Temsirolimus and Cixutumumab in Treating Patients With Locally Advanced, Metastatic, or Recurrent Soft Tissue Sarcoma or Bone Sarcoma

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01016015
• Collaborator: (none)
• Enrollment: 178
• Locations: 24
• Arm: 1
• Duration (Months): 56
• Patients Per Site: 7.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This phase II trial studies how well temsirolimus and cixutumumab works in treating patients with locally advanced, metastatic, or recurrent soft tissue sarcoma or bone sarcoma. Temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cixutumumab, can block tumor growth by blocking the ability of tumor cells to grow and spread. Giving temsirolimus with cixutumumab may be an effective treatment for soft tissue or bone sarcoma.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Osteosarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Osteosarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma	Biological: Cixutumumab; Other: Laboratory Biomarker Analysis; Drug: Temsirolimus	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the proportion of patients progression-free at 12 weeks (progression free survival [PFS], defined as Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 complete response [CR] + partial response [PR] + stable disease [SD]) with (A) Insulin-like growth factor (IGF)-1receptor (R)+ soft tissue sarcomas; (B) IGF-1R+ bone tumors; or (C) IGF-1R(-) sarcomas, who are treated weekly with intravenous A12 (cixutumumab) and temsirolimus.

SECONDARY OBJECTIVES:

1. To determine the overall response rate (defined as CR + PR). II. To determine the overall survival. III. To determine the correlation of clinical outcome with pre- and post-treatment IGF-1R pathway related markers in plasma (pre and post therapy), archived tissue, and pre- and post-treatment tumor biopsies.

OUTLINE:

Patients receive cixutumumab intravenously (IV) over 60 minutes and temsirolimus IV over 30 minutes on days 1, 8, 15, 22, 29, and 36. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for at least 4 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 178 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study of Temsirolimus (CCI-779, NSC 683864) and IGF-1 Receptor Antibody Cixutumumab (IMC-A12, NSC 742460) in Patients With Metastatic Sarcomas
• Study Start Date: Nov 1, 2009
• Actual Primary Completion Date: Jul 1, 2014
• Actual Study Completion Date: Jul 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (cixutumumab and temsirolimus) Patients receive cixutumumab IV over 60 minutes and temsirolimus IV over 30 minutes on days 1, 8, 15, 22, 29, and 36. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity.	Biological: Cixutumumab; Given IV; Other Names: Anti-IGF-1R Recombinant Monoclonal Antibody IMC-A12 IMC-A12 ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Temsirolimus; Given IV; Other Names: CCI-779 CCI-779 Rapamycin Analog Cell Cycle Inhibitor 779 Rapamycin Analog Rapamycin Analog CCI-779 Torisel

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival Rate, Defined as CR + PR + SD, as Assessed by RECIST Criteria [From study entry until recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurement recorded on study), death or date of last contact, assessed at 12 weeks]

   From study entry until recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurement recorded on study), death or date of last contact, assessed at 12 weeks

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed sarcoma of soft tissue or bone; all patients will have IGF-1R testing at Memorial Sloan-Kettering Cancer Center (MSKCC) by immunohistochemistry (IHC); patients with confirmation of IGF-1R status in pre-existing tumor specimens will be enrolled on one of three arms of the study:

• Arm A: IHC IGF-1R (+) sarcomas of soft tissue

• Arm B: IHC IGF-1R (+) sarcomas of bone

• Arm C: Any IGF-1R (-) sarcomas

• Subjects must have metastatic and/or locally advanced or locally recurrent disease

• Patients treated at Memorial Sloan Kettering Cancer Center must consent to tumor biopsies before therapy and after the 2nd week of therapy; subjects 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; measurable disease (a 'target' lesion) is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded); each lesion must be >= 10 mm when measured by computed tomography (CT) (CT scan slice thickness no greater than 5 mm);

= 10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with calipers should be recorded as non-measurable); and >= 20 mm by chest x-ray

• A minimum of 1 and a maximum of 4 prior systemic therapy regimens for recurrent/metastatic disease; the last dose of systemic therapy (include tyrosine kinase inhibitors) must have been given at least 4 weeks prior to initiation of therapy; patients receiving carmustine (BCNU) or mitomycin C must have received their last dose of such therapy at least 6 weeks prior to initiation of therapy

