Rituximab and Cyclophosphamide Followed by Vaccine Therapy in Treating Patients With Relapsed Hodgkin Lymphoma

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
• Overall Status: Completed
• CT.gov ID: NCT00134082
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 31
• Location: 1
• Arm: 1
• Actual Duration (Months): 86
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

RATIONALE: 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. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of cancer cells either by killing the cells or by stopping them from dividing. Vaccines made from another person's cancer cells may help the body build an effective immune response to kill cancer cells. Giving rituximab together with chemotherapy and vaccine therapy may kill more cancer cells

PURPOSE: This phase I/II trial is studying how well giving rituximab together with cyclophosphamide and vaccine therapy works in treating patients with relapsed Hodgkin lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma	Biological: KGEL vaccine; Biological: Filgrastim; Biological: Rituximab; Drug: Cyclophosphamide	Phase 1/Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the safety and tolerability of rituximab and high-dose cyclophosphamide followed by vaccine therapy comprising an allogeneic vaccine that expresses Hodgkin's tumor antigens and sargramostim (GM-CSF) (KGEL vaccine) as salvage therapy in patients with relapsed Hodgkin lymphoma.

• Determine the immunologic response to this vaccine in these patients.

Secondary

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

• Determine the patterns of cellular immune reconstitution in patients treated with this regimen.

OUTLINE: This is an open-label study.

Patients receive rituximab IV on days -10 and -7 and then on days 29, 36, 43, and 50 (weeks 4-7) and high-dose (transplant-dose) cyclophosphamide IV on days -3 to 0 without stem cell rescue. Patients receive filgrastim (G-CSF) subcutaneously once daily beginning on day 6 and continuing until blood counts recover. Patients also receive vaccine therapy comprising an allogeneic vaccine that expresses Hodgkin's tumor antigens and sargramostim (GM-CSF) (KGEL vaccine) intradermally on day 1, and weeks 4, 8, 12, 16, and 24.

After completion of high-dose cyclophosphamide, patients are followed every 3 months for 3 years, and then annually thereafter.

PROJECTED ACCRUAL: Approximately 25 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pilot Study of Rituximab, High Dose Cyclophosphamide, and GM-CSF Based Immunotherapy for Relapsed Hodgkin's Lymphoma
• Actual Study Start Date: Nov 1, 2005
• Actual Primary Completion Date: Jan 1, 2013
• Actual Study Completion Date: Jan 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Immunotherapy All participants received two days of rituximab, then four days of high-dose cyclophosphamide followed by filgrastim. Participants then received six doses of KGEL vaccine over 24 weeks interspersed with four additional doses of rituximab.

Biological: KGEL vaccine; Vaccine was administered at weeks 0, 4, 8, 12, 16, and 24 at a dose of 1 x 10^8 cells per dose. The first dose was given on Day +1.; Biological: Filgrastim; 5 mcg/kg/day starting on Day +6 until ANC is >= 1000/mcL.; Other Names: G-CSF ; Biological: Rituximab; 375 mg/m^2/day on Days -10, -7, and at weeks 4, 5, 6, and 7.; Other Names: Rituxan ; Drug: Cyclophosphamide; 50 mg/kg/day on Day -3, -2, -1, and 0.; Other Names: Cytoxan

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Grade 3-5 Adverse Events [Up to 36 months]

   Number of participants who experienced at least one grade 3-5 adverse event by CTCAE 3.0 that was attributed to protocol intervention.

2. Percentage of Participants With an Increase in Frequency of LMP2-specific CD8+ T Cells [Change from 3 months to 6 months]

   Percentage of participants with an increase in frequency of LMP2-specific CD8+ T cells. Increase in frequency is defined as at least one order of magnitude higher than baseline measurement.

Secondary Outcome Measures

1. Survival [Up to 6 years]

   Median number of months that participants were alive (overall survival) and alive without disease relapse or new diagnosis of myelodysplasia or acute leukemia (event-free survival).

2. Days to Neutrophil and Platelet Engraftment [Up to 46 days]

   Median number of days to absolute neutrophil count (ANC) >= 500/mcL and platelet count >=20000/mcL.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically confirmed classical Hodgkin's lymphoma

• Relapsed disease with achievement of at least a partial response or a metabolic response to most recent salvage therapy

• No primary induction failure, defined as disease progression during or within 2 months after completion of first-line therapy

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-1

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,000/mm^3

• Platelet count ≥ 75,000/mm^3

Hepatic

• Bilirubin ≤ 2.0 mg/dL* NOTE: *Unless due to lymphoma or Gilbert's syndrome

Renal

• Creatinine ≤ 2.0 mg/dL

Cardiovascular

• Ejection fraction ≥ 45% by echocardiogram or MUGA

Pulmonary

• DLCO ≥ 50% of predicted (corrected for alveolar volume)

