Vincristine, Doxorubicin, Cyclophosphamide and Dexrazoxane (VACdxr) in High Risk Ewing's Sarcoma Patients

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00038142
• Collaborator: (none)
• Enrollment: 46
• Location: 1
• Arms: 2
• Duration (Months): 220
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Objectives:

1. To determine if dose intensive Vincristine, Doxorubicin, Cyclophosphamide and Dexrazoxane (VACdxr) with or without ImmTherTM can improve the 2-year disease-free survival seen with standard VAC therapy.

2. To evaluate the feasibility and describe the toxicity associated with VACdxr.

3. To evaluate the feasibility and describe the toxicity of administering ImmTherTM on a weekly basis for 50- 52 weeks.

4. To determine which therapy (VACdxr+ or VACdxr-) is worthy of further evaluation.

Condition or Disease	Intervention/Treatment	Phase
Ewing's Sarcoma	Drug: Vincristine; Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Dexrazoxane; Biological: ImmTher	Phase 2

Detailed Description

Patients will be assigned at random (as by the toss of a coin) to receive 1 of 2 treatments.

Arm A: VACdxr will be given over 2 days through a needle in a vein. On day 1, vincristine will be given over 15 minutes, and doxorubicin will be given over 30 minutes.

Dexrazoxane will be given 30 minutes before doxorubicin; this drug protects the heart from damage by doxorubicin. Cyclophosphamide will be given once a day on days 1 and 2. This will make up 1 cycle of VACdxr treatment; the cycle will be repeated every 3 weeks for up to 6 cycles.

To prevent some side effects of VACdxr, the drugs Mesna and Neupogen/or Neulasta will also be given. Mesna helps prevent bladder damage. Neupogen is a growth factor that stimulates the body to make more white blood cells. Neulasta is a growth factor related to Neupogen.

After cycle 3, surgery may be done to remove any tumor that remains. The principal investigator will also decide whether radiation treatment should be done. If so, patients will receive radiation therapy.

Starting 1 month after all treatment is done, patients will receive ImmTher. ImmTher stimulates the body's white blood cells to attack and kill tumor cells. The drug will be given through a needle in a vein over 1 hour, every week for 1 year.

Arm B: Patients will be treated the same as patients in Arm A, except that they will not receive ImmTher.

Patients may have to stay in the hospital during VACdxr treatment and after surgery. Patients will receive ImmTher in the outpatient clinic.

Before treatment starts, patients will have a complete exam including blood and urine tests and an EKG and ECHO or multiple gated acquisition scan (MUGA) (heart function tests). X-rays and CT, MRI, bone marrow aspiration, and bone scans will be done. Women will have a pregnancy test.

After each treatment with drugs, after surgery, and after radiation treatment, patients will have checkups. These will include blood and urine tests and sometimes x-rays.

After cycle 3 of VACdxr, patients will have chest x-ray and x-ray of primary tumor. CT chest, MRI, bone marrow aspiration and bone scans will be done after 3 cycles as indicated. These tests will be done to record and measure tumors.

After treatment stops, patients will return for checkups every 3 months for 2 years.

