Combination Chemotherapy and Rituximab in Treating Patients With Newly Diagnosed Burkitt's Lymphoma or Leukemia

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
• Overall Status: Completed
• CT.gov ID: NCT00133991
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 23
• Locations: 2
• Arm: 1
• Actual Duration (Months): 97
• Patients Per Site: 11.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. Monoclonal antibodies, such as rituximab, can block cancer 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 combination chemotherapy together with rituximab may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving combination chemotherapy together with rituximab works in treating patients with newly diagnosed Burkitt's lymphoma or leukemia.

Condition or Disease	Intervention/Treatment	Phase
Leukemia; Lymphoma	Biological: Filgrastim; Biological: Rituximab; Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Methotrexate; Drug: Prednisone; Drug: Hydrocortisone; Drug: Vincristine; Drug: Leucovorin	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the overall response rate, 1-year event-free survival, and overall survival of adult patients with newly diagnosed Burkitt or atypical Burkitt lymphoma or leukemia treated with dose-intensified induction therapy comprising cyclophosphamide, vincristine, prednisone, and rituximab followed by consolidation therapy comprising rituximab and high-dose cyclophosphamide.

• Determine the grade 3 or higher non-hematologic toxic effects and overall tolerability of this regimen in these patients.

Secondary

• Determine the 3-year event-free survival and overall survival of patients treated with this regimen.

• Determine the general patterns of CNS and systemic relapse in patients treated with this regimen.

OUTLINE: This is a multicenter study.

• Dose-intensified CVP induction therapy: Patients receive cyclophosphamide IV and vincristine IV on day 1. Patients also receive oral prednisone on days 1-5 and rituximab IV on days 1 and 8, and high-dose methotrexate IV with leucovorin calcium IV rescue on day 8. Patients receive filgrastim (G-CSF) subcutaneously (SC) once daily beginning on day 3 and continuing until blood counts recover. Treatment repeats approximately every 14 days for 2 courses.

• CNS therapy: Patients receive cytarabine intrathecally (IT) with or without hydrocortisone IT on days 1, 4, and 11 of each induction therapy course. Patients with evidence of CNS involvement by lymphoma continue to receive cytarabine IT twice weekly during any induction therapy treatment delay. Patients who demonstrate CSF clearance receive cytarabine IT once weekly for 4 doses and then once every other week for 4 doses during consolidation therapy. Patients with disease progression during induction therapy or persistent CNS involvement by lymphoma are removed from the study. All other patients proceed to consolidation therapy.

• Consolidation therapy: Patients receive rituximab IV on day -4 and high-dose cyclophosphamide IV on days -3, -2, -1, and 0. Patients receive G-CSF SC once daily beginning on day 6 and continuing until blood counts recover OR pegfilgrastim SC once on day 6. Patients then receive rituximab IV once weekly for 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for 3 years.

PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study within 3 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Intensified CVP, Rituximab, and High Dose Cyclophosphamide for Adult Burkitt or Burkitt-Like Lymphoma
• Actual Study Start Date: Jul 1, 2005
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: Aug 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: R-CVP + HiCy Protocol intervention consists of two fifteen-day cycles of cyclophosphamide (Cy), vincristine (V), prednisone (P), rituximab (R), with filgrastim support. CNS intervention consists of three days of cytarabine and hydrocortisone and one day of methotrexate (with leucovorin support) for each cycle. After those two cycles, rituximab and high-dose cyclophosphamide (HiCy) will be given.

Biological: Filgrastim; 5 mcg/kg/day starting on Day 3 after each R-CVP cycle and on Day 6 after HiCy.; Other Names: Neupogen G-CSF ; Biological: Rituximab; 375 mg/m^2 on Day 1 and Day 8 of each R-CVP cycle. 375 mg/m^2 on Day -4 of HiCy and weekly for four weeks after HiCy.; Other Names: Rituxan ; Drug: Cyclophosphamide; 1500 mg/m^2 on Day 1 of each R-CVP cycle. 50 mg/kg/day on Days -3, -2, -1, and 0 of HiCy.; Other Names: Cytoxan Cy CTX HiCy ; Drug: Cytarabine; 100 mg intrathecal on Days 1, 4, and 11 of each cycle of R-CVP.; Other Names: Ara-C ; Drug: Methotrexate; 3 g/m^2 on Day 8 of each cycle of R-CVP.; Other Names: MTX ; Drug: Prednisone; 100 mg on Days 1-5 of each cycle of R-CVP.; Other Names: Deltasone ; Drug: Hydrocortisone; 50 mg intrathecal on Days 1, 4, and 11 of each cycle of R-CVP.; Drug: Vincristine; 1.4 mg/m^2 on Day 1 of each cycle of R-CVP.; Other Names: Oncovin ; Drug: Leucovorin; 25 mg four times daily after methotrexate administration. Dosing continues until adequate methotrexate levels are reached.; Other Names: Folinic acid

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate [Up to 3 months]

   Number of participants who have a complete or partial remission (2007 International Working Group criteria).