• Patients with brain metastasis that have been treated with definitive surgery or radiation and 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

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

• Absolute neutrophil count >= 1.5 x 10^9/l; patients with neutropenia on a familial basis may still be enrolled on study; please contact the Principal Investigator (PI) who will discuss the patient with Cancer Therapy Evaluation Program (CTEP)

• Platelets >= 100 x 10^9/l

• Total bilirubin =< 1.5 x upper limit of normal (ULN); in patients with bilirubin > 1-1.5 X ULN, the starting dose of temsirolimus is 15 mg/week

• Albumin >= 3 g/dL

• Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =< 3.0 x institution ULN; in patients with ALT or AST elevated > 1.0- 3.0 X ULN, the starting dose of temsirolimus is 15 mg/week

• Serum creatinine =< 1.5 x ULN

• Serum glucose =< 120 mg/dL; nonfasting or fasting; if a patient has a non-fasting glucose of over 120 mg/dL, the patient may be retested in the fasting state to determine if they are eligible for study; a non-fasting glucose of 120 or less renders the patient eligible for study

• Fasting total cholesterol =< 300 mg/dL

• Fasting triglycerides =< 300 mg/dL; patients with neutropenia on a familial basis may still be enrolled on study; please contact the PI who will discuss the patient with CTEP

• Patients must not have current evidence of another malignancy

• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) and have pregnancy testing prior to study entry and for the duration of study participation (every 2 cycles of therapy); should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

• Adverse events related to prior tumor-specific therapy must have resolved to less than or equal to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (version 4.0) grade 1 prior to study entry (except alopecia)

• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Patients who have had major surgery or a course of glucocorticoid therapy lasting longer than 5 days within 4 weeks prior to entering the study, or those who have not recovered from adverse events to =< NCI CTCAE (version 4.0) grade 1, associated with surgery; excluded from such considerations are surgical changes not expected to improve, e.g. removal of muscle tissue; patients may be on replacement glucocorticoids for pre-existing glucocorticoid deficiency (e.g. Addison's disease) or topical glucocorticoids for dermatological conditions (e.g. psoriasis)

• Patients must be >= 4 weeks beyond treatment of any systemic therapy, other investigational therapy, biological, targeted agents or radiotherapy, and must have recovered to =< Grade 1 toxicity or previous baseline for each toxicity; specifically excluded are the laboratory examinations serum lipase or amylase (without overt pancreatitis), hypophosphatemia, hypomagnesemia, and lymphopenia; patients may have received palliative low dose radiotherapy to the limbs 1-4 weeks before this therapy provided pelvis, sternum, scapulae, vertebrae, or skull were not included in the radiotherapy field

• Patients may not have received prior IGFR1 inhibitors

• Patients may not have received prior mammalian target of rapamycin (mTOR) inhibitors (such as sirolimus, everolimus, ridaforolimus, or temsirolimus)

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to temsirolimus, A12, or other agents used in the study

• Patients with hyperglycemia, defined as fasting serum glucose above 120 mg/dl, or those patients already on oral anti-diabetic or insulin therapy

• Uncontrolled intercurrent illness including, but not limited to, known ongoing or active infection, including human immunodeficiency virus (HIV), active hepatitis B or C, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (specifically, atrial fibrillation or ventricular dysrhythmias except ventricular premature contractions), or psychiatric illness/social situations that would limit compliance with study requirements

• Pregnant women and women who are breast-feeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCLA / Jonsson Comprehensive Cancer Center	Los Angeles	California	United States	90095
2	Mayo Clinic in Florida	Jacksonville	Florida	United States	32224-9980
3	Moffitt Cancer Center	Tampa	Florida	United States	33612
4	Northwestern University	Chicago	Illinois	United States	60611
5	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
6	Decatur Memorial Hospital	Decatur	Illinois	United States	62526
7	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois	United States	60201
8	Memorial Medical Center	Springfield	Illinois	United States	62781-0001
9	University of Maryland/Greenebaum Cancer Center	Baltimore	Maryland	United States	21201
10	University of Michigan University Hospital	Ann Arbor	Michigan	United States	48109
11	University of Michigan	Ann Arbor	Michigan	United States	48109
12	Mayo Clinic	Rochester	Minnesota	United States	55905
13	Albert Einstein College of Medicine	Bronx	New York	United States	10461
14	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467-2490
15	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
16	SUNY College at Old Westbury	Old Westbury	New York	United States	11568-0210
17	Carolinas Medical Center	Charlotte	North Carolina	United States	28203
18	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
19	Medical University of South Carolina	Charleston	South Carolina	United States	29425
20	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232
21	M D Anderson Cancer Center	Houston	Texas	United States	77030
22	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia	United States	23298
23	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
24	University Health Network-Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: William Tap, 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: NCT01016015
• Other Study ID Numbers: NCI-2011-01408; NCI-2011-01408; CDR0000659358; 09-097; 8121; N01CM00032; N01CM00038; N01CM00071; N01CM00100; P30CA008748
• First Posted: Nov 18, 2009
• Last Update Posted: Jul 30, 2015
• Last Verified: May 1, 2014

