Sulindac and Tamoxifen in Treating Patients With Desmoid Tumor

• Sponsor: Children's Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00068419
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 70
• Location: 1
• Arm: 1
• Duration (Months): 74.8
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

This phase II trial is studying how well giving sulindac together with tamoxifen works in treating patients with desmoid tumor. Sulindac may stop the growth of cancer cells by blocking the enzymes necessary for cancer cell growth. Hormone therapy using tamoxifen may fight cancer by blocking the use of estrogen. Combining sulindac with tamoxifen may kill more cancer cells.

Condition or Disease	Intervention/Treatment	Phase
Desmoid Tumor	Drug: tamoxifen citrate; Drug: sulindac; Other: laboratory biomarker analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To estimate the safety and efficacy of sulindac and tamoxifen in patients with recurrent desmoid tumor (DT) and primary DT that is not readily amenable to surgery or radiation therapy.

SECONDARY OBJECTIVES:

1. Determine the tumor response rate in patients treated with this regimen.

2. Correlate changes in Magnetic Resonance Imaging (MRI) signal features of the tumor with clinical outcome in patients treated with this regimen.

3. Correlate pathological studies of cyclooxygenase-2 (COX-2) and estrogen/progesterone receptor expression in the tumor with clinical outcome in patients treated with this regimen.

4. Collect information about clinical factors that make a tumor unresectable at diagnosis and resectable during the four courses of study treatment.

5. Determine whether short-term endocrine toxicity is associated with treatment with this regimen in these patients.

OUTLINE: This is a multicenter study.

Patients receive oral sulindac and oral tamoxifen twice daily for up to 12 months (four 3-month courses) in the absence of disease progression or unacceptable toxicity. Patients who achieve a complete response (CR) receive 1 additional month of treatment beyond documentation of CR.

After completion of study treatment, patients are followed for 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Sulindac and Tamoxifen in Patients With Desmoid Tumors That Are Recurrent or Not Amenable to Standard Therapy
• Study Start Date: Feb 1, 2004
• Actual Primary Completion Date: Apr 26, 2010
• Actual Study Completion Date: Apr 26, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (enzyme inhibitor therapy, anti-estrogen therapy) Patients receive oral sulindac and oral tamoxifen citrate twice daily for up to 12 months (four 3-month courses) in the absence of disease progression or unacceptable toxicity. Patients who achieve a complete response (CR) receive 1 additional month of treatment beyond documentation of CR.	Drug: tamoxifen citrate; Given orally; Other Names: Nolvadex TAM tamoxifen TMX ; Drug: sulindac; Given orally; Other Names: Aflodac Algocetil Clinoril SULIN ; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Percentage of Patients Failure Free at 2 Years Following Study Entry [Up to 2 years]

   Kaplan Meier estimate of failure free survival at 2 years, where failure free survival is defined as the time to relapse, progression, second malignancy, and death whichever occurs first.

2. Percentage of Patients Experiencing a Grade 3 or Higher Adverse Event During Therapy. [Up to 12 months]

   The percentage of patients experiencing a grade 3 or higher adverse event as assessed by the National Cancer Institute Common Toxicity Terminology for Adverse Events v3.0

Secondary Outcome Measures

1. Percentage of Patients With Tumor Response From Imaging [Baseline up to 5 years]

   Percentage of patients with a tumor response where tumor response is assessed according to Response Evaluation Criteria in Solid Tumors (RECIST)

2. Mean Change in Response Measured by MRI [From baseline to up to 5 years]

   The mean change in response measured by MRI. Response is assessed by the lesion size which is derived from the sum of the longest of the three orthogonal diameters (from MRI) of each target lesion.

3. Percentage of Patients Failure Free at 2 Years by Pathological Response [From enrollment to up to 2 years]

   The failure free survival is compared by the log-rank test between patient subgroups defined by pathological response of cyclooxygenase-2 (COX-2) and estrogen/progesterone receptor expression

4. Percentage of Patients Experiencing Short-term Endocrine Toxicity [At study entry]

   The percentage of patients experiencing short-term endocrine toxicity between treatment groups is compared using the chi-square test

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically confirmed desmoid tumor, meeting 1 of the following criteria:

• Newly diagnosed disease

• Not previously treated

• Not amenable to complete surgical resection and/or radiotherapy

• If surgical resection was attempted, there must be gross residual disease measurable by MRI

• Radiographically documented recurrent or progressive disease

• No prior chemotherapy or radiotherapy for the present recurrence

• Tumors that progressed on prior chemotherapy are allowed provided patients have not received chemotherapy for this recurrence

• Measurable disease by gadolinium-enhanced MRI

• No other fibroblastic lesions or fibromatoses

• Lipofibromatosis or desmoplastic fibroma of the bone allowed

• Performance status - Karnofsky Score 50-100% (patients over age 16)