Immunologic

• No known HIV positivity

• No active infection requiring oral or IV antibiotics

• No autoimmune or other disease requiring long-term systemic steroids or other long-term immunosuppressants

Other

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• Able to tolerate high-dose therapy

• 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 bone marrow transplantation

Endocrine therapy

• Not specified

Radiotherapy

• Concurrent radiotherapy for disease progression after high-dose cyclophosphamide allowed at the discretion of the principal investigator

Surgery

• Not specified

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

Sponsors and Collaborators

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

Investigators

• Study Chair: Richard Ambinder, 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: NCT00134082
• Other Study ID Numbers: J0528; P50CA096888; P30CA006973; NA_00035358
• First Posted: Aug 24, 2005
• Last Update Posted: Feb 26, 2019
• Last Verified: Feb 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: recurrent adult Hodgkin lymphoma
• Additional relevant MeSH terms: Lymphoma; Hodgkin Disease; Cyclophosphamide; Rituximab

Study Results

Participant Flow

Pre-assignment Detail	One participant was a screen failure.

Arm/Group Title	Immunotherapy
Arm/Group Description	All participants received two days of rituximab, then four days of high-dose cyclophosphamide followed by filgrastim. Participants then received six doses of KGEL vaccine over 24 weeks interspersed with four additional doses of rituximab. KGEL vaccine: Vaccine was administered at weeks 0, 4, 8, 12, 16, and 24 at a dose of 1 x 10^8 cells per dose. The first dose was given on Day +1. Filgrastim: 5 mcg/kg/day starting on Day +6 until ANC is >= 1000/mcL. Rituximab: 375 mg/m^2/day on Days -10, -7, and at weeks 4, 5, 6, and 7. Cyclophosphamide: 50 mg/kg/day on Day -3, -2, -1, and 0.
Period Title: Overall Study
STARTED	30
COMPLETED	27
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Immunotherapy
Arm/Group Description	All participants received two days of rituximab, then four days of high-dose cyclophosphamide followed by filgrastim. Participants then received six doses of KGEL vaccine over 24 weeks interspersed with four additional doses of rituximab. KGEL vaccine: Vaccine was administered at weeks 0, 4, 8, 12, 16, and 24 at a dose of 1 x 10^8 cells per dose. The first dose was given on Day +1. Filgrastim: 5 mcg/kg/day starting on Day +6 until ANC is >= 1000/mcL. Rituximab: 375 mg/m^2/day on Days -10, -7, and at weeks 4, 5, 6, and 7. Cyclophosphamide: 50 mg/kg/day on Day -3, -2, -1, and 0.
Overall Participants	30
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	29 96.7%
>=65 years	1 3.3%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	39.5
Sex: Female, Male (Count of Participants)
Female	13 43.3%
Male	17 56.7%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (Count of Participants)
United States	30 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Grade 3-5 Adverse Events
Description	Number of participants who experienced at least one grade 3-5 adverse event by CTCAE 3.0 that was attributed to protocol intervention.
Time Frame	Up to 36 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Immunotherapy
Arm/Group Description	All participants received two days of rituximab, then four days of high-dose cyclophosphamide followed by filgrastim. Participants then received six doses of KGEL vaccine over 24 weeks interspersed with four additional doses of rituximab. KGEL vaccine: Vaccine was administered at weeks 0, 4, 8, 12, 16, and 24 at a dose of 1 x 10^8 cells per dose. The first dose was given on Day +1. Filgrastim: 5 mcg/kg/day starting on Day +6 until ANC is >= 1000/mcL. Rituximab: 375 mg/m^2/day on Days -10, -7, and at weeks 4, 5, 6, and 7. Cyclophosphamide: 50 mg/kg/day on Day -3, -2, -1, and 0.
Measure Participants	30
Count of Participants [Participants]	6 20%

2. Primary Outcome

Title	Percentage of Participants With an Increase in Frequency of LMP2-specific CD8+ T Cells
Description	Percentage of participants with an increase in frequency of LMP2-specific CD8+ T cells. Increase in frequency is defined as at least one order of magnitude higher than baseline measurement.
Time Frame	Change from 3 months to 6 months

Outcome Measure Data

Analysis Population Description

Although the specimens were collected per protocol, they were not interpretable and therefore no data was collected to assess this outcome measure

Arm/Group Title	Immunotherapy
Arm/Group Description	All participants received two days of rituximab, then four days of high-dose cyclophosphamide followed by filgrastim. Participants then received six doses of KGEL vaccine over 24 weeks interspersed with four additional doses of rituximab. KGEL vaccine: Vaccine was administered at weeks 0, 4, 8, 12, 16, and 24 at a dose of 1 x 10^8 cells per dose. The first dose was given on Day +1. Filgrastim: 5 mcg/kg/day starting on Day +6 until ANC is >= 1000/mcL. Rituximab: 375 mg/m^2/day on Days -10, -7, and at weeks 4, 5, 6, and 7. Cyclophosphamide: 50 mg/kg/day on Day -3, -2, -1, and 0.
Measure Participants	0

