Bortezomib and Rituximab in Treating Patients With Post-Transplant Lymphoproliferative Disorders

• Sponsor: Masonic Cancer Center, University of Minnesota (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00869323
• Collaborator: Millennium Pharmaceuticals, Inc. (Industry)
• Enrollment: 3
• Locations: 2
• Arm: 1
• Duration (Months): 93
• Patients Per Site: 1.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer. Monoclonal antibodies, such as rituximab, can block cancer cell growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving bortezomib together with rituximab may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving bortezomib together with rituximab works in treating patients with post-transplant lymphoproliferative disorders.

Condition or Disease	Intervention/Treatment	Phase
Lymphoproliferative Disorder	Biological: rituximab; Drug: bortezomib	Phase 2

Detailed Description

OBJECTIVES:

Primary

• To estimate the overall (complete and partial) response rates in patients with CD20+ post-transplant lymphoproliferative disorders treated with bortezomib and rituximab.

Secondary

• To evaluate the duration of remission, time to treatment failure, relapse-free survival, and overall survival of these patients.

• To characterize the quantitative and qualitative toxicities of this regimen.

OUTLINE:

• Induction therapy: Patients receive bortezomib intravenously (IV) and rituximab IV on days 1, 8, 15, and 22.

Patients achieving complete remission (CR) after completion of induction therapy proceed to maintenance therapy after 6 months of rest. Patients achieving partial remission (PR) or stable disease after completion of induction therapy receive additional bortezomib IV on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR/PR after completion of bortezomib therapy proceed to maintenance therapy after 3 months of rest.

• Maintenance therapy: Patients receive bortezomib IV and rituximab IV on days 1, 8, 15, and 22. Treatment repeats every 6 months for 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Bortezomib and Rituximab for Patients With Post Transplant Lymphoproliferative Disorders (PTLD)
• Study Start Date: Mar 1, 2009
• Actual Primary Completion Date: Mar 1, 2013
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treated Patients This group includes patients receiving Bortezomib and Rituximab for post-transplant lymphoproliferative disorders (PTLD).	Biological: rituximab; 375 mg/m^2 intravenously on Days 1,8, 15 and 22; Other Names: Rituxan ; Drug: bortezomib; 1.3 mg/m^2 intravenous bolus days 1, 8, 15 and 22; Other Names: Velcade

Outcome Measures

Primary Outcome Measures

1. Number of Patients With Overall (Complete and Partial) Response Rates [Day 1 to 2 Years Post Treatment]

Secondary Outcome Measures

1. Remission Duration Among Patients Who Respond to Treatment [Day 1 to 8 Months Post Treatment]

2. Time to Treatment Failure [Day 1 to Time of Disease Progression]

3. Relapse-free Survival [at 2 years]

4. Overall Survival [at 2 years]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically confirmed CD20+ B-cell post-transplant lymphoproliferative disorder

• Has undergone prior solid organ transplant

• Measurable disease as defined by Non-Hodgkin Lymphoma Response Criteria

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Absolute neutrophil count (ANC) ≥ 1,000/mm³

• Platelet count ≥ 75,000/mm³

• Creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 40 mL/min

• Alanine transaminase (ALT) and Aspartate aminotransferase (AST) ≤ 3 times upper limit of normal

• Total bilirubin ≤ 2.0 mg/dL

Exclusion Criteria:

• Pregnant or nursing

• Fertile patients must use effective contraception during and for 3 months after completion of study treatment

• Peripheral neuropathy ≥ grade 2

• Known lymphomatous meningitis or central nervous system (CNS) involvement

• HIV infection

• Uncontrolled infection

• Myocardial infarction within the past 6 months or uncontrolled angina

• New York Heart Association class III-IV heart failure

• Severe uncontrolled ventricular arrhythmias

• Evidence of acute ischemia or active conduction system abnormalities by electrocardiogram (EKG)

