Velcade, Trisenox, Vitamin C and Melphalan for Myeloma Patients

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00469209
• Collaborator: Cephalon (Industry)
• Enrollment: 60
• Location: 1
• Arms: 3
• Duration (Months): 30
• Patients Per Site Per Month: 2

Study Details

Study Description

Brief Summary

Primary Objectives:

1. To evaluate the toxicity and safety of a combination of bortezomib with arsenic trioxide, ascorbic acid and high-dose melphalan in patients with multiple myeloma

2. To evaluate the efficacy of a combination of bortezomib with arsenic trioxide, ascorbic acid and high-dose melphalan in patients with multiple myeloma

3. To determine the effects of bortezomib on melphalan pharmacokinetics

Condition or Disease	Intervention/Treatment	Phase
Myeloma	Drug: Trisenox (Arsenic Trioxide); Drug: Velcade (Bortezomib); Drug: Melphalan; Drug: Vitamin C (Ascorbic Acid)	Phase 1/Phase 2

Detailed Description

Melphalan is designed to damage the DNA of cells, which may cause cancer cells to die. High-dose melphalan is considered the standard of care for multiple myeloma. Bortezomib is designed to block a protein that plays a role in cell function and growth, which may cause cancer cells to die. Arsenic trioxide may cause cancer cells to die, and researchers want to find out if arsenic trioxide helps melphalan in killing cancer cells. Vitamin C makes arsenic trioxide more available inside the cancer cells, and researchers want to learn if Vitamin C makes arsenic trioxide more effective.

Before you can start treatment on this study, you will have "screening tests." These tests will help the doctor decide if you are eligible to take part in this study. You will have a physical exam, including measurement of vital signs (blood pressure, heart rate, temperature, and breathing rate). Your complete medical history will be recorded. You will have a dental exam to check for any infected teeth or gums that may flare up after chemotherapy.

You will have a bone marrow aspirate and biopsy. To collect a bone marrow aspirate/biopsy, an area of the hip or chest bone is numbed with anesthetic, and a small amount of bone marrow is withdrawn through a large needle. Cytogenetic tests will be performed on the aspirate sample to look for any genetic abnormalities in your DNA. You will have x-rays of your bones taken. The study doctor will look at the x-rays to see if there are any myeloma-related bone changes. You will also have a chest x-ray.

You will have blood (about 2 tablespoons) and urine collected for routine tests. You will have a pulmonary function test, to check if your lungs are strong enough for high-dose chemotherapy. You will have an electrocardiogram (ECG -- a test that measures the electrical activity of the heart). You will also have a MUGA scan to evaluate the function of your heart. Women who are able to have children must have a negative blood pregnancy test. The blood will be drawn as part of the 2 tablespoons drawn at screening.

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the toss of dice) to one of 3 treatment groups. There is an equal chance of being assigned to any of the 3 groups. All 3 groups will receive melphalan, arsenic trioxide, and Vitamin C. The second and third groups will also receive bortezomib, but at different dose levels. The first 3 participants assigned to receive bortezomib on this study will receive the lower of 2 bortezomib dose levels.

You will receive arsenic trioxide through a needle in a vein over 2 hours, once a day for 7 days (Days -9 to -3). At the same time, you will receive Vitamin C once a day through the vein for 7 days. After you receive the arsenic trioxide on Days -4 and -3, you will receive melphalan through the vein over 30 minutes.

If you are in Group 2 or 3, you will receive bortezomib by an intravenous (IV) push on Days -9, -6, and -3. An IV push takes a short period of time (less than 1 minute).

You will receive standard inpatient and outpatient stem cell transplant care and testing. You will have to sign a separate consent form that describes the transplant procedure and its risks. Your stem cells will be reinfused 2 days after the last dose of melphalan. To check for any side effects, you will have an ECG performed 14 days after the transplant.

If intolerable side effects from the chemotherapy occur or there is sign of disease after the transplant, you will be taken off study. If you have already received melphalan and side effects occur, then the transplant will happen. However, if intolerable side effects develop before melphalan, then you may be taken off study without having the transplant. If you are taken off study early, you still may need to return for routine post-transplant follow-up visits, if your transplant physician decides it is necessary.

If there is no sign of disease after the transplant, you will have routine follow-up visits. Blood (about 2 tablespoons) will be drawn for routine tests at least once a week during the first month after the transplant, and then once every month for the next 3 months after that. At about 3, 6, and 12 months after the transplant, you will have bone marrow biopsies and aspirates performed to check the status of the disease. You will have blood (about 2 tablespoons) and urine collected for routine tests. At 12 months after the transplant, you will have x-rays of your bones taken.

One (1) year after the transplant, your participation in this study will be over.