• Additional relevant MeSH terms: Sarcoma; Osteosarcoma; Recurrence; Sirolimus; Antibodies, Monoclonal

Study Results

Participant Flow

Arm/Group Title	Cixutumumab and Temsirolimus
Arm/Group Description	Patients receive cixutumumab IV over 60 minutes and temsirolimus IV over 30 minutes on days 1, 8, 15, 22, 29, and 36. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	178
COMPLETED	159
NOT COMPLETED	19

Baseline Characteristics

Arm/Group Title	Cixutumumab and Temsirolimus
Arm/Group Description	Patients receive cixutumumab IV over 60 minutes and temsirolimus IV over 30 minutes on days 1, 8, 15, 22, 29, and 36. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity.
Overall Participants	178
Age (Count of Participants)
<=18 years	4 2.2%
Between 18 and 65 years	144 80.9%
>=65 years	30 16.9%
Sex: Female, Male (Count of Participants)
Female	80 44.9%
Male	98 55.1%
Region of Enrollment (participants) [Number]
United States	178 100%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival Rate, Defined as CR + PR + SD, as Assessed by RECIST Criteria
Description	From study entry until recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurement recorded on study), death or date of last contact, assessed at 12 weeks
Time Frame	From study entry until recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurement recorded on study), death or date of last contact, assessed at 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cixutumumab and Temsirolimus
Arm/Group Description	Patients receive cixutumumab IV over 60 minutes and temsirolimus IV over 30 minutes on days 1, 8, 15, 22, 29, and 36. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	159
Partial Response	4 2.2%
Progression of Disease	57 32%
Stable Disease	98 55.1%