• Concurrent serious medical or psychiatric disorder (e.g., active infection or uncontrolled diabetes) that, in the opinion of the investigator, would compromise the safety of the patient or compromise the patient's ability to complete the study

• Diagnosis or treatment for another malignancy within the past 3 years, except completely resected basal cell carcinoma or squamous cell carcinoma of the skin, in situ malignancy, or curatively treated low-risk prostate cancer

• Known hypersensitivity to rituximab, bortezomib, boron, or any of the other agents used in this study

• Less than 14 days since prior investigational drugs

• Less than 4 weeks since prior bortezomib therapy (12 weeks for rituximab) and recovered from toxic effects prior to enrollment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Minnesota Medical Center - Fairview	Minneapolis	Minnesota	United States	55455
2	Washington University School of Medicine - Oncology Division	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Masonic Cancer Center, University of Minnesota
• Millennium Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Anne H. Blaes, MD, Masonic Cancer Center, University of Minnesota

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Masonic Cancer Center, University of Minnesota
• ClinicalTrials.gov Identifier: NCT00869323
• Other Study ID Numbers: 2008LS043; MT2008-05R; 0806M37121
• First Posted: Mar 26, 2009
• Last Update Posted: Dec 5, 2017
• Last Verified: Dec 1, 2017

• Keywords provided by Masonic Cancer Center, University of Minnesota: post-transplant lymphoproliferative disorder
• Additional relevant MeSH terms: Lymphoproliferative Disorders; Disease; Rituximab; Bortezomib

Study Results

Participant Flow

Arm/Group Title	Treated Study Participants
Arm/Group Description	Study participants receiving bortezomib and rituximab for post-transplant lymphoproliferative disorders (PTLD). Induction Therapy: rituximab: 375 mg/m^2 intravenously on Days 1,8, 15 and 22 bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 8, 15 and 22 If complete response, start Maintenance Therapy. If partial response or stable disease, start Single Agent Bortezomib. If progressive disease, discontinue study treatment. Single Agent Bortezomib bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 4, 8, 11 every 21 days for 4 cycles. If complete response or partial response, start Maintenance Therapy. If stable disease or progressive disease, discontinue study treatment. Maintenance Therapy: rituximab: 375 mg/m^2 intravenously on Days 1,8, 15 and 22 bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 8, 15 and 22 Repeat every 6 months for a total of 4 cycles.
Period Title: Induction Therapy
STARTED	3
COMPLETED	3
NOT COMPLETED	0
Period Title: Induction Therapy
STARTED	2
COMPLETED	1
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Treated Study Participants
Arm/Group Description	Study participants receiving bortezomib and rituximab for post-transplant lymphoproliferative disorders (PTLD). Induction Therapy: rituximab: 375 mg/m^2 intravenously on Days 1,8, 15 and 22 bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 8, 15 and 22 If complete response, start Maintenance Therapy. If partial response or stable disease, start Single Agent Bortezomib. If progressive disease, discontinue study treatment. Single Agent Bortezomib bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 4, 8, 11 every 21 days for 4 cycles. If complete response or partial response, start Maintenance Therapy. If stable disease or progressive disease, discontinue study treatment. Maintenance Therapy: rituximab: 375 mg/m^2 intravenously on Days 1,8, 15 and 22 bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 8, 15 and 22 Repeat every 6 months for a total of 4 cycles.
Overall Participants	3
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	2 66.7%
>=65 years	1 33.3%
Sex: Female, Male (Count of Participants)
Female	2 66.7%
Male	1 33.3%