2. Overall Survival [1 year and 3 years]

   Percentage of participants alive at 1 year and at 3 years.

3. Event-free Survival [1 year and 3 years]

   Percentage of participants alive without relapse at 1 year and 3 years.

4. Percentage of Participants Experiencing Grade 3-5 Toxicity [Up to 2 years]

   Percentage of participants experiencing at least one grade 3-5 adverse event (by CTCAE 3.0 criteria).

Secondary Outcome Measures

1. Relapse Pattern [Up to 6 months]

   Percentage of participants experiencing central nervous system (CNS) and systemic relapse.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically confirmed diagnosis of 1 of the following:

• Classic, sporadic Burkitt's lymphoma

• Burkitt's leukemia (FAB L3 acute lymphoblastic leukemia)

• Atypical Burkitt/Burkitt's-like lymphoma or leukemia, defined by the following criteria:

• Characteristic morphologic features

• High proliferative index AND Ki-67 ≥ 85%

• Any stage allowed

• Newly diagnosed or untreated disease

• Steroids allowed

PATIENT CHARACTERISTICS:

Age

• 30 and over

Performance status

• Not specified

Life expectancy

• Not specified

Renal

• No known irreversible renal dysfunction that would preclude treatment with high-dose cyclophosphamide

Cardiovascular

• No known significant cardiac dysfunction that would preclude treatment with high-dose cyclophosphamide

Other

• Not pregnant or nursing

• No known HIV positivity

• No other malignancy within the past 3 years except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No prior chemotherapy for lymphoma

• A maximum of 2 prior doses of intrathecal chemotherapy are allowed

Endocrine therapy

• Not specified

Radiotherapy

• No prior radiation therapy for lymphoma

Surgery

• Prior complete or incomplete surgical resection of lymphoma allowed

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21231-2410
2	Drexel University College of Medicine - Center City Hahnemann Campus	Philadelphia	Pennsylvania	United States	19102

Sponsors and Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• National Cancer Institute (NCI)

Investigators

• Study Chair: Yvette L. Kasamon, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT00133991
• Other Study ID Numbers: J0409; P50CA096888; P30CA006973; NA_00035765
• First Posted: Aug 24, 2005
• Last Update Posted: Sep 17, 2018
• Last Verified: Sep 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: untreated adult acute lymphoblastic leukemia; L3 adult acute lymphoblastic leukemia; contiguous stage II adult Burkitt lymphoma; noncontiguous stage II adult Burkitt lymphoma; stage I adult Burkitt lymphoma; stage III adult Burkitt lymphoma; stage IV adult Burkitt lymphoma
• Additional relevant MeSH terms: Burkitt Lymphoma; Lymphoma; Leukemia; Leucovorin; Cytarabine; Prednisone; Hydrocortisone; Cyclophosphamide; Rituximab; Methotrexate; Vincristine

Study Results

Participant Flow

Pre-assignment Detail	2 participants were found to be HIV+ after initiating the study and are considered to be screen failures as defined by the protocol.

Arm/Group Title	R-CVP + HiCy
Arm/Group Description	Protocol intervention consists of two fifteen-day cycles of cyclophosphamide (Cy), vincristine (V), prednisone (P), rituximab (R), with filgrastim support. CNS intervention consists of three days of cytarabine and hydrocortisone and one day of methotrexate (with leucovorin support) for each cycle. After those two cycles, rituximab and high-dose cyclophosphamide (HiCy) will be given.
Period Title: Overall Study
STARTED	21
COMPLETED	17
NOT COMPLETED	4

Baseline Characteristics

Arm/Group Title	R-CVP + HiCy
Arm/Group Description	Protocol intervention consists of two fifteen-day cycles of cyclophosphamide (Cy), vincristine (V), prednisone (P), rituximab (R), with filgrastim support. CNS intervention consists of three days of cytarabine and hydrocortisone and one day of methotrexate (with leucovorin support) for each cycle. After those two cycles, rituximab and high-dose cyclophosphamide (HiCy) will be given.
Overall Participants	21
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	17 81%
>=65 years	4 19%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	53
Sex: Female, Male (Count of Participants)
Female	7 33.3%
Male	14 66.7%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate
Description	Number of participants who have a complete or partial remission (2007 International Working Group criteria).
Time Frame	Up to 3 months

Outcome Measure Data

Analysis Population Description

The 4 participants who died during treatment were not analyzed for this outcome.