Adverse Events

Arm/Group Title	Cixutumumab and Temsirolimus
Arm/Group Description	Patients receive cixutumumab IV over 60 minutes and temsirolimus IV over 30 minutes on days 1, 8, 15, 22, 29, and 36. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Cixutumumab and Temsirolimus
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Cixutumumab and Temsirolimus
	Affected / at Risk (%)	# Events
Total	83/175 (47.4%)
Blood and lymphatic system disorders
Anemia	4/175 (2.3%)	4
Blood and lymph system disorder	1/175 (0.6%)	1
Cardiac disorders
Cardiac arrest	1/175 (0.6%)	1
Pericardial effusion	2/175 (1.1%)	2
Supraventricular tachycardia	1/175 (0.6%)	1
Eye disorders
Eye disorder	1/175 (0.6%)	1
Gastrointestinal disorders
Abdominal pain	3/175 (1.7%)	6
Ascites	1/175 (0.6%)	1
Colitis	3/175 (1.7%)	3
Colonic fistula	1/175 (0.6%)	1
Colonic obstruction	1/175 (0.6%)	1
Colonic perforation	1/175 (0.6%)	1
Diarrhea	9/175 (5.1%)	10
Mucositis-Oral	12/175 (6.9%)	14
Nausea	1/175 (0.6%)	1
Proctitis	1/175 (0.6%)	1
Vomiting	1/175 (0.6%)	1
General disorders
Death NOS	11/175 (6.3%)	11
Edema-Limb	1/175 (0.6%)	1
Fatigue	1/175 (0.6%)	1
Fever	3/175 (1.7%)	3
Localized edema	1/175 (0.6%)	1
Non-cardiac chest pain	1/175 (0.6%)	1
Pain	5/175 (2.9%)	5
Hepatobiliary disorders
Hepatobiliary disorder	2/175 (1.1%)	2
Infections and infestations
Catheter related infection	1/175 (0.6%)	1
Infection and Infestations	3/175 (1.7%)	3
Lung Infection	7/175 (4%)	8
Mucosal infection	2/175 (1.1%)	2
Paronychia	2/175 (1.1%)	2
Urinary tract infection	4/175 (2.3%)	7
Injury, poisoning and procedural complications
Fracture	2/175 (1.1%)	2
Investigations
Alanine aminotransferase increased	2/175 (1.1%)	2
Alkaline phosphatase increased	1/175 (0.6%)	1
Aspartate aminotransferase increased	2/175 (1.1%)	2
Blood Bilirubin increase	1/175 (0.6%)	1
Electrocardiogram QT corrected interval prolonged	1/175 (0.6%)	1
Lymphocyte count decrease	1/175 (0.6%)	1
Platelet count decreased	10/175 (5.7%)	10
White blood cell decreased	7/175 (4%)	10
Metabolism and nutrition disorders
Anorexia	1/175 (0.6%)	1
Dehydration	5/175 (2.9%)	5
Glucose intolerance	1/175 (0.6%)	1
Hyperglycemia	2/175 (1.1%)	2
Hypertriglyceridemia	4/175 (2.3%)	4
Hypoalbuminemia	2/175 (1.1%)	2
Hypocalcemia	2/175 (1.1%)	2
Hypokalemia	1/175 (0.6%)	1
Hypomagnesemia	2/175 (1.1%)	2
Hyponatremia	7/175 (4%)	7
Hypophosphatemia	1/175 (0.6%)	1
Hypotension	1/175 (0.6%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/175 (0.6%)	1
Generalized muscle weakness	1/175 (0.6%)	1
Muscle weakness lower limbs	1/175 (0.6%)	1
Pain in extremity	2/175 (1.1%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	6/175 (3.4%)	8
Nervous system disorders
Intracranial hemorrhage	1/175 (0.6%)	2
Syncope	1/175 (0.6%)	1
Psychiatric disorders
Confusion	1/175 (0.6%)	1
Renal and urinary disorders
Renal and urinary disorder	3/175 (1.7%)	3
Respiratory, thoracic and mediastinal disorders
Bronchopulmonary hemorrhage	1/175 (0.6%)	1
Cough	2/175 (1.1%)	2
Dyspnea	6/175 (3.4%)	7
Hypoxia	2/175 (1.1%)	2
Pleural effusion	5/175 (2.9%)	5
Pneumothorax	3/175 (1.7%)	3
Resp, thoracic & mediastinal disorder Other, spec	1/175 (0.6%)	1
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia syndrome	1/175 (0.6%)	1
Rash acneiform	1/175 (0.6%)	1
Rash maculo papular	1/175 (0.6%)	1
Skin infection	1/175 (0.6%)	1
Skin ulceration	1/175 (0.6%)	2
Surgical and medical procedures
Surgical and medical procedures	1/175 (0.6%)	1
Vascular disorders
Thromboembolic event	3/175 (1.7%)	3
Other (Not Including Serious) Adverse Events
	Cixutumumab and Temsirolimus
	Affected / at Risk (%)	# Events
Total	62/175 (35.4%)
Investigations
Activated partial thromboplastin time prolonged	14/175 (8%)	25
Alanine aminotransferase	32/175 (18.3%)	60
Alkaline phosphatase increased	32/175 (18.3%)	175
Aspartate aminotransferase increased	31/175 (17.7%)	132
Blood Bilirubin increased	12/175 (6.9%)	29
Cholesterol, High	41/175 (23.4%)	139
Creatinine increased	19/175 (10.9%)	192
Hyponatremia	30/175 (17.1%)	133
Lymphocyte count decrease	18/175 (10.3%)	98
Neutrophil count decrease	21/175 (12%)	59
Platelet Count decrease	50/175 (28.6%)	404
White blood cell decrease	44/175 (25.1%)	285
Metabolism and nutrition disorders
Hyperglycemia	61/175 (34.9%)	915
Hyperkalemia	8/175 (4.6%)	21
Hypertriglyceridemia	40/175 (22.9%)	159
Hypoalbuminemia	51/175 (29.1%)	509
Hypocalcemia	26/175 (14.9%)	157
Hypokalemia	15/175 (8.6%)	57
Hypophosphatemia	19/175 (10.9%)	52
INR increased	31/175 (17.7%)	107

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.