This is an investigational study. Bortezomib, arsenic trioxide, and melphalan are commercially available and FDA-approved for use in patients with myeloma. However, their use in combination with Vitamin C (also commercially available) is investigational. Up to 60 patients will take part in this study. All will be enrolled at M. D. Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Study of the Combination of Bortezomib With Arsenic Trioxide, Ascorbic Acid and High-Dose Melphalan for Patients With Multiple Myeloma
• Study Start Date: Jun 1, 2006
• Actual Primary Completion Date: Dec 1, 2008
• Actual Study Completion Date: Dec 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: No Bortezomib Arm 1: Melphalan 100 mg/m^2 intravenous (IV) days -4,-3 + Arsenic Trioxide 0.25 mg/kg IV for 7 days + Vitamin C IV daily	Drug: Trisenox (Arsenic Trioxide); 0.25 mg/kg by vein over 2 hours, once a day for 7 days (Days -9 to -3).; Other Names: ATO ; Drug: Melphalan; 100 mg/m2 by vein days -4,-3, over 30 minutes; Other Names: Alkeran ; Drug: Vitamin C (Ascorbic Acid); 1000 mg once a day through the vein for 7 days.
Active Comparator: Bortezomib 1.0 mg/m^2 Arm 2: Bortezomib (Level 1) 1.0 mg/m^2 IV push on Days -9, -6, and -3, Melphalan 100 mg/m^2 IV days -4,-3 + Arsenic Trioxide 0.25 mg/kg IV for 7 days + Vitamin C IV daily	Drug: Trisenox (Arsenic Trioxide); 0.25 mg/kg by vein over 2 hours, once a day for 7 days (Days -9 to -3).; Other Names: ATO ; Drug: Velcade (Bortezomib); Arm 1 (Level 1): 1.0 mg/m^2 intravenous (IV) push on Days -9, -6, and -3. An IV push takes a short period of time (less than 1 minute). Arm 2 (Level 2): 1.5 mg/m^2 intravenous (IV) push on Days -9, -6, and -3. An IV push takes a short period of time (less than 1 minute).; Other Names: PDP-341 MLN341 PS-341 ; Drug: Melphalan; 100 mg/m2 by vein days -4,-3, over 30 minutes; Other Names: Alkeran ; Drug: Vitamin C (Ascorbic Acid); 1000 mg once a day through the vein for 7 days.
Active Comparator: Bortezomib 1.5 mg/m^2 Arm 3: Bortezomib (Level 2) 1.5 mg/m^2 IV push on Days -9, -6, and -3, Melphalan + Arsenic Trioxide 0.25 mg/kg IV for 7 days + Vitamin C IV daily	Drug: Trisenox (Arsenic Trioxide); 0.25 mg/kg by vein over 2 hours, once a day for 7 days (Days -9 to -3).; Other Names: ATO ; Drug: Velcade (Bortezomib); Arm 1 (Level 1): 1.0 mg/m^2 intravenous (IV) push on Days -9, -6, and -3. An IV push takes a short period of time (less than 1 minute). Arm 2 (Level 2): 1.5 mg/m^2 intravenous (IV) push on Days -9, -6, and -3. An IV push takes a short period of time (less than 1 minute).; Other Names: PDP-341 MLN341 PS-341 ; Drug: Melphalan; 100 mg/m2 by vein days -4,-3, over 30 minutes; Other Names: Alkeran ; Drug: Vitamin C (Ascorbic Acid); 1000 mg once a day through the vein for 7 days.

Outcome Measures

Primary Outcome Measures

1. Number of Patients Reaching Complete Response (CR) [Baseline through Day 180, with assessments at Day 90 and Day 180]

   Number of participants with CR at Day 180 who had maintained CR for at minimum of 4 weeks, and who had: No monoclonal protein in urine/serum when analyzed by immunofixation electrophoresis; bone marrow normal by morphological examination with <5% plasma cells, <1% aneuploid light chain restricted population by flow cytometry for DNA/cIg; and, while healing of bony lesion is not required, no new lytic lesion should appear. Further compression fracture of spine not considered progressive disease.

Secondary Outcome Measures

1. Time to Toxicity [Baseline to event occurence (assessed weekly first 30 days)]

   The time to patient toxicity of drug combination bortezomib with arsenic trioxide, ascorbic acid and high-dose melphalan defined in days from baseline measure to occurence of adverse events grade 4 (life threatening or disabling) according to National Cancer Institute Common Toxicity Criteria (CTC), version 3.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. 1. Primary Refractory Disease (defined as failure to achieve even a partial response to induction therapy) b) Consolidation of a partial remission (defined as a decrease but continued presence of monoclonal protein on serum and urine immunofixation electrophoresis, and/or the presence of plasmacytosis on bone marrow aspirate and biopsy) c) Relapsing after prior therapy (disease relapsing after achieving a partial or complete response to prior conventional or high-dose therapy).