• Performance status - Lansky Score 50-100% (patients age 16 and under)

• At least 8 weeks

• Absolute neutrophil count at least 1,000/mm^3

• Platelet count at least 100,000/mm^3 (transfusion independent)

• Hemoglobin at least 10.0 g/dL (transfusion allowed)

• No hemophilia

• No von Willebrand disease

• No other clinically significant bleeding diathesis

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)

• Alanine aminotransferase (ALT) less than 2.5 times ULN

• Creatinine adjusted according to age as follows:

• No greater than 0.4 mg/dL (≤ 5 months)

• No greater than 0.5 mg/dL (6 months -11 months)

• No greater than 0.6 mg/dL (1 year-23 months)

• No greater than 0.8 mg/dL (2 years-5 years)

• No greater than 1.0 mg/dL (6 years-9 years)

• No greater than 1.2 mg/dL (10 years-12 years)

• No greater than 1.4 mg/dL (13 years and over [female])

• No greater than 1.5 mg/dL (13 years to 15 years [male])

• No greater than 1.7 mg/dL (16 years and over [male])

• Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min

• No prior deep venous thrombosis

• Electrocardiogram (EKG) normal

• Chest x-ray normal

• No prior significant gastrointestinal hemorrhage

• No prior peptic ulcer disease

• Not pregnant or nursing

• Fertile patients must use effective nonhormonal contraception

• No evidence of active graft-versus-host disease

• No allergy to aspirin

• Recovered from prior immunotherapy

• At least 7 days since prior anticancer biologic agents

• At least 6 months since prior allogeneic stem cell transplantation

• More than 1 week since prior growth factors

• No concurrent immunomodulating agents

• No prior nonsteroidal anti-inflammatory drugs (NSAIDs) for desmoid tumor

• More than 2 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosoureas) and recovered

• No concurrent anticancer chemotherapy

• No prior estrogen antagonists for desmoid tumor

• No concurrent hormonal contraceptives

• No concurrent steroids except for non tumor indications (e.g., asthma or severe allergic reactions)

• No concurrent NSAIDs for desmoid tumor

• Occasional NSAIDs for musculoskeletal or other pain are allowed

• Recovered from prior radiotherapy

• No concurrent adjuvant radiotherapy

• No concurrent participation in another COG therapeutic study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Oncology Group	Monrovia	California	United States	91016

Sponsors and Collaborators

• Children's Oncology Group
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Stephen Skapek, MD, Children's Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT00068419
• Other Study ID Numbers: ARST0321; NCI-2009-00424; CDR0000322260; COG-ARST0321; U10CA098543
• First Posted: Sep 11, 2003
• Last Update Posted: Feb 19, 2020
• Last Verified: Feb 1, 2019

• Additional relevant MeSH terms: Fibromatosis, Aggressive; Tamoxifen; Sulindac

Study Results

Participant Flow

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy, Anti-estrogen Therapy)
Arm/Group Description	Patients receive oral sulindac and oral tamoxifen citrate twice daily for up to 12 months (four 3-month courses) in the absence of disease progression or unacceptable toxicity. Patients who achieve a complete response (CR) receive 1 additional month of treatment beyond documentation of CR.
Period Title: Overall Study
STARTED	70
COMPLETED	10
NOT COMPLETED	60

Baseline Characteristics

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy, Anti-estrogen Therapy)
Arm/Group Description	Patients receive oral sulindac and oral tamoxifen citrate twice daily for up to 12 months (four 3-month courses) in the absence of disease progression or unacceptable toxicity. Patients who achieve a complete response (CR) receive 1 additional month of treatment beyond documentation of CR.
Overall Participants	70
Age (Count of Participants)
<=18 years	62 88.6%
Between 18 and 65 years	8 11.4%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	35 50%
Male	35 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	10 14.3%
Not Hispanic or Latino	56 80%
Unknown or Not Reported	4 5.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 2.9%
Native Hawaiian or Other Pacific Islander	1 1.4%
Black or African American	11 15.7%
White	51 72.9%
More than one race	0 0%
Unknown or Not Reported	5 7.1%
Region of Enrollment (participants) [Number]
United States	63 90%
Canada	7 10%

Outcome Measures

1. Primary Outcome

Title	Percentage of Patients Failure Free at 2 Years Following Study Entry
Description	Kaplan Meier estimate of failure free survival at 2 years, where failure free survival is defined as the time to relapse, progression, second malignancy, and death whichever occurs first.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

All eligible patients.

