the number of days from the day of first Lithium administration to the participant's death. As of the time of analysis (03/10/2011), median overall survival duration was not reached.
Time Frame	Up to 4 years

Outcome Measure Data

Analysis Population Description

The median OS time had not been reached.

Arm/Group Title	Lithium
Arm/Group Description:	Lithium carbonate was dosed on a flat scale of mg/day and not by weight or body surface area (BSA). Lithium carbonate was provided as a 300mg tablet and was taken daily without breaks in treatment. Lithium Carbonate: Lithium 300mg PO TID escalating to a lithium level of 0.8-1.2. Lithium carbonate was administered the first week at 300 mg flat dose three times each day. A serum lithium level was checked after 4-5 days of treatment by drawing a blood sample prior to the morning dose of lithium. Evaluated every 8 weeks.
Overall Number of Participants Analyzed	15
Median (Full Range); Unit of Measure: participants
	NA [1]; (NA to NA)

[1]

50% of participants had not died at the time that the final statistics were run.

Adverse Events

Time Frame	Adverse event data were collected on or after Day 0 through 4 years.
Adverse Event Reporting Description	Adverse events were reported in a routine manner at scheduled times during the trial. Additionally, certain adverse events were reported in an expedited manner for more timely monitoring of patient safety and care.
Arm/Group Title	Lithium
Arm/Group Description	Lithium carbonate was dosed on a flat scale of mg/day and not by weight or body surface area (BSA). Lithium carbonate was provided as a 300mg tablet and was taken daily without breaks in treatment. Lithium Carbonate: Lithium 300mg PO TID escalating to a lithium level of 0.8-1.2. Lithium carbonate was administered the first week at 300 mg flat dose three times each day. A serum lithium level was checked after 4-5 days of treatment by drawing a blood sample prior to the morning dose of lithium. Evaluated every 8 weeks.
All-Cause Mortality
	Lithium
	Affected / at Risk (%)
Total	--/--
Serious Adverse Events
	Lithium
	Affected / at Risk (%)	# Events
Total	2/15 (13.33%)
Gastrointestinal disorders
Ileus, GI † 1	1/15 (6.67%)	1
Stricture/stenosis † 1	1/15 (6.67%)	1
General disorders
Pain † 1	2/15 (13.33%)	3
Investigations
Creatinine † 1	1/15 (6.67%)	1
Hemoglobin † 1	1/15 (6.67%)	1
Sodium † 1	1/15 (6.67%)	1
Metabolism and nutrition disorders
Glucose † 1	1/15 (6.67%)	1
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, CTCAE (3.0)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Lithium
	Affected / at Risk (%)	# Events
Total	14/15 (93.33%)
Blood and lymphatic system disorders
Anemia † 1	3/15 (20.00%)	5
Elevated white blood count † 1	1/15 (6.67%)	1
Stricture of mesenteric artery † 1	1/15 (6.67%)	1
Thrombocytopenia † 1	4/15 (26.67%)	9
Endocrine disorders
Elevated TSH † 1	1/15 (6.67%)	2
High Parathyroid Hormone † 1	1/15 (6.67%)	2
Hyperthyroidism † 1	1/15 (6.67%)	3
Gastrointestinal disorders
Abdominal pain † 1	9/15 (60.00%)	14
Anorexia † 1	6/15 (40.00%)	7
Constipation † 1	2/15 (13.33%)	3
Diarrhea † 1	7/15 (46.67%)	15
Gas pain † 1	1/15 (6.67%)	1
Hemorrhoids † 1	1/15 (6.67%)	1
Increased gas † 1	1/15 (6.67%)	1
Nausea † 1	7/15 (46.67%)	9
Vomiting † 1	4/15 (26.67%)	6
General disorders
Cold † 1	1/15 (6.67%)	1
Cold sensation in hands † 1	1/15 (6.67%)	1
Edema † 1	1/15 (6.67%)	1
Emotional changes † 1	1/15 (6.67%)	1
Fatigue † 1	11/15 (73.33%)	20
Fever † 1	1/15 (6.67%)	1
Panic Attacks † 1	1/15 (6.67%)	1
Hepatobiliary disorders
Acute cholecystitis † 1	1/15 (6.67%)	1
Investigations
Creatinine † 1	4/15 (26.67%)	6
High ALT † 1	1/15 (6.67%)	1
High AST † 1	1/15 (6.67%)	1
High INR † 1	1/15 (6.67%)	1
Hyperbilirubinemia † 1	1/15 (6.67%)	8
Hypercalcemia † 1	2/15 (13.33%)	3
Lymphopenia † 1	4/15 (26.67%)	9
Metabolism and nutrition disorders
Dehydration † 1	1/15 (6.67%)	1
Hyperglycemia † 1	5/15 (33.33%)	15
Hypocalcemia † 1	1/15 (6.67%)	1
Hypokalemia † 1	1/15 (6.67%)	5
Hyponatremia † 1	1/15 (6.67%)	1
Hypophosphatemia † 1	1/15 (6.67%)	1
Low Anion Gap † 1	1/15 (6.67%)	2
Musculoskeletal and connective tissue disorders
Back pain † 1	1/15 (6.67%)	1
Shaky legs † 1	1/15 (6.67%)	1
Unsteady Gait † 1	1/15 (6.67%)	1
Nervous system disorders
Dizziness † 1	2/15 (13.33%)	2
Headache † 1	1/15 (6.67%)	1
Memory Impairment † 1	2/15 (13.33%)	2
Tremors † 1	5/15 (33.33%)	6
Psychiatric disorders
Cognitive disturbance/confusion † 1	2/15 (13.33%)	2
Insomnia † 1	2/15 (13.33%)	4
Renal and urinary disorders
Frequency † 1	1/15 (6.67%)	1
Low EGFR † 1	1/15 (6.67%)	1
Respiratory, thoracic and mediastinal disorders
Cough † 1	1/15 (6.67%)	1
Dyspnea † 1	1/15 (6.67%)	1
Nasal congestion † 1	1/15 (6.67%)	1
Sore throat † 1	1/15 (6.67%)	1
Skin and subcutaneous tissue disorders
Puritis † 1	1/15 (6.67%)	1
Vascular disorders
Flushing † 1	1/15 (6.67%)	1
Hot flashes † 1	1/15 (6.67%)	1
Ischemia of small bowel leading to necrosis † 1	1/15 (6.67%)	1
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, CTCAE (3.0)