2. Age up to 75 years.

3. Zubrod performance status of <2.

4. Left ventricular ejection fraction >40%. No uncontrolled arrhythmias or symptomatic cardiac disease.

5. Forced expiratory volume (FEV1), forced volume vital capacity (FVC) and Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) >40%. No symptomatic pulmonary disease.

6. Serum bilirubin <2 times upper limit of normal, alanine aminotransferase/SGPT <4 times upper limit of normal. No evidence of chronic active hepatitis or cirrhosis. No effusion or ascites >1L prior to drainage.

7. HIV-negative.

8. Negative Beta human chorionic gonadotrophin (hCG) test in a woman with child bearing potential, defined as not post-menopausal for 12 months or no previous surgical sterilization

9. Patient or guardian able to sign informed consent

10. Corrected QT interval less than 470 msec.

Exclusion Criteria:

1. Corrected QT interval greater than 470 msec.

2. Patients in complete remission (defined as the absence of monoclonal protein on serum and urine immunofixation electrophoresis, and the absence of plasmacytosis in bone marrow aspirate and biopsy).

3. Patients with non-secretory myeloma.

Contacts and Locations

Locations

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

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• Cephalon

Investigators

• Principal Investigator: Muzaffar H. Qazilbash, MD, M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• UT MD Anderson Cancer Center website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT00469209
• Other Study ID Numbers: 2005-0893
• First Posted: May 4, 2007
• Last Update Posted: Sep 24, 2020
• Last Verified: Sep 1, 2020

• Keywords provided by M.D. Anderson Cancer Center: Multiple Myeloma; Melphalan; Trisenox; Arsenic Trioxide; Ascorbic Acid; Vitamin C; Velcade; Bortezomib
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Ascorbic Acid; Bortezomib; Melphalan; Arsenic Trioxide

Study Results

Participant Flow

Recruitment Details	Recruitment period June 2006 to December 2008. All participants recruited at UT MD Anderson Cancer Center.

Arm/Group Title	No Bortezomib	Bortezomib 1.0 mg/m^2	Bortezomib 1.5 mg/m^2
Arm/Group Description	Melphalan 100 mg/m^2 intravenous (IV) days -4,-3 + Arsenic Trioxide 0.25 mg/kg IV for 7 days + Vitamin C IV daily	Bortezomib (Level 1) 1.0 mg/m^2 IV push on Days -9, -6, and -3, Melphalan 100 mg/m^2 IV days -4,-3 + Arsenic Trioxide 0.25 mg/kg IV for 7 days + Vitamin C IV daily	Bortezomib (Level 2) 1.5 mg/m^2 IV push on Days -9, -6, and -3, Melphalan + Arsenic Trioxide 0.25 mg/kg IV for 7 days + Vitamin C IV daily
Period Title: Overall Study
STARTED	20	20	20
COMPLETED	19	20	19
NOT COMPLETED	1	0	1

Baseline Characteristics

Arm/Group Title	No Bortezomib	Bortezomib 1.0 mg/m^2	Bortezomib 1.5 mg/m^2	Total
Arm/Group Description	Melphalan 100 mg/m^2 intravenous (IV) days -4,-3 + Arsenic Trioxide 0.25 mg/kg IV for 7 days + Vitamin C IV daily	Bortezomib (Level 1) 1.0 mg/m^2 IV push on Days -9, -6, and -3, Melphalan 100 mg/m^2 IV days -4,-3 + Arsenic Trioxide 0.25 mg/kg IV for 7 days + Vitamin C IV daily	Bortezomib (Level 2) 1.5 mg/m^2 IV push on Days -9, -6, and -3, Melphalan + Arsenic Trioxide 0.25 mg/kg IV for 7 days + Vitamin C IV daily	Total of all reporting groups
Overall Participants	20	20	20	60
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	61	59	64	60
Sex: Female, Male (Count of Participants)
Female	12 60%	9 45%	6 30%	27 45%
Male	8 40%	11 55%	14 70%	33 55%
Region of Enrollment (participants) [Number]
United States	20 100%	20 100%	20 100%	60 100%

Outcome Measures

1. Primary Outcome

Title	Number of Patients Reaching Complete Response (CR)
Description	Number of participants with CR at Day 180 who had maintained CR for at minimum of 4 weeks, and who had: No monoclonal protein in urine/serum when analyzed by immunofixation electrophoresis; bone marrow normal by morphological examination with <5% plasma cells, <1% aneuploid light chain restricted population by flow cytometry for DNA/cIg; and, while healing of bony lesion is not required, no new lytic lesion should appear. Further compression fracture of spine not considered progressive disease.
Time Frame	Baseline through Day 180, with assessments at Day 90 and Day 180

Outcome Measure Data

Analysis Population Description

Analysis was per protocol.

