Everolimus in Combination With Imatinib Mesylate in Treating Patients With Locally Advanced, Locally Recurrent, or Metastatic Soft Tissue Sarcoma

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01281865
• Collaborator: (none)
• Enrollment: 14
• Location: 1
• Arm: 1
• Duration (Months): 33
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This phase I/II clinical trial is studying the side effects and best dose of everolimus when given with imatinib mesylate and to see how well they work in treating patients with locally advanced, locally recurrent or metastatic soft tissue sarcoma. Everolimus and imatinib mesylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or Disease	Intervention/Treatment	Phase
Adult Synovial Sarcoma; Recurrent Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma	Other: diagnostic laboratory biomarker analysis; Drug: everolimus; Drug: imatinib mesylate	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the maximum-tolerated dose (MTD) of everolimus in combination with imatinib mesylate in patients with synovial sarcoma. (Phase I) II. To determine the overall response rate (RR = CR + PR). (Phase II)

SECONDARY OBJECTIVES:

1. To determine RR, progression-free survival (PFS), and overall survival (OS). (Phase I) II. To determine predictors of response. (Phase II) III. To obtain tissue biopsy and plasma samples for correlative studies pre- and post-treatment. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of everolimus followed by a phase II study.

Patients receive everolimus orally (PO) once daily and imatinib mesylate PO once daily on days 1-28. Course repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood and tumor tissue sample collection at baseline and periodically during study for correlative biomarker and protein expression studies.

After completion of study therapy, patients are followed up for 30 days.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1b/2 Study of Imatinib in Combination With Everolimus in Synovial Sarcoma
• Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: Oct 1, 2013
• Actual Study Completion Date: Oct 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (everolimus and imatinib mesylate) Patients receive everolimus PO once daily and imatinib mesylate PO once daily on days 1-28. Course repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood and tumor tissue sample collection at baseline and periodically during study for correlative biomarker and protein expression studies.

Other: diagnostic laboratory biomarker analysis; Correlative studies; Drug: everolimus; Given PO; Other Names: 42-O-(2-hydroxy)ethyl rapamycin Afinitor RAD001 ; Drug: imatinib mesylate; Given PO; Other Names: CGP 57148 Gleevec Glivec

Outcome Measures

Primary Outcome Measures

1. Response Rate (CR + PR) Assessed by RECIST 1.1 (Phase II) [At 8 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically or cytologically confirmed synovial sarcoma that is platelet-derived growth factor receptor, alpha polypeptide positive (PDGFRA+)

• Metastatic and/or locally advanced or locally recurrent disease

• Patients must consent to tumor biopsies before therapy and after the second week of therapy

• Patients who do not have accessible tumor for biopsy may be enrolled at the discretion of the principal investigator

• Patients must have measurable disease, by RECIST 1.1, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm by conventional techniques or as ≥ 10 mm by spiral CT scan

• Tumor lesions that are situated in a previously irradiated area may be considered measurable for the purposes of this study only if there is evidence of growth of the area following a course of irradiation that cannot be attributed to necrosis or bleeding into the tumor

• Patients with brain metastasis that has been treated with definitive surgery or radiotherapy, and who have been clinically stable for 3 months following the procedure with no neurological signs or symptoms and no requirement for systemic glucocorticoids, are eligible for study

• ECOG performance status 0-1

• Life expectancy greater than 3 months

• ANC ≥ 1,500/mm³

• Platelet count ≥ 75,000/mm³

• Total bilirubin ≤ 1.5 times upper limit of normal (ULN) (except for patients with known Gilbert syndrome)

• AST/ALT ≤ 3 times ULN

• Serum creatinine ≤ 1.5 times ULN

• Serum glucose ≤ 120 mg/dL

• Total cholesterol < 300 mg/dL

• Triglycerides < 2.5 times ULN

• Not pregnant or nursing

• Negative pregnancy test

• Women of child-bearing potential and men must agree to use adequate contraception (hormonal, barrier method of birth control, or abstinence) during therapy and for at least 8 weeks after completion of therapy

• Patients must not have current evidence of another malignancy

• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to everolimus, imatinib mesylate, or other agents used in the study