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Overall (Complete and Partial) Response Rates
Time Frame	Day 1 to 2 Years Post Treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treated Study Participants
Arm/Group Description	Study participants receiving bortezomib and rituximab for post-transplant lymphoproliferative disorders (PTLD). Induction Therapy: rituximab: 375 mg/m^2 intravenously on Days 1,8, 15 and 22 bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 8, 15 and 22 If complete response, start Maintenance Therapy. If partial response or stable disease, start Single Agent Bortezomib. If progressive disease, discontinue study treatment. Single Agent Bortezomib bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 4, 8, 11 every 21 days for 4 cycles. If complete response or partial response, start Maintenance Therapy. If stable disease or progressive disease, discontinue study treatment. Maintenance Therapy: rituximab: 375 mg/m^2 intravenously on Days 1,8, 15 and 22 bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 8, 15 and 22 Repeat every 6 months for a total of 4 cycles.
Measure Participants	3
Number [participants]	2 66.7%

2. Secondary Outcome

Title	Remission Duration Among Patients Who Respond to Treatment
Time Frame	Day 1 to 8 Months Post Treatment

Outcome Measure Data

Analysis Population Description

Both of the participants who responded to treatment were in remission at last contact or death.

Arm/Group Title	Treated Study Participants
Arm/Group Description	Study participants receiving bortezomib and rituximab for post-transplant lymphoproliferative disorders (PTLD). Induction Therapy: rituximab: 375 mg/m^2 intravenously on Days 1,8, 15 and 22 bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 8, 15 and 22 If complete response, start Maintenance Therapy. If partial response or stable disease, start Single Agent Bortezomib. If progressive disease, discontinue study treatment. Single Agent Bortezomib bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 4, 8, 11 every 21 days for 4 cycles. If complete response or partial response, start Maintenance Therapy. If stable disease or progressive disease, discontinue study treatment. Maintenance Therapy: rituximab: 375 mg/m^2 intravenously on Days 1,8, 15 and 22 bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 8, 15 and 22 Repeat every 6 months for a total of 4 cycles.
Measure Participants	2
Median (Full Range) [months]	45

3. Secondary Outcome

Title	Time to Treatment Failure
Time Frame	Day 1 to Time of Disease Progression

Outcome Measure Data

Analysis Population Description

Two participants had a complete response at the time they completed the study and were not included in this outcome measure.

Arm/Group Title	Treated Study Participants
Arm/Group Description	Study participants receiving bortezomib and rituximab for post-transplant lymphoproliferative disorders (PTLD). Induction Therapy: rituximab: 375 mg/m^2 intravenously on Days 1,8, 15 and 22 bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 8, 15 and 22 If complete response, start Maintenance Therapy. If partial response or stable disease, start Single Agent Bortezomib. If progressive disease, discontinue study treatment. Single Agent Bortezomib bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 4, 8, 11 every 21 days for 4 cycles. If complete response or partial response, start Maintenance Therapy. If stable disease or progressive disease, discontinue study treatment. Maintenance Therapy: rituximab: 375 mg/m^2 intravenously on Days 1,8, 15 and 22 bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 8, 15 and 22 Repeat every 6 months for a total of 4 cycles.
Measure Participants	1
Number [months]	1

4. Secondary Outcome

Title	Relapse-free Survival
Time Frame	at 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treated Study Participants
Arm/Group Description	Study participants receiving bortezomib and rituximab for post-transplant lymphoproliferative disorders (PTLD). Induction Therapy: rituximab: 375 mg/m^2 intravenously on Days 1,8, 15 and 22 bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 8, 15 and 22 If complete response, start Maintenance Therapy. If partial response or stable disease, start Single Agent Bortezomib. If progressive disease, discontinue study treatment. Single Agent Bortezomib bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 4, 8, 11 every 21 days for 4 cycles. If complete response or partial response, start Maintenance Therapy. If stable disease or progressive disease, discontinue study treatment. Maintenance Therapy: rituximab: 375 mg/m^2 intravenously on Days 1,8, 15 and 22 bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 8, 15 and 22 Repeat every 6 months for a total of 4 cycles.
Measure Participants	3
Number [participants]	2 66.7%

