Busulfan, Melphalan, and Bortezomib Before First-Line Stem Cell Transplant in Treating Patients With Multiple Myeloma

• Sponsor: Albert Einstein College of Medicine (Other)
• Overall Status: Completed
• CT.gov ID: NCT01605032
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 19
• Locations: 4
• Arm: 1
• Duration (Months): 72.9
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This phase II trial studies how well busulfan, melphalan, and bortezomib before first-line stem cell transplant works in treating patients with multiple myeloma. Giving chemotherapy before a peripheral blood stem cell transplant may stop the growth of cancer cells by stopping them from dividing or killing them. After treatment, stem cells are collected from the patient's blood and stored. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy.

Condition or Disease	Intervention/Treatment	Phase
DS Stage I Plasma Cell Myeloma; DS Stage II Plasma Cell Myeloma; DS Stage III Plasma Cell Myeloma; Refractory Plasma Cell Myeloma	Drug: Busulfan; Drug: Melphalan; Drug: Bortezomib; Procedure: Autologous Hematopoietic Stem Cell Transplantation; Procedure: Peripheral Blood Stem Cell Transplantation	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To determine the complete response rate as defined by the International Myeloma Working Group (IMWG) criteria for patients with multiple myeloma treated with high dose chemotherapy with pharmacokinetic (PK) directed intravenous (IV) busulfan, bortezomib and melphalan (Bu/BTZ/Mel140) followed by autologous hematopoietic stem cell transplantation (ASCT) as first line therapy.

SECONDARY OBJECTIVES:

1. To determine the overall response rate of the regimen Bu/BTZ/Mel140. II. To determine the treatment related toxicity and mortality of the regimen, including 100-day mortality rates.

2. To determine the duration of response, time to progression, progression-free survival, event-free survival and overall survival for this conditioning regimen.

3. To determine whether there is a gender or race difference in the pharmacokinetic profile of IV busulfan.

4. To determine methylation and gene expression signatures of pre-treatment bone marrow plasma cells and explore associations of these signatures with outcome.

OUTLINE:

CONDITIONING: Patients receive busulfan IV over 3 hours on days -6 to -3, melphalan IV over 20 minutes on day -2, and bortezomib IV over 3-5 seconds on days -6, -3, 1, and 4.

TRANSPLANT: Patients undergo autologous peripheral blood stem cell transplant (PBSCT) on day 0.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study Assessing the Efficacy and Toxicity of PK--directed Intravenous Busulfan in Combination With High--Dose Melphalan and Bortezomib as Conditioning Regimen for First--Line Autologous Hematopoietic Stem Cell Transplantation in Patients With Multiple Myeloma
• Study Start Date: Feb 1, 2012
• Actual Primary Completion Date: Mar 1, 2018
• Actual Study Completion Date: Mar 1, 2018

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (busulfan, melphalan, bortezomib, autologous PBSCT) CONDITIONING: Patients receive busulfan IV over 3 hours on days -6 to -3, melphalan IV over 20 minutes on day -2, and bortezomib IV over 3-5 seconds on days -6, -3, 1, and 4. TRANSPLANT: Patients undergo autologous PBSCT on day 0.

Drug: Busulfan; Given IV; Drug: Melphalan; Given IV; Other Names: Alkeran ; Drug: Bortezomib; Given IV; Procedure: Autologous Hematopoietic Stem Cell Transplantation; Undergo autologous PBSCT; Other Names: Autologous Stem Cell Transplantation ; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo autologous PBSCT; Other Names: PBPC transplantation Peripheral Blood Progenitor Cell Transplantation Peripheral Stem Cell Support Peripheral Stem Cell Transplantation

Outcome Measures

Primary Outcome Measures

1. Rate of Complete Response as Determined by the IMWG Criteria [Day 100]

   Number of patients achieved complete response after the treatment regimen

Secondary Outcome Measures

1. Overall Response Rate [Up to day 100]

   Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

2. Mortality [Up to day 100]

3. Time-to-progression [From start of treatment to disease progression with deaths, up to 2 years]

4. Progression-free Survival [2 years]

   The progression free survival was assessed over a period of 2 years

5. Overall Survival [2 years]

   The overall survival of patients was measured of a period of 2 years.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 72 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed multiple myeloma

• Measurable disease must be present as defined by protein criteria (quantifiable M-component in serum, urine or serum free light chains) in order to evaluate response as per IMWG; non-secretory patients are eligible provided the patient has > 20% plasmacytosis OR multiple (> 3) focal plasmacytomas or focal lesions on magnetic resonance imaging (MRI)