Arm/Group Title	No Bortezomib	Bortezomib 1.0 mg/m^2	Bortezomib 1.5 mg/m^2
Arm/Group Description	Melphalan 100 mg/m^2 intravenous (IV) days -4,-3 + Arsenic Trioxide 0.25 mg/kg IV for 7 days + Vitamin C IV daily	Bortezomib (Level 1) 1.0 mg/m^2 IV push on Days -9, -6, and -3, Melphalan 100 mg/m^2 IV days -4,-3 + Arsenic Trioxide 0.25 mg/kg IV for 7 days + Vitamin C IV daily	Bortezomib (Level 2) 1.5 mg/m^2 IV push on Days -9, -6, and -3, Melphalan + Arsenic Trioxide 0.25 mg/kg IV for 7 days + Vitamin C IV daily
Measure Participants	20	20	20
Number [participants]	4 20%	1 5%	4 20%

2. Secondary Outcome

Title	Time to Toxicity
Description	The time to patient toxicity of drug combination bortezomib with arsenic trioxide, ascorbic acid and high-dose melphalan defined in days from baseline measure to occurence of adverse events grade 4 (life threatening or disabling) according to National Cancer Institute Common Toxicity Criteria (CTC), version 3.
Time Frame	Baseline to event occurence (assessed weekly first 30 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Study period 2 years.
Arm/Group Title	No Bortezomib		Bortezomib 1.0 mg/m^2		Bortezomib 1.5 mg/m^2
Arm/Group Description	Melphalan 100 mg/m^2 intravenous (IV) days -4,-3 + Arsenic Trioxide 0.25 mg/kg IV for 7 days + Vitamin C IV daily		Bortezomib (Level 1) 1.0 mg/m^2 IV push on Days -9, -6, and -3, Melphalan 100 mg/m^2 IV days -4,-3 + Arsenic Trioxide 0.25 mg/kg IV for 7 days + Vitamin C IV daily		Bortezomib (Level 2) 1.5 mg/m^2 IV push on Days -9, -6, and -3, Melphalan + Arsenic Trioxide 0.25 mg/kg IV for 7 days + Vitamin C IV daily
All Cause Mortality
	No Bortezomib		Bortezomib 1.0 mg/m^2		Bortezomib 1.5 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	No Bortezomib		Bortezomib 1.0 mg/m^2		Bortezomib 1.5 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/20 (15%)		2/20 (10%)		2/20 (10%)
Cardiac disorders
ventriculat tachycardia/hypotension	0/20 (0%)	0	1/20 (5%)	1	0/20 (0%)	0
Gastrointestinal disorders
small bowel obstruction	0/20 (0%)	0	0/20 (0%)	0	1/20 (5%)	1
Infections and infestations
pneumonitis/death	1/20 (5%)	1	0/20 (0%)	0	0/20 (0%)	0
pneumonia	0/20 (0%)	0	1/20 (5%)	1	0/20 (0%)	0
Renal and urinary disorders
acute renal failure	1/20 (5%)	1	0/20 (0%)	0	0/20 (0%)	0
Respiratory, thoracic and mediastinal disorders
pleural effusion	1/20 (5%)	1	0/20 (0%)	0	0/20 (0%)	0
pulmonary embolus	0/20 (0%)	0	0/20 (0%)	0	1/20 (5%)	1
Other (Not Including Serious) Adverse Events
	No Bortezomib		Bortezomib 1.0 mg/m^2		Bortezomib 1.5 mg/m^2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/20 (20%)		5/20 (25%)		5/20 (25%)
Gastrointestinal disorders
mucositis	3/20 (15%)	3	3/20 (15%)	3	1/20 (5%)	1
diarrhea	0/20 (0%)	0	1/20 (5%)	1	0/20 (0%)	0
General disorders
low back pain	0/20 (0%)	0	0/20 (0%)	0	1/20 (5%)	1
Hepatobiliary disorders
elevated transaminases	0/20 (0%)	0	0/20 (0%)	0	1/20 (5%)	1
Renal and urinary disorders
hydronephrosis	0/20 (0%)	0	1/20 (5%)	1	0/20 (0%)	0
Respiratory, thoracic and mediastinal disorders
dyspnea	1/20 (5%)	1	0/20 (0%)	0	0/20 (0%)	0
pulmonary edema	0/20 (0%)	0	0/20 (0%)	0	2/20 (10%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.