5. Secondary Outcome

Title	Overall Survival
Time Frame	at 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treated Study Participants
Arm/Group Description	Study participants receiving bortezomib and rituximab for post-transplant lymphoproliferative disorders (PTLD). Induction Therapy: rituximab: 375 mg/m^2 intravenously on Days 1,8, 15 and 22 bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 8, 15 and 22 If complete response, start Maintenance Therapy. If partial response or stable disease, start Single Agent Bortezomib. If progressive disease, discontinue study treatment. Single Agent Bortezomib bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 4, 8, 11 every 21 days for 4 cycles. If complete response or partial response, start Maintenance Therapy. If stable disease or progressive disease, discontinue study treatment. Maintenance Therapy: rituximab: 375 mg/m^2 intravenously on Days 1,8, 15 and 22 bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 8, 15 and 22 Repeat every 6 months for a total of 4 cycles.
Measure Participants	3
Number [participants]	1 33.3%

Adverse Events

Arm/Group Title	Treated Study Participants
Arm/Group Description	Study participants receiving bortezomib and rituximab for post-transplant lymphoproliferative disorders (PTLD). Induction Therapy: rituximab: 375 mg/m^2 intravenously on Days 1,8, 15 and 22 bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 8, 15 and 22 If complete response, start Maintenance Therapy. If partial response or stable disease, start Single Agent Bortezomib. If progressive disease, discontinue study treatment. Single Agent Bortezomib bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 4, 8, 11 every 21 days for 4 cycles. If complete response or partial response, start Maintenance Therapy. If stable disease or progressive disease, discontinue study treatment. Maintenance Therapy: rituximab: 375 mg/m^2 intravenously on Days 1,8, 15 and 22 bortezomib: 1.3 mg/m^2 intravenous bolus days 1, 8, 15 and 22 Repeat every 6 months for a total of 4 cycles.
All Cause Mortality
	Treated Study Participants
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treated Study Participants
	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)
Blood and lymphatic system disorders
Anemia	1/3 (33.3%)
Gastrointestinal disorders
Gastrointestinal hemorrhage	1/3 (33.3%)
General disorders
Fever	1/3 (33.3%)
Infections and infestations
Urinary tract infection	1/3 (33.3%)
Pneumonia	1/3 (33.3%)
Musculoskeletal and connective tissue disorders
Pain in extremity	1/3 (33.3%)
Myoclonus	1/3 (33.3%)
Nervous system disorders
Confusion	1/3 (33.3%)
Neuropathic pain	1/3 (33.3%)
Psychosis	1/3 (33.3%)
Delerium	1/3 (33.3%)
Seizure	1/3 (33.3%)
Renal and urinary disorders
Renal failure	1/3 (33.3%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/3 (33.3%)
Acute respiratory distress syndrome	1/3 (33.3%)
Respiratory failure	1/3 (33.3%)
Vascular disorders
Hypertension	1/3 (33.3%)
Other (Not Including Serious) Adverse Events
	Treated Study Participants
	Affected / at Risk (%)	# Events
Total	3/3 (100%)
Blood and lymphatic system disorders
Anemia	2/3 (66.7%)
Gastrointestinal disorders
Dehydration	1/3 (33.3%)
Rectal bleeding	1/3 (33.3%)
Nausea	1/3 (33.3%)
Vomiting	1/3 (33.3%)
General disorders
Fever	1/3 (33.3%)
Fatigue/malaise	1/3 (33.3%)
Infections and infestations
Pneumonia	1/3 (33.3%)
Investigations
Aspartate aminotransferase increased	1/3 (33.3%)
Alanine aminotransferase increased	1/3 (33.3%)
Metabolism and nutrition disorders
Hypercalcemia	1/3 (33.3%)
Musculoskeletal and connective tissue disorders
Myoclonus	1/3 (33.3%)
Nervous system disorders
Confusion	1/3 (33.3%)
Neuropathic pain	1/3 (33.3%)
Psychosis	1/3 (33.3%)
Renal and urinary disorders
Cystitis	1/3 (33.3%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/3 (33.3%)
Acute respiratory distress syndrome	1/3 (33.3%)
Lung nodule	1/3 (33.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.