This is an investigational study. ImmTher is an investigational agent. All other study drugs are approved by the U.S. Food and Drug Administration. As many as 104 patients will take part in the study; about 95 of these will be treated at M.D. Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Phase II Study of Vincristine, Doxorubicin, Cyclophosphamide and Dexrazoxane (VACdxr) With or Without ImmTher for Newly Diagnosed High Risk Ewing's Sarcoma
• Study Start Date: Nov 1, 1997
• Actual Primary Completion Date: Mar 1, 2016
• Actual Study Completion Date: Mar 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A: VACdxr With ImmTher Chemotherapy repeated every 3 weeks for 6 cycles: Vincristine 2.0 mg/m^2 (max 2.0 mg) intravenous (IV), Doxorubicin 90 mg/m^2 IV over 30 minutes, Cyclophosphamide 2.0 g/m^2 IV daily for 2 days. Dexrazoxane 900 mg/m^2 IV (30 minutes prior to doxorubicin). ImmTher 900 mcg/m^2 IV over 1 hour every week x 50-52 weeks.	Drug: Vincristine; 2.0 mg/m^2 (max 2.0 mg) IV x 1 repeated every 3 weeks X 6.; Drug: Doxorubicin; 90 mg/m^2 IV over 30 min x 1 repeated every 3 weeks X 6.; Other Names: Adriamycin Rubex ; Drug: Cyclophosphamide; 2.0 g/m^2 IV daily x 2 days repeated every 3 weeks X 6.; Other Names: Cytoxan Neosar ; Drug: Dexrazoxane; 900 mg/m^2 IV (30 min prior to doxorubicin) repeated every 3 weeks X 6.; Other Names: DXR Zinecard ; Biological: ImmTher; 900 mcg/m^2 IV over 1 hour every week x 50-52 weeks.
Active Comparator: Arm B: VACdxr Chemotherapy repeated every 3 weeks for 6 cycles: Vincristine 2.0 mg/m^2 (max 2.0 mg) IV. Doxorubicin 90 mg/m^2 IV over 30 minutes, Cyclophosphamide 2.0 g/m^2 IV daily for 2 days, Dexrazoxane 900 mg/m^2 IV (30 minutes prior to doxorubicin).	Drug: Vincristine; 2.0 mg/m^2 (max 2.0 mg) IV x 1 repeated every 3 weeks X 6.; Drug: Doxorubicin; 90 mg/m^2 IV over 30 min x 1 repeated every 3 weeks X 6.; Other Names: Adriamycin Rubex ; Drug: Cyclophosphamide; 2.0 g/m^2 IV daily x 2 days repeated every 3 weeks X 6.; Other Names: Cytoxan Neosar ; Drug: Dexrazoxane; 900 mg/m^2 IV (30 min prior to doxorubicin) repeated every 3 weeks X 6.; Other Names: DXR Zinecard

Outcome Measures

Primary Outcome Measures

1. 2-year Disease-free Survival (DFS): Effect of Treatment With Combination Drugs in VACdxr Given in High Doses With or Without ImmTher to Help Participants With Ewing's Sarcoma Live Longer [2 years]

   DFS defined as survival of participants to two years post study entry without relapse.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• High risk Ewing's Family of tumors (metastatic disease at diagnosis, humerus, femur or trunk primary, bulky primary (greater than 8 cm)), or LDH greater or equal to 900 IU/ml prior to biopsy.

• No prior chemotherapy.

• Written informed consent

• Normal cardiac function (ejection fraction greater or equal to 50%).

• Males and non pregnant females.

• Biologic age 3-60 years old.

• Adequate bone marrow function (defined as an absolute peripheral granulocyte count of>500/mm3, platelet count of >75,000/mm3, and hemoglobin >8g/dl with transfusion if required).

• Adequate renal function defined as blood urea nitrogen (BUN) <30mg% and serum creatinine <1.5 x normal for age or creatinine clearance >70.

• Patients of child bearing potential must agree to use an effective method of contraception.

• Normal hepatic function (bilirubin <1.5mg/dl, serum glutamate oxaloacetate transaminase (SGOT) or serum glutamate pyruvate transaminase (SGPT) <3x normal).

Exclusion Criteria: N/A

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center

Investigators

• Principal Investigator: Eugenie S. Kleinerman, MD, M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT00038142
• Other Study ID Numbers: ID97-198; NCI-2012-01285
• First Posted: May 30, 2002
• Last Update Posted: Jan 29, 2020
• Last Verified: Jan 1, 2020

• Keywords provided by M.D. Anderson Cancer Center: Ewing's Sarcoma; Vincristine; Doxorubicin; Adriamycin; Rubex; Cyclophosphamide; Dexrazoxane; Zinecard; VACdxr; ImmTher
• Additional relevant MeSH terms: Sarcoma; Sarcoma, Ewing; Cyclophosphamide; Doxorubicin; Vincristine; Dexrazoxane; Razoxane

Study Results

Participant Flow

Recruitment Details	Recruitment Period: November 13, 1997 to December 7, 2009. Recruitment was done within medical clinic settings.
Pre-assignment Detail	Study closed early with low recruitment due to the sponsor going out of business therefore drug no longer manufactured.