• Patients must have received induction chemotherapy for myeloma, but not more than 12 months of prior chemotherapy for this disease, and must be eligible for the first planned autologous transplant

• A minimum stem cell dose of 2.0 x 10^6 cluster of differentiation 34-positive (CD34+) cells/kg has been collected

• Life expectancy of greater than 12 months

• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

• Leukocytes >= 3,000/mcL (unless myeloma related)

• Absolute neutrophil count >= 1,500/mcL (unless myeloma related)

• Platelets >= 50,000/mcL (unless myeloma related)

• Total bilirubin =< 2 x institutional upper limit of normal unless 2nd to Gilbert's disease

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal

• Creatinine =< 1.5 x institutional upper limit of normal OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

• Ejection fraction by echocardiogram (ECHO) or multi gated acquisition scan (MUGA) >= 40% performed within 60 days prior to registration

• Patients must have adequate pulmonary function studies: > 50% of predicted on mechanical aspects (forced expiratory volume in one second [FEV1], forced vital capacity [FVC]) and diffusion capacity (diffusing capacity of the lung for carbon monoxide [DLCO]) > 50% of predicted, within 60 days of registration; if the patients is unable to complete pulmonary function tests due to multiple myeloma (MM) related pain or condition, exception may be granted if the principal investigator (PI) documents that the patient is a candidate for high dose therapy

• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for at least six months following the stem cell transplantation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately

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

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier

• Prior treatment history of autologous hematopoietic stem cell transplant (HSCT) or high-dose chemotherapy with stem cell rescue for any medical reason, not limited to myeloma treatment

• Patients may not be receiving any other investigational agents

• Patients with known brain metastases should be excluded from this clinical trial

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to or other agents used in the study, such as busulfan, melphalan, bortezomib, boron, or mannitol

• Grade 2 or greater peripheral neuropathy within 14 days prior to enrollment

• Unresolved grade >= 3 non-hematologic toxicity from previous therapy; patients with grade 2 toxicity will be eligible at the discretion of the PI

• Prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ; cancer treated with curative intent < 5 years will not be allowed unless approved by the PI; cancer treated with curative intent > 5 years will be allowed

• Patients must not have significant co-morbid medical condition

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; patients must not have suffered recent (< 6 months) myocardial infarction, unstable angina, difficult to control congestive heart failure, uncontrolled hypertension, or difficult to control cardiac arrhythmias

• Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with busulfan

• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

• Patients found to have an active hepatitis B infection (hepatitis B surface antigen +) are not eligible unless they meet ONE of the following criteria:

• Patient is able to start dual anti-hepatitis (Hep) B therapy prior to enrollment with adefovir and telbivudine

• Patient is already on dual anti-hepatitis B therapy

• Consultation and co-management with a hepatitis expert regarding hepatitis B treatment is strongly encouraged before and during the trial

• Patients, who are positive for hepatitis B core antibody, but negative for the hepatitis B surface antigen, should be started on lamivudine 100 mg daily until at least 3 months post stem cell transplant

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rutgers Cancer Institute of New Jersey	New Brunswick	New Jersey	United States	08903
2	Albert Einstein College of Medicine	Bronx	New York	United States	10461
3	NYU Cancer Institute	New York	New York	United States	10016
4	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065

Sponsors and Collaborators

• Albert Einstein College of Medicine
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Ira Braunschweig, Albert Einstein College of Medicine

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 1, 2015
• Informed Consent Form - Apr 15, 2014

More Information

Publications

None provided.

• Responsible Party: Ira Braunschweig, Principal Investigator, Albert Einstein College of Medicine
• ClinicalTrials.gov Identifier: NCT01605032
• Other Study ID Numbers: 11-12-434; NCI-2013-01207; 11-102; 11-12-434; P30CA013330
• First Posted: May 24, 2012
• Last Update Posted: Aug 20, 2020
• Last Verified: Aug 1, 2020

• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Bortezomib; Melphalan; Busulfan