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy, Anti-estrogen Therapy)
Arm/Group Description	Patients receive oral sulindac and oral tamoxifen citrate twice daily for up to 12 months (four 3-month courses) in the absence of disease progression or unacceptable toxicity. Patients who achieve a complete response (CR) receive 1 additional month of treatment beyond documentation of CR.
Measure Participants	59
Number (95% Confidence Interval) [percentage of participants]	36 51.4%

2. Primary Outcome

Title	Percentage of Patients Experiencing a Grade 3 or Higher Adverse Event During Therapy.
Description	The percentage of patients experiencing a grade 3 or higher adverse event as assessed by the National Cancer Institute Common Toxicity Terminology for Adverse Events v3.0
Time Frame	Up to 12 months

Outcome Measure Data

Analysis Population Description

All eligible patients

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy, Anti-estrogen Therapy)
Arm/Group Description	Patients receive oral sulindac and oral tamoxifen citrate twice daily for up to 12 months (four 3-month courses) in the absence of disease progression or unacceptable toxicity. Patients who achieve a complete response (CR) receive 1 additional month of treatment beyond documentation of CR.
Measure Participants	59
Number (95% Confidence Interval) [Percentage of participants]	3.4 4.9%

3. Secondary Outcome

Title	Percentage of Patients With Tumor Response From Imaging
Description	Percentage of patients with a tumor response where tumor response is assessed according to Response Evaluation Criteria in Solid Tumors (RECIST)
Time Frame	Baseline up to 5 years

Outcome Measure Data

Analysis Population Description

All eligible patients

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy, Anti-estrogen Therapy)
Arm/Group Description	Patients receive oral sulindac and oral tamoxifen citrate twice daily for up to 12 months (four 3-month courses) in the absence of disease progression or unacceptable toxicity. Patients who achieve a complete response (CR) receive 1 additional month of treatment beyond documentation of CR.
Measure Participants	59
Number (95% Confidence Interval) [Percentage of participants]	8.0 11.4%

4. Secondary Outcome

Title	Mean Change in Response Measured by MRI
Description	The mean change in response measured by MRI. Response is assessed by the lesion size which is derived from the sum of the longest of the three orthogonal diameters (from MRI) of each target lesion.
Time Frame	From baseline to up to 5 years

Outcome Measure Data

Analysis Population Description

Outcome not reported because the required data were not recorded.

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy, Anti-estrogen Therapy)
Arm/Group Description	Patients receive oral sulindac and oral tamoxifen citrate twice daily for up to 12 months (four 3-month courses) in the absence of disease progression or unacceptable toxicity. Patients who achieve a complete response (CR) receive 1 additional month of treatment beyond documentation of CR.
Measure Participants	0

5. Secondary Outcome

Title	Percentage of Patients Failure Free at 2 Years by Pathological Response
Description	The failure free survival is compared by the log-rank test between patient subgroups defined by pathological response of cyclooxygenase-2 (COX-2) and estrogen/progesterone receptor expression
Time Frame	From enrollment to up to 2 years

Outcome Measure Data

Analysis Population Description

Data not available for analysis due to no data were collected

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy, Anti-estrogen Therapy)
Arm/Group Description	Patients receive oral sulindac and oral tamoxifen citrate twice daily for up to 12 months (four 3-month courses) in the absence of disease progression or unacceptable toxicity. Patients who achieve a complete response (CR) receive 1 additional month of treatment beyond documentation of CR.
Measure Participants	0

6. Secondary Outcome

Title	Percentage of Patients Experiencing Short-term Endocrine Toxicity
Description	The percentage of patients experiencing short-term endocrine toxicity between treatment groups is compared using the chi-square test
Time Frame	At study entry

Outcome Measure Data

Analysis Population Description

Data not available for analysis due to no data were collected.

Arm/Group Title	Treatment (Enzyme Inhibitor Therapy, Anti-estrogen Therapy)
Arm/Group Description	Patients receive oral sulindac and oral tamoxifen citrate twice daily for up to 12 months (four 3-month courses) in the absence of disease progression or unacceptable toxicity. Patients who achieve a complete response (CR) receive 1 additional month of treatment beyond documentation of CR.
Measure Participants	0