Arm/Group Title	R-CVP + HiCy
Arm/Group Description	Protocol intervention consists of two fifteen-day cycles of cyclophosphamide (Cy), vincristine (V), prednisone (P), rituximab (R), with filgrastim support. CNS intervention consists of three days of cytarabine and hydrocortisone and one day of methotrexate (with leucovorin support) for each cycle. After those two cycles, rituximab and high-dose cyclophosphamide (HiCy) will be given.
Measure Participants	17
Complete remission	11 52.4%
Partial remission	2 9.5%

2. Primary Outcome

Title	Overall Survival
Description	Percentage of participants alive at 1 year and at 3 years.
Time Frame	1 year and 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R-CVP + HiCy
Arm/Group Description	Protocol intervention consists of two fifteen-day cycles of cyclophosphamide (Cy), vincristine (V), prednisone (P), rituximab (R), with filgrastim support. CNS intervention consists of three days of cytarabine and hydrocortisone and one day of methotrexate (with leucovorin support) for each cycle. After those two cycles, rituximab and high-dose cyclophosphamide (HiCy) will be given.
Measure Participants	21
1 year	57 271.4%
3 years	57 271.4%

3. Primary Outcome

Title	Event-free Survival
Description	Percentage of participants alive without relapse at 1 year and 3 years.
Time Frame	1 year and 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R-CVP + HiCy
Arm/Group Description	Protocol intervention consists of two fifteen-day cycles of cyclophosphamide (Cy), vincristine (V), prednisone (P), rituximab (R), with filgrastim support. CNS intervention consists of three days of cytarabine and hydrocortisone and one day of methotrexate (with leucovorin support) for each cycle. After those two cycles, rituximab and high-dose cyclophosphamide (HiCy) will be given.
Measure Participants	21
1 year	52 247.6%
3 years	52 247.6%

4. Primary Outcome

Title	Percentage of Participants Experiencing Grade 3-5 Toxicity
Description	Percentage of participants experiencing at least one grade 3-5 adverse event (by CTCAE 3.0 criteria).
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R-CVP + HiCy
Arm/Group Description	Protocol intervention consists of two fifteen-day cycles of cyclophosphamide (Cy), vincristine (V), prednisone (P), rituximab (R), with filgrastim support. CNS intervention consists of three days of cytarabine and hydrocortisone and one day of methotrexate (with leucovorin support) for each cycle. After those two cycles, rituximab and high-dose cyclophosphamide (HiCy) will be given.
Measure Participants	21
Count of Participants [Participants]	21 100%

5. Secondary Outcome

Title	Relapse Pattern
Description	Percentage of participants experiencing central nervous system (CNS) and systemic relapse.
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

The 4 participants who died during treatment were not analyzed for this outcome.

Arm/Group Title	R-CVP + HiCy
Arm/Group Description	Protocol intervention consists of two fifteen-day cycles of cyclophosphamide (Cy), vincristine (V), prednisone (P), rituximab (R), with filgrastim support. CNS intervention consists of three days of cytarabine and hydrocortisone and one day of methotrexate (with leucovorin support) for each cycle. After those two cycles, rituximab and high-dose cyclophosphamide (HiCy) will be given.
Measure Participants	17
Systemic relapse only	3 14.3%
Systemic and CNS relapse	2 9.5%