Study Results

Participant Flow

Arm/Group Title	Treatment (Busulfan, Melphalan, Bortezomib, Autologous PBSCT)
Arm/Group Description	CONDITIONING: Patients receive busulfan IV over 3 hours on days -6 to -3, melphalan IV over 20 minutes on day -2, and bortezomib IV over 3-5 seconds on days -6, -3, 1, and 4. TRANSPLANT: Patients undergo autologous PBSCT on day 0. Busulfan: Given IV Melphalan: Given IV Bortezomib: Given IV Autologous Hematopoietic Stem Cell Transplantation: Undergo autologous PBSCT Peripheral Blood Stem Cell Transplantation: Undergo autologous PBSCT
Period Title: Overall Study
STARTED	19
COMPLETED	18
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Treatment (Busulfan, Melphalan, Bortezomib, Autologous PBSCT)
Arm/Group Description	CONDITIONING: Patients receive busulfan IV over 3 hours on days -6 to -3, melphalan IV over 20 minutes on day -2, and bortezomib IV over 3-5 seconds on days -6, -3, 1, and 4. TRANSPLANT: Patients undergo autologous PBSCT on day 0. Busulfan: Given IV Melphalan: Given IV Bortezomib: Given IV Autologous Hematopoietic Stem Cell Transplantation: Undergo autologous PBSCT Peripheral Blood Stem Cell Transplantation: Undergo autologous PBSCT
Overall Participants	19
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	55
Sex: Female, Male (Count of Participants)
Female	6 31.6%
Male	13 68.4%
Race and Ethnicity Not Collected (Count of Participants)
ISS stage at diagnosis (participants) [Number]
Stage 1	4 21.1%
Stage 2	7 36.8%
Stage 3	5 26.3%
Stage unkown	3 15.8%
Cytogenetics/FISH at diagnosis (participants) [Number]
High risk	2 10.5%
Intermediate risk	2 10.5%
Standard risk	6 31.6%
Unknown	10 52.6%
Previous treatment (participants) [Number]
Bortezomib-containing regimen	17 89.5%
Immunomodulatory agent-containing regimen	7 36.8%
Response before ASCT (Count of Participants)
Complete response	1 5.3%
Very Good partial response	2 10.5%
Partial response	10 52.6%
Stable disease	5 26.3%
Progressive disease	1 5.3%

Outcome Measures

1. Primary Outcome

Title	Rate of Complete Response as Determined by the IMWG Criteria
Description	Number of patients achieved complete response after the treatment regimen
Time Frame	Day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Busulfan, Melphalan, Bortezomib, Autologous PBSCT)
Arm/Group Description	CONDITIONING: Patients receive busulfan IV over 3 hours on days -6 to -3, melphalan IV over 20 minutes on day -2, and bortezomib IV over 3-5 seconds on days -6, -3, 1, and 4. TRANSPLANT: Patients undergo autologous PBSCT on day 0. Busulfan: Given IV Melphalan: Given IV Bortezomib: Given IV Autologous Hematopoietic Stem Cell Transplantation: Undergo autologous PBSCT Peripheral Blood Stem Cell Transplantation: Undergo autologous PBSCT
Measure Participants	19
Count of Participants [Participants]	2 10.5%

2. Secondary Outcome

Title	Overall Response Rate
Description	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame	Up to day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Busulfan, Melphalan, Bortezomib, Autologous PBSCT)
Arm/Group Description	CONDITIONING: Patients receive busulfan IV over 3 hours on days -6 to -3, melphalan IV over 20 minutes on day -2, and bortezomib IV over 3-5 seconds on days -6, -3, 1, and 4. TRANSPLANT: Patients undergo autologous PBSCT on day 0. Busulfan: Given IV Melphalan: Given IV Bortezomib: Given IV Autologous Hematopoietic Stem Cell Transplantation: Undergo autologous PBSCT Peripheral Blood Stem Cell Transplantation: Undergo autologous PBSCT
Measure Participants	19
Complete response	2 10.5%
Partial response	17 89.5%

3. Secondary Outcome

Title	Mortality
Time Frame	Up to day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Busulfan, Melphalan, Bortezomib, Autologous PBSCT)
Arm/Group Description	CONDITIONING: Patients receive busulfan IV over 3 hours on days -6 to -3, melphalan IV over 20 minutes on day -2, and bortezomib IV over 3-5 seconds on days -6, -3, 1, and 4. TRANSPLANT: Patients undergo autologous PBSCT on day 0. Busulfan: Given IV Melphalan: Given IV Bortezomib: Given IV Autologous Hematopoietic Stem Cell Transplantation: Undergo autologous PBSCT Peripheral Blood Stem Cell Transplantation: Undergo autologous PBSCT
Measure Participants	19
Count of Participants [Participants]	1 5.3%

4. Secondary Outcome

Title	Time-to-progression
Time Frame	From start of treatment to disease progression with deaths, up to 2 years