Adverse Events

Time Frame	Duration of protocol therapy plus 30 days.
Adverse Event Reporting Description	Reporting is for all patients who received protocol therapy (11 patients were ineligible for protocol therapy).
Arm/Group Title	Treatment (Enzyme Inhibitor Therapy, Anti-estrogen Therapy)
Arm/Group Description	Patients receive oral sulindac and oral tamoxifen citrate twice daily for up to 12 months (four 3-month courses) in the absence of disease progression or unacceptable toxicity. Patients who achieve a complete response (CR) receive 1 additional month of treatment beyond documentation of CR.
All Cause Mortality
	Treatment (Enzyme Inhibitor Therapy, Anti-estrogen Therapy)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Enzyme Inhibitor Therapy, Anti-estrogen Therapy)
	Affected / at Risk (%)	# Events
Total	2/59 (3.4%)
Gastrointestinal disorders
Abdominal pain	1/59 (1.7%)
Psychiatric disorders
Depression	1/59 (1.7%)
Other (Not Including Serious) Adverse Events
	Treatment (Enzyme Inhibitor Therapy, Anti-estrogen Therapy)
	Affected / at Risk (%)	# Events
Total	42/59 (71.2%)
Blood and lymphatic system disorders
Anemia	6/59 (10.2%)
Ear and labyrinth disorders
Hearing impaired	1/59 (1.7%)
Tinnitus	3/59 (5.1%)
Endocrine disorders
Endocrine disorders - Other	3/59 (5.1%)
Eye disorders
Eye disorders - Other	5/59 (8.5%)
Gastrointestinal disorders
Abdominal pain	20/59 (33.9%)
Constipation	8/59 (13.6%)
Diarrhea	5/59 (8.5%)
Dry mouth	1/59 (1.7%)
Dyspepsia	1/59 (1.7%)
Dysphagia	2/59 (3.4%)
Esophagitis	1/59 (1.7%)
Flatulence	1/59 (1.7%)
Gastritis	2/59 (3.4%)
Gastrointestinal disorders - Other	1/59 (1.7%)
Mucositis oral	1/59 (1.7%)
Nausea	8/59 (13.6%)
Rectal hemorrhage	1/59 (1.7%)
Stomach pain	3/59 (5.1%)
Vomiting	16/59 (27.1%)
General disorders
Edema limbs	1/59 (1.7%)
Fatigue	8/59 (13.6%)
Fever	3/59 (5.1%)
Gait disturbance	1/59 (1.7%)
Non-cardiac chest pain	1/59 (1.7%)
Pain	1/59 (1.7%)
Infections and infestations
Catheter related infection	1/59 (1.7%)
Conjunctivitis infective	1/59 (1.7%)
Sinusitis	1/59 (1.7%)
Investigations
Alanine aminotransferase increased	8/59 (13.6%)
Alkaline phosphatase increased	2/59 (3.4%)
Aspartate aminotransferase increased	7/59 (11.9%)
Blood gonadotrophin abnormal	2/59 (3.4%)
Creatinine increased	2/59 (3.4%)
Electrocardiogram QT corrected interval prolonged	7/59 (11.9%)
GGT increased	1/59 (1.7%)
Investigations - Other	1/59 (1.7%)
Lymphocyte count decreased	2/59 (3.4%)
Neutrophil count decreased	4/59 (6.8%)
Serum amylase increased	1/59 (1.7%)
Weight gain	1/59 (1.7%)
White blood cell decreased	3/59 (5.1%)
Metabolism and nutrition disorders
Acidosis	2/59 (3.4%)
Anorexia	2/59 (3.4%)
Hyperglycemia	8/59 (13.6%)
Hyperkalemia	2/59 (3.4%)
Hypermagnesemia	2/59 (3.4%)
Hypernatremia	3/59 (5.1%)
Hypertriglyceridemia	1/59 (1.7%)
Hypocalcemia	4/59 (6.8%)
Hypoglycemia	2/59 (3.4%)
Hypokalemia	1/59 (1.7%)
Hypomagnesemia	3/59 (5.1%)
Hyponatremia	3/59 (5.1%)
Hypophosphatemia	9/59 (15.3%)
Obesity	1/59 (1.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/59 (3.4%)
Back pain	2/59 (3.4%)
Myalgia	1/59 (1.7%)
Neck pain	1/59 (1.7%)
Pain in extremity	5/59 (8.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	1/59 (1.7%)
Nervous system disorders
Ataxia	1/59 (1.7%)
Dizziness	5/59 (8.5%)
Dysgeusia	1/59 (1.7%)
Headache	12/59 (20.3%)
Peripheral sensory neuropathy	1/59 (1.7%)
Psychiatric disorders
Depression	3/59 (5.1%)
Renal and urinary disorders
Renal and urinary disorders - Other	3/59 (5.1%)
Urinary tract pain	1/59 (1.7%)
Urine discoloration	1/59 (1.7%)
Reproductive system and breast disorders
Gynecomastia	1/59 (1.7%)
Irregular menstruation	1/59 (1.7%)
Vaginal discharge	1/59 (1.7%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/59 (1.7%)
Cough	3/59 (5.1%)
Voice alteration	1/59 (1.7%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	1/59 (1.7%)
Nail loss	1/59 (1.7%)
Pruritus	2/59 (3.4%)
Rash maculo-papular	1/59 (1.7%)
Skin and subcutaneous tissue disorders - Other	1/59 (1.7%)
Skin ulceration	1/59 (1.7%)
Urticaria	1/59 (1.7%)
Vascular disorders
Flushing	1/59 (1.7%)
Hot flashes	3/59 (5.1%)
Hypertension	2/59 (3.4%)
Vascular disorders - Other	2/59 (3.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Must obtain prior Sponsor approval.