• No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, including HIV, active hepatitis B or C, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, poorly controlled diabetes, or psychiatric illness/social situations that would limit compliance with study requirements

• No patients with significant compromised respiratory problems or an active and unexplained pneumonitis

• No concurrent combination antiretroviral therapy for HIV-positive patients

• At least 4 weeks since any number of prior chemotherapy regimens (6 weeks for carmustine or mitomycin C) for recurrent/metastatic disease

• No prior tyrosine kinase inhibitors

• Recovered to ≤ grade 1 NCI CTCAE version 4 adverse events related to prior tumor-specific therapy

• No patients who have had major surgery within the past 4 weeks, or who have not recovered from adverse events to ≤ grade 1 NCI CTCAE adverse events associated with surgery

• Surgical changes not expected to improve ( e.g., removal of muscle tissue) allowed

• No prior mTOR inhibitors, such as sirolimus, everolimus, ridaforolimus, or temsirolimus

• No other concurrent investigational agents

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Mary Louise Keohan, Memorial Sloan Kettering Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01281865
• Other Study ID Numbers: NCI-2011-02577; NCI-2011-02577; CDR0000693826; 10-167; 8603; P30CA008748; U01CA069856
• First Posted: Jan 24, 2011
• Last Update Posted: Oct 8, 2014
• Last Verified: Jun 1, 2013

• Additional relevant MeSH terms: Sarcoma; Sarcoma, Synovial; Everolimus; Imatinib Mesylate

Study Results

Participant Flow

Recruitment Details	Protocol Open to Accrual: 01/20/2011 Protocol Closed to Accrual: 10/23/2012 Primary Completion Date (if applicable):10/22/2013 Recruitment Location is the medical clinic

Arm/Group Title	Arm 1-Treatment (Everolimus and Imatinib Mesylate)	Arm 2-Treatment (Everolimus and Imatinib Mesylate)
Arm/Group Description	Cycle=28 days: Everolimus: 5 mg PO QD, STI571 (imatinib, Gleevec): 400 mg PO QD	Cycle=28 days: Everolimus: 10 mg PO QD, STI571 (imatinib, Gleevec): 400 mg PO QD
Period Title: Overall Study
STARTED	12	2
COMPLETED	9	1
NOT COMPLETED	3	1

Baseline Characteristics

Arm/Group Title	Arm 1-Treatment (Everolimus and Imatinib Mesylate)	Arm 2-Treatment (Everolimus and Imatinib Mesylate)	Total
Arm/Group Description	Cycle=28 days: Everolimus: 5 mg PO QD, STI571 (imatinib, Gleevec): 400 mg PO QD	Cycle=28 days: Everolimus: 10 mg PO QD, STI571 (imatinib, Gleevec): 400 mg PO QD	Total of all reporting groups
Overall Participants	12	2	14
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	11 91.7%	2 100%	13 92.9%
>=65 years	1 8.3%	0 0%	1 7.1%
Sex: Female, Male (Count of Participants)
Female	6 50%	1 50%	7 50%
Male	6 50%	1 50%	7 50%
Region of Enrollment (participants) [Number]
United States	12 100%	2 100%	14 100%

Outcome Measures

1. Primary Outcome

Title	Response Rate (CR + PR) Assessed by RECIST 1.1 (Phase II)
Time Frame	At 8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1-Treatment (Everolimus and Imatinib Mesylate)	Arm 2-Treatment (Everolimus and Imatinib Mesylate)
Arm/Group Description	Cycle=28 days: Everolimus: 5 mg PO QD, STI571 (imatinib, Gleevec): 400 mg PO QD	Cycle=28 days: Everolimus: 10 mg PO QD, STI571 (imatinib, Gleevec): 400 mg PO QD
Measure Participants	9	1
Progression of Disease	4 33.3%	1 50%
Stable Disease	5 41.7%	0 0%