Limitations and Caveats

[Not Specified]

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.

Results Point of Contact

• Name/Title: Dr. Noelle LoConte
• Organization: University of Wisconsin Carbone Cancer Center
• Phone: 608-265-5883
• EMail: ns3@medicine.wisc.edu

Publications of Results:

Lubner SJ, Kunnimalaiyaan M, Holen KD, Ning L, Ndiaye M, Loconte NK, Mulkerin DL, Schelman WR, Chen H. A preclinical and clinical study of lithium in low-grade neuroendocrine tumors. Oncologist. 2011;16(4):452-7. doi: 10.1634/theoncologist.2010-0323. Epub 2011 Mar 10.

• Responsible Party: University of Wisconsin, Madison
• ClinicalTrials.gov Identifier: NCT00501540
• Other Study ID Numbers: CO07203; R21CA117117-01A2 ( U.S. NIH Grant/Contract ); H-2007-0065 ( Other Identifier: Institutional Review Board ); NCI-2011-00616 ( Registry Identifier: NCI Trial ID ); A534260 ( Other Identifier: UW Madison ); SMPH\MEDICINE\HEM-ONC ( Other Identifier: UW Madison )
• First Submitted: July 13, 2007
• First Posted: July 16, 2007
• Results First Submitted: December 5, 2016
• Results First Posted: May 3, 2017
• Last Update Posted: November 26, 2019