Arm/Group Title	Arm A: VACdxr With ImmTher	Arm B: VACdxr
Arm/Group Description	Chemotherapy repeated every 3 weeks for 6 cycles: Vincristine 2.0 mg/m^2 (max 2.0 mg) intravenous (IV), Doxorubicin 90 mg/m^2 IV over 30 minutes, Cyclophosphamide 2.0 g/m^2 IV daily for 2 days. Dexrazoxane 900 mg/m^2 IV (30 minutes prior to doxorubicin). ImmTher 900 mcg/m^2 IV over 1 hour every week for 50-52 weeks.	Chemotherapy repeated every 3 weeks for 6 cycles: Vincristine 2.0 mg/m^2 (max 2.0 mg) IV. Doxorubicin 90 mg/m^2 IV over 30 minutes, Cyclophosphamide 2.0 g/m^2 IV daily for 2 days, Dexrazoxane 900 mg/m^2 IV (30 minutes prior to doxorubicin).
Period Title: Overall Study
STARTED	32	14
COMPLETED	10	7
NOT COMPLETED	22	7

Baseline Characteristics

Arm/Group Title	Arm A: VACdxr With ImmTher	Arm B: VACdxr	Total
Arm/Group Description	Chemotherapy repeated every 3 weeks for 6 cycles: Vincristine 2.0 mg/m^2 (max 2.0 mg) intravenous (IV), Doxorubicin 90 mg/m^2 IV over 30 minutes, Cyclophosphamide 2.0 g/m^2 IV daily for 2 days. Dexrazoxane 900 mg/m^2 IV (30 minutes prior to doxorubicin). ImmTher 900 mcg/m^2 IV over 1 hour every week for 50-52 weeks.	Chemotherapy repeated every 3 weeks for 6 cycles: Vincristine 2.0 mg/m^2 (max 2.0 mg) IV. Doxorubicin 90 mg/m^2 IV over 30 minutes, Cyclophosphamide 2.0 g/m^2 IV daily for 2 days, Dexrazoxane 900 mg/m^2 IV (30 minutes prior to doxorubicin).	Total of all reporting groups
Overall Participants	32	14	46
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	15	17	16
Sex: Female, Male (Count of Participants)
Female	13 40.6%	6 42.9%	19 41.3%
Male	19 59.4%	8 57.1%	27 58.7%
Region of Enrollment (participants) [Number]
United States	32 100%	14 100%	46 100%

Outcome Measures

1. Primary Outcome

Title	2-year Disease-free Survival (DFS): Effect of Treatment With Combination Drugs in VACdxr Given in High Doses With or Without ImmTher to Help Participants With Ewing's Sarcoma Live Longer
Description	DFS defined as survival of participants to two years post study entry without relapse.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Data was not collected due to early termination of the protocol

Arm/Group Title	Arm A: VACdxr With ImmTher	Arm B: VACdxr
Arm/Group Description	Chemotherapy repeated every 3 weeks for 6 cycles: Vincristine 2.0 mg/m^2 (max 2.0 mg) intravenous (IV), Doxorubicin 90 mg/m^2 IV over 30 minutes, Cyclophosphamide 2.0 g/m^2 IV daily for 2 days. Dexrazoxane 900 mg/m^2 IV (30 minutes prior to doxorubicin). ImmTher 900 mcg/m^2 IV over 1 hour every week for 50-52 weeks.	Chemotherapy repeated every 3 weeks for 6 cycles: Vincristine 2.0 mg/m^2 (max 2.0 mg) IV. Doxorubicin 90 mg/m^2 IV over 30 minutes, Cyclophosphamide 2.0 g/m^2 IV daily for 2 days, Dexrazoxane 900 mg/m^2 IV (30 minutes prior to doxorubicin).
Measure Participants	0	0