Adverse Events

Time Frame	Up to 2 years
Adverse Event Reporting Description	Adverse events were tracked monthly through the completion of study intervention and then every three months for up to two years total.
Arm/Group Title	R-CVP + HiCy
Arm/Group Description	Protocol intervention consists of two fifteen-day cycles of cyclophosphamide (Cy), vincristine (V), prednisone (P), rituximab (R), with filgrastim support. CNS intervention consists of three days of cytarabine and hydrocortisone and one day of methotrexate (with leucovorin support) for each cycle. After those two cycles, rituximab and high-dose cyclophosphamide (HiCy) will be given.
All Cause Mortality
	R-CVP + HiCy
	Affected / at Risk (%)	# Events
Total	9/21 (42.9%)
Serious Adverse Events
	R-CVP + HiCy
	Affected / at Risk (%)	# Events
Total	12/21 (57.1%)
Cardiac disorders
Atrial fibrillation	1/21 (4.8%)	1
Hypotension	1/21 (4.8%)	2
Pericarditis	1/21 (4.8%)	1
Gastrointestinal disorders
Colitis	1/21 (4.8%)	1
General disorders
Somnolence	1/21 (4.8%)	1
Hepatobiliary disorders
Ascites	1/21 (4.8%)	1
Infections and infestations
Blood infection	1/21 (4.8%)	1
Encephalitis	1/21 (4.8%)	1
Febrile neutropenia	2/21 (9.5%)	2
Pneumonia	1/21 (4.8%)	1
Sepsis	1/21 (4.8%)	1
Metabolism and nutrition disorders
Tumor lysis syndrome	1/21 (4.8%)	1
Musculoskeletal and connective tissue disorders
Pain - chest	1/21 (4.8%)	1
Wound complication	1/21 (4.8%)	1
Nervous system disorders
Stroke	1/21 (4.8%)	1
Subdural hematoma	1/21 (4.8%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	1/21 (4.8%)	1
Dyspnea	1/21 (4.8%)	1
Hypoxia	1/21 (4.8%)	1
Other (Not Including Serious) Adverse Events
	R-CVP + HiCy
	Affected / at Risk (%)	# Events
Total	21/21 (100%)
Cardiac disorders
Atrial fibrillation	2/21 (9.5%)	2
Bradycardia	2/21 (9.5%)	4
Deep vein thrombosis	3/21 (14.3%)	3
Edema	5/21 (23.8%)	10
Hypertension	2/21 (9.5%)	2
Hypotension	7/21 (33.3%)	23
Lightheadedness	4/21 (19%)	5
Tachycardia	2/21 (9.5%)	3
Gastrointestinal disorders
Constipation	9/21 (42.9%)	19
Anorexia	3/21 (14.3%)	3
Diarrhea	6/21 (28.6%)	12
Dysphagia	2/21 (9.5%)	3
Mucositis	2/21 (9.5%)	7
Nausea	6/21 (28.6%)	18
Vomiting	7/21 (33.3%)	20
Xerostomia	2/21 (9.5%)	3
General disorders
Anasarca	2/21 (9.5%)	2
Chills	3/21 (14.3%)	5
Cough	3/21 (14.3%)	5
Fatigue	7/21 (33.3%)	13
Headache	11/21 (52.4%)	27
Immune system disorders
Allergic reaction	3/21 (14.3%)	3
Transfusion reaction	3/21 (14.3%)	4
Infections and infestations
Febrile neutropenia	6/21 (28.6%)	8
Fever	6/21 (28.6%)	14
Infection	5/21 (23.8%)	8
Pneumonia	2/21 (9.5%)	2
Thrush	4/21 (19%)	5
Investigations
Anemia	3/21 (14.3%)	6
High alkaline phosphatase	2/21 (9.5%)	7
High ALT	3/21 (14.3%)	9
High AST	5/21 (23.8%)	14
Hyperbilirubinemia	5/21 (23.8%)	14
Hyperglycemia	3/21 (14.3%)	11
Hypoalbuminemia	2/21 (9.5%)	5
Hypocalcemia	3/21 (14.3%)	7
Hypokalemia	3/21 (14.3%)	7
Hypophosphatemia	2/21 (9.5%)	3
Leukopenia	8/21 (38.1%)	42
Lymphopenia	4/21 (19%)	26
Neutropenia	5/21 (23.8%)	17
Thrombocytopenia	6/21 (28.6%)	36
Musculoskeletal and connective tissue disorders
Incontinence	3/21 (14.3%)	7
Pain - general	3/21 (14.3%)	4
Pain - abdomen	7/21 (33.3%)	12
Pain - back	9/21 (42.9%)	15
Pain - chest	4/21 (19%)	4
Pain - foot	2/21 (9.5%)	2
Pain - hip	2/21 (9.5%)	2
Pain - leg	5/21 (23.8%)	5
Pain - neck	3/21 (14.3%)	3
Nervous system disorders
Blurred vision	2/21 (9.5%)	2
Confusion	3/21 (14.3%)	3
Dizziness	4/21 (19%)	7
Drowsiness	2/21 (9.5%)	4
Facial droop	2/21 (9.5%)	2
Hallucination	2/21 (9.5%)	3
Insomnia	2/21 (9.5%)	2
Neuropathy	9/21 (42.9%)	19
Somnolence	2/21 (9.5%)	3
Weakness	3/21 (14.3%)	11
Renal and urinary disorders
Hematuria	2/21 (9.5%)	2
Renal failure	2/21 (9.5%)	2
Urinary frequency	2/21 (9.5%)	2
Urinary retention	2/21 (9.5%)	2
Reproductive system and breast disorders
Vaginal bleeding	2/21 (9.5%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnea	10/21 (47.6%)	18
Hypoxia	6/21 (28.6%)	12
Pleural effusion	2/21 (9.5%)	2
Wheezing	3/21 (14.3%)	7
Skin and subcutaneous tissue disorders
Rash	3/21 (14.3%)	3
Sweating	4/21 (19%)	4

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.