Outcome Measure Data

Analysis Population Description

The outcome measure 'Time to Progression' was not collected

Arm/Group Title	Treatment (Busulfan, Melphalan, Bortezomib, Autologous PBSCT)
Arm/Group Description	CONDITIONING: Patients receive busulfan IV over 3 hours on days -6 to -3, melphalan IV over 20 minutes on day -2, and bortezomib IV over 3-5 seconds on days -6, -3, 1, and 4. TRANSPLANT: Patients undergo autologous PBSCT on day 0. Busulfan: Given IV Melphalan: Given IV Bortezomib: Given IV Autologous Hematopoietic Stem Cell Transplantation: Undergo autologous PBSCT Peripheral Blood Stem Cell Transplantation: Undergo autologous PBSCT
Measure Participants	0

5. Secondary Outcome

Title	Progression-free Survival
Description	The progression free survival was assessed over a period of 2 years
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Busulfan, Melphalan, Bortezomib, Autologous PBSCT)
Arm/Group Description	CONDITIONING: Patients receive busulfan IV over 3 hours on days -6 to -3, melphalan IV over 20 minutes on day -2, and bortezomib IV over 3-5 seconds on days -6, -3, 1, and 4. TRANSPLANT: Patients undergo autologous PBSCT on day 0. Busulfan: Given IV Melphalan: Given IV Bortezomib: Given IV Autologous Hematopoietic Stem Cell Transplantation: Undergo autologous PBSCT Peripheral Blood Stem Cell Transplantation: Undergo autologous PBSCT
Measure Participants	19
Count of Participants [Participants]	11 57.9%

6. Secondary Outcome

Title	Overall Survival
Description	The overall survival of patients was measured of a period of 2 years.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Busulfan, Melphalan, Bortezomib, Autologous PBSCT)
Arm/Group Description	CONDITIONING: Patients receive busulfan IV over 3 hours on days -6 to -3, melphalan IV over 20 minutes on day -2, and bortezomib IV over 3-5 seconds on days -6, -3, 1, and 4. TRANSPLANT: Patients undergo autologous PBSCT on day 0. Busulfan: Given IV Melphalan: Given IV Bortezomib: Given IV Autologous Hematopoietic Stem Cell Transplantation: Undergo autologous PBSCT Peripheral Blood Stem Cell Transplantation: Undergo autologous PBSCT
Measure Participants	19
Count of Participants [Participants]	18 94.7%

Adverse Events

Time Frame	Up to 2 years
Arm/Group Title	Treatment (Busulfan, Melphalan, Bortezomib, Autologous PBSCT)
Arm/Group Description	CONDITIONING: Patients receive busulfan IV over 3 hours on days -6 to -3, melphalan IV over 20 minutes on day -2, and bortezomib IV over 3-5 seconds on days -6, -3, 1, and 4. TRANSPLANT: Patients undergo autologous PBSCT on day 0. Busulfan: Given IV Melphalan: Given IV Bortezomib: Given IV Autologous Hematopoietic Stem Cell Transplantation: Undergo autologous PBSCT Peripheral Blood Stem Cell Transplantation: Undergo autologous PBSCT
All Cause Mortality
	Treatment (Busulfan, Melphalan, Bortezomib, Autologous PBSCT)
	Affected / at Risk (%)	# Events
Total	1/19 (5.3%)
Serious Adverse Events
	Treatment (Busulfan, Melphalan, Bortezomib, Autologous PBSCT)
	Affected / at Risk (%)	# Events
Total	1/19 (5.3%)
Respiratory, thoracic and mediastinal disorders
Death - 70 days after the autologous stem cell transplant	1/19 (5.3%)
Other (Not Including Serious) Adverse Events
	Treatment (Busulfan, Melphalan, Bortezomib, Autologous PBSCT)
	Affected / at Risk (%)	# Events
Total	19/19 (100%)
Endocrine disorders
Transaminitis	13/19 (68.4%)
Gastrointestinal disorders
Oral mucositis	18/19 (94.7%)
Dysphagia/Odynophagia	17/19 (89.5%)
Nausea and/or vomitting	18/19 (94.7%)
Diarrhea	15/19 (78.9%)
Abdominal pain	3/19 (15.8%)
General disorders
Electrolyte abnormalities	17/19 (89.5%)
Fever without neutropenia	4/19 (21.1%)
Immune system disorders
Febrile neutropenia	14/19 (73.7%)
Infections and infestations
Infections	8/19 (42.1%)
Respiratory, thoracic and mediastinal disorders
Noninfectious pulmonary toxicity	2/19 (10.5%)

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.