Adverse Events

Time Frame	Adverse event (AE) data collected for up to 6 three-week cycles of chemotherapy then up to 30 days post drug treatment which may be received for one year if receiving ImmTher.
Adverse Event Reporting Description	One participant from Arm A not treated was excluded from AE reporting. Since the study regimen utilizes high dose chemotherapy, grade 4 myelosuppression (neutropenia, leukopenia, granulocytopenia, anemia and thrombocytopenia) & nausea/vomiting are expected. Constitutional symptoms (fever, chills, fatigue, headache, myalgia) are expected side effects of ImmTher, a biologic agent. A grade 4 toxicity of any of those listed expected events or hospitalizations not be reported as Serious AEs.
Arm/Group Title	Arm A: VACdxr With ImmTher		Arm B: VACdxr
Arm/Group Description	Chemotherapy repeated every 3 weeks for 6 cycles: Vincristine 2.0 mg/m^2 (max 2.0 mg) intravenous (IV), Doxorubicin 90 mg/m^2 IV over 30 minutes, Cyclophosphamide 2.0 g/m^2 IV daily for 2 days. Dexrazoxane 900 mg/m^2 IV (30 minutes prior to doxorubicin). ImmTher 900 mcg/m^2 IV over 1 hour every week for 50-52 weeks.		Chemotherapy repeated every 3 weeks for 6 cycles: Vincristine 2.0 mg/m^2 (max 2.0 mg) IV. Doxorubicin 90 mg/m^2 IV over 30 minutes, Cyclophosphamide 2.0 g/m^2 IV daily for 2 days, Dexrazoxane 900 mg/m^2 IV (30 minutes prior to doxorubicin).
All Cause Mortality
	Arm A: VACdxr With ImmTher		Arm B: VACdxr
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm A: VACdxr With ImmTher		Arm B: VACdxr
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/31 (3.2%)		0/14 (0%)
Respiratory, thoracic and mediastinal disorders
Respiratory Distress	1/31 (3.2%)	1	0/14 (0%)	0
Other (Not Including Serious) Adverse Events
	Arm A: VACdxr With ImmTher		Arm B: VACdxr
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/31 (100%)		14/14 (100%)
Blood and lymphatic system disorders
Anemia	23/31 (74.2%)	23	10/14 (71.4%)	10
Febrile Neutropenia	2/31 (6.5%)	2	0/14 (0%)	0
Granulocytopenia	20/31 (64.5%)	20	10/14 (71.4%)	10
Leukopenia	22/31 (71%)	22	10/14 (71.4%)	10
Lymphocytopenia	2/31 (6.5%)	2	1/14 (7.1%)	1
Lymphopenia	1/31 (3.2%)	1	0/14 (0%)	0
Platelete Increase	1/31 (3.2%)	1	0/14 (0%)	0
Cardiac disorders
Cardiac Function	2/31 (6.5%)	2	0/14 (0%)	0
Cardiaovascular General	1/31 (3.2%)	1	0/14 (0%)	0
Chest Pain	1/31 (3.2%)	1	0/14 (0%)	0
Palpitations	1/31 (3.2%)	1	0/14 (0%)	0
Restrictive cardiomyopathy	1/31 (3.2%)	1	0/14 (0%)	0
Supraventricular tachycardia	1/31 (3.2%)	1	0/14 (0%)	0
Ventricular Tachycardia	1/31 (3.2%)	1	0/14 (0%)	0
Ear and labyrinth disorders
Otitis, Middle Ear	1/31 (3.2%)	1	0/14 (0%)	0
Eye disorders
Blurred Vision	1/31 (3.2%)	1	0/14 (0%)	0
Gastrointestinal disorders
Abdomen Pain	1/31 (3.2%)	1	0/14 (0%)	0
Colitis	1/31 (3.2%)	1	0/14 (0%)	0
Constipation	11/31 (35.5%)	11	4/14 (28.6%)	4
Diarrhea	13/31 (41.9%)	13	6/14 (42.9%)	6
Dysphagia	1/31 (3.2%)	1	1/14 (7.1%)	1
Mucositis	1/31 (3.2%)	1	0/14 (0%)	0
Mucositis (Clinical assessment)	2/31 (6.5%)	2	0/14 (0%)	0
Nausea	1/31 (3.2%)	1	1/14 (7.1%)	1
Nausea Alone	22/31 (71%)	22	9/14 (64.3%)	9
Stomatitis	14/31 (45.2%)	14	2/14 (14.3%)	2
Typhlitis	1/31 (3.2%)	1	0/14 (0%)	0