Adverse Events

Arm/Group Title	Arm 1-Treatment (Everolimus and Imatinib Mesylate)		Arm 2-Treatment (Everolimus and Imatinib Mesylate)
Arm/Group Description	Cycle=28 days: Everolimus: 5 mg PO QD, STI571 (imatinib, Gleevec): 400 mg PO QD		Cycle=28 days: Everolimus: 10 mg PO QD, STI571 (imatinib, Gleevec): 400 mg PO QD
All Cause Mortality
	Arm 1-Treatment (Everolimus and Imatinib Mesylate)		Arm 2-Treatment (Everolimus and Imatinib Mesylate)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm 1-Treatment (Everolimus and Imatinib Mesylate)		Arm 2-Treatment (Everolimus and Imatinib Mesylate)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/12 (16.7%)		1/2 (50%)
Gastrointestinal disorders
Intra-abdominal hemorrhage	1/12 (8.3%)	1	0/2 (0%)	0
General disorders
Sudden death NOS	0/12 (0%)	0	1/2 (50%)	1
Investigations
Neutrophil count decreased	1/12 (8.3%)	1	0/2 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm 1-Treatment (Everolimus and Imatinib Mesylate)		Arm 2-Treatment (Everolimus and Imatinib Mesylate)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/12 (83.3%)		2/2 (100%)
Blood and lymphatic system disorders
Anemia	9/12 (75%)	57	2/2 (100%)	6
Gastrointestinal disorders
Constipation	1/12 (8.3%)	1	1/2 (50%)	1
Diarrhea	3/12 (25%)	3	1/2 (50%)	1
Mucositis-oral	4/12 (33.3%)	4	2/2 (100%)	3
Nausea	2/12 (16.7%)	7	2/2 (100%)	3
Vomiting	0/12 (0%)	0	1/2 (50%)	1
General disorders
Edema face	0/12 (0%)	0	1/2 (50%)	1
Facial pain	0/12 (0%)	0	1/2 (50%)	2
Fatigue	5/12 (41.7%)	7	2/2 (100%)	2
Fever	0/12 (0%)	0	1/2 (50%)	1
Infections and infestations
Skin infection	0/12 (0%)	0	1/2 (50%)	1
Investigations
Alanine aminotransferase increased	5/12 (41.7%)	28	2/2 (100%)	4
Alkaline phosphatase increased	4/12 (33.3%)	24	2/2 (100%)	6
Aspartate aminotransferase increased	7/12 (58.3%)	19	2/2 (100%)	6
Blood bilirubin increased	2/12 (16.7%)	2	1/2 (50%)	1
Cholesterol high	7/12 (58.3%)	45	1/2 (50%)	1
Creatinine increased	3/12 (25%)	19	0/2 (0%)	0
Lymphocyte count decreased	4/12 (33.3%)	5	0/2 (0%)	0
Neutrophil count decreased	3/12 (25%)	10	0/2 (0%)	0
Platelet count decreased	9/12 (75%)	24	2/2 (100%)	5
White blood cell decreased	8/12 (66.7%)	47	0/2 (0%)	0
Metabolism and nutrition disorders
Anorexia	1/12 (8.3%)	1	1/2 (50%)	1
Hyperglycemia	9/12 (75%)	75	2/2 (100%)	6
Hypernatremia	2/12 (16.7%)	2	0/2 (0%)	0
Hypertriglyceridemia	8/12 (66.7%)	48	1/2 (50%)	6
Hypoalbuminemia	4/12 (33.3%)	27	0/2 (0%)	0
Hypocalcemia	2/12 (16.7%)	2	0/2 (0%)	0
Hypokalemia	5/12 (41.7%)	11	1/2 (50%)	1
Hyponatremia	1/12 (8.3%)	1	0/2 (0%)	0
Hypophosphatemia	8/12 (66.7%)	19	2/2 (100%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	1/12 (8.3%)	1	0/2 (0%)	0
Nervous system disorders
Dysgeusia	0/12 (0%)	0	1/2 (50%)	1
Peripheral sensory neuropathy	1/12 (8.3%)	1	0/2 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/12 (8.3%)	1	0/2 (0%)	0
Dyspnea	1/12 (8.3%)	1	0/2 (0%)	0
Pneumonitis	1/12 (8.3%)	1	0/2 (0%)	0
Skin and subcutaneous tissue disorders
Papulopustular rash	1/12 (8.3%)	1	0/2 (0%)	0
Rash maculo-papular	3/12 (25%)	5	1/2 (50%)	1
Skin and subcutaneous tissue disorders Other, specify-dry split fingernails	1/12 (8.3%)	1	0/2 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.