Vomiting	21/31 (67.7%)	21	10/14 (71.4%)	10
General disorders
Abdominal Cramping	0/31 (0%)	0	1/14 (7.1%)	1
Candidiasis	0/31 (0%)	0	1/14 (7.1%)	1
Drug Fever	12/31 (38.7%)	12	0/14 (0%)	0
Edema	1/31 (3.2%)	1	0/14 (0%)	0
Fatigue	13/31 (41.9%)	13	1/14 (7.1%)	1
Fever Unknown Origin	1/31 (3.2%)	1	0/14 (0%)	0
Fever Without Neutropenia	4/31 (12.9%)	4	4/14 (28.6%)	4
Pain	1/31 (3.2%)	1	0/14 (0%)	0
Pain (Nos)	3/31 (9.7%)	3	0/14 (0%)	0
Pain, Other	7/31 (22.6%)	7	0/14 (0%)	0
Rigors, Chills	19/31 (61.3%)	19	0/14 (0%)	0
Infections and infestations
Infection	1/31 (3.2%)	1	0/14 (0%)	0
Infection Neutropenia	4/31 (12.9%)	4	0/14 (0%)	0
Infection Without Neutropenia	0/31 (0%)	0	1/14 (7.1%)	1
Investigations
Alanine Aminotransferase/ Serum Glutamic Pyruvic Transamnase	1/31 (3.2%)	1	0/14 (0%)	0
Amylase Increase	1/31 (3.2%)	1	0/14 (0%)	0
Bleed Platelets Grade 3, 4	1/31 (3.2%)	1	0/14 (0%)	0
Fever Neutropenic	17/31 (54.8%)	17	8/14 (57.1%)	8
Weight Loss	1/31 (3.2%)	1	0/14 (0%)	0
Metabolism and nutrition disorders
Anorexia	7/31 (22.6%)	7	3/14 (21.4%)	3
Dehydration	1/31 (3.2%)	1	1/14 (7.1%)	1
Hyperuricemia	1/31 (3.2%)	1	0/14 (0%)	0
Hypoalbuminemia	1/31 (3.2%)	1	0/14 (0%)	0
Hypocalcemia	1/31 (3.2%)	1	0/14 (0%)	0
Hypokalemia	1/31 (3.2%)	1	1/14 (7.1%)	1
Hypomagnesemia	0/31 (0%)	0	1/14 (7.1%)	1
Triglyceride, Serum Increase	1/31 (3.2%)	1	0/14 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	3/31 (9.7%)	3	0/14 (0%)	0
Myalgia	0/31 (0%)	0	0/14 (0%)	0
Pain (Back)	2/31 (6.5%)	2	0/14 (0%)	0
Pain, Back Other	4/31 (12.9%)	4	0/14 (0%)	0
Nervous system disorders
Dizziness	1/31 (3.2%)	1	0/14 (0%)	0
Headache	19/31 (61.3%)	19	3/14 (21.4%)	3
Neuropathy: Motor	2/31 (6.5%)	2	0/14 (0%)	0
Neuropathy: Sensor	1/31 (3.2%)	1	1/14 (7.1%)	1
Pain Neuropathic	1/31 (3.2%)	1	1/14 (7.1%)	1
Sensory neuropathy	3/31 (9.7%)	3	0/14 (0%)	0
Tremors	1/31 (3.2%)	1	0/14 (0%)	0
Psychiatric disorders
Insomnia	1/31 (3.2%)	1	0/14 (0%)	0
Mood Alteration	1/31 (3.2%)	1	0/14 (0%)	0
Renal and urinary disorders
Dysuria	3/31 (9.7%)	3	1/14 (7.1%)	1
Hematuria	3/31 (9.7%)	3	2/14 (14.3%)	2
Urinary Retention	1/31 (3.2%)	1	0/14 (0%)	0
Reproductive system and breast disorders
Hot Flashes	1/31 (3.2%)	1	0/14 (0%)	0
Irregular Menses	1/31 (3.2%)	1	0/14 (0%)	0
Vaginal Mucositis	1/31 (3.2%)	1	0/14 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/31 (3.2%)	1	0/14 (0%)	0
Dyspnea	1/31 (3.2%)	1	0/14 (0%)	0
Hiccoughs	1/31 (3.2%)	1	0/14 (0%)	0
Sore Throat	4/31 (12.9%)	4	1/14 (7.1%)	1
Skin and subcutaneous tissue disorders
Alopecia	9/31 (29%)	9	6/14 (42.9%)	6
Atrophy, Subcutaneious	1/31 (3.2%)	1	0/14 (0%)	0
Dermatology/Skin	2/31 (6.5%)	2	0/14 (0%)	0
Nail Changes	6/31 (19.4%)	6	0/14 (0%)	0
Petechiae	1/31 (3.2%)	1	0/14 (0%)	0
Rash/Desquamation	1/31 (3.2%)	1	0/14 (0%)	0
Sweating	1/31 (3.2%)	1	0/14 (0%)	0
Vascular disorders
Hypotension	3/31 (9.7%)	3	0/14 (0%)	0
Thrombocytopenia	23/31 (74.2%)	23	10/14 (71.4%)	10

Limitations/Caveats

Study terminated early leading to small numbers of subjects analyzed; therefore, unable to accrue required number of participants to determine statistical significance.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There IS 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.