3. Secondary Outcome

Title	Survival
Description	Median number of months that participants were alive (overall survival) and alive without disease relapse or new diagnosis of myelodysplasia or acute leukemia (event-free survival).
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Immunotherapy
Arm/Group Description	All participants received two days of rituximab, then four days of high-dose cyclophosphamide followed by filgrastim. Participants then received six doses of KGEL vaccine over 24 weeks interspersed with four additional doses of rituximab. KGEL vaccine: Vaccine was administered at weeks 0, 4, 8, 12, 16, and 24 at a dose of 1 x 10^8 cells per dose. The first dose was given on Day +1. Filgrastim: 5 mcg/kg/day starting on Day +6 until ANC is >= 1000/mcL. Rituximab: 375 mg/m^2/day on Days -10, -7, and at weeks 4, 5, 6, and 7. Cyclophosphamide: 50 mg/kg/day on Day -3, -2, -1, and 0.
Measure Participants	30
Overall survival	31.5
Event-free survival	24.1

4. Secondary Outcome

Title	Days to Neutrophil and Platelet Engraftment
Description	Median number of days to absolute neutrophil count (ANC) >= 500/mcL and platelet count >=20000/mcL.
Time Frame	Up to 46 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Immunotherapy
Arm/Group Description	All participants received two days of rituximab, then four days of high-dose cyclophosphamide followed by filgrastim. Participants then received six doses of KGEL vaccine over 24 weeks interspersed with four additional doses of rituximab. KGEL vaccine: Vaccine was administered at weeks 0, 4, 8, 12, 16, and 24 at a dose of 1 x 10^8 cells per dose. The first dose was given on Day +1. Filgrastim: 5 mcg/kg/day starting on Day +6 until ANC is >= 1000/mcL. Rituximab: 375 mg/m^2/day on Days -10, -7, and at weeks 4, 5, 6, and 7. Cyclophosphamide: 50 mg/kg/day on Day -3, -2, -1, and 0.
Measure Participants	30
Days until ANC >= 500mcL	17
Days until Platelet Count >=20000/mcL	21.5

Adverse Events

Time Frame	Up to 3 years
Adverse Event Reporting Description	The following adverse events only were collected on this study: All adverse events attributed to the vaccine All grade 3-5 nonhematologic toxicities until 30 days post last dose of vaccine Any hospitalization or death until 30 days post last dose of vaccine Grade 3-4 neutropenia until 1 year post completion of high-dose cyclophosphamide
Arm/Group Title	Immunotherapy
Arm/Group Description	All participants received two days of rituximab, then four days of high-dose cyclophosphamide followed by filgrastim. Participants then received six doses of KGEL vaccine over 24 weeks interspersed with four additional doses of rituximab. KGEL vaccine: Vaccine was administered at weeks 0, 4, 8, 12, 16, and 24 at a dose of 1 x 10^8 cells per dose. The first dose was given on Day +1. Filgrastim: 5 mcg/kg/day starting on Day +6 until ANC is >= 1000/mcL. Rituximab: 375 mg/m^2/day on Days -10, -7, and at weeks 4, 5, 6, and 7. Cyclophosphamide: 50 mg/kg/day on Day -3, -2, -1, and 0.
All Cause Mortality
	Immunotherapy
	Affected / at Risk (%)	# Events
Total	1/30 (3.3%)
Serious Adverse Events
	Immunotherapy
	Affected / at Risk (%)	# Events
Total	15/30 (50%)
Gastrointestinal disorders
Nausea and vomiting	1/30 (3.3%)	1
General disorders
Rigors	1/30 (3.3%)	1
Infections and infestations
Influenza A	1/30 (3.3%)	1
Febrile neutropenia	9/30 (30%)	9
Infection, not specified	1/30 (3.3%)	1
Investigations
Cytopenia	1/30 (3.3%)	1
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	1/30 (3.3%)	1
Pain - back	1/30 (3.3%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory failure	1/30 (3.3%)	1
Vascular disorders
Thrombus	1/30 (3.3%)	1
Other (Not Including Serious) Adverse Events
	Immunotherapy
	Affected / at Risk (%)	# Events
Total	30/30 (100%)
Gastrointestinal disorders
Nausea	3/30 (10%)	3
Vomiting	2/30 (6.7%)	2
General disorders
Fatigue	21/30 (70%)	26
Fever	3/30 (10%)	4
Headache	12/30 (40%)	28
Infections and infestations
Pneumonia	2/30 (6.7%)	2
Investigations
Anemia	2/30 (6.7%)	28
Leukopenia	2/30 (6.7%)	16
Lymphopenia	4/30 (13.3%)	14
Neutropenia	29/30 (96.7%)	110
Thrombocytopenia	4/30 (13.3%)	31
Musculoskeletal and connective tissue disorders
Arthralgia	3/30 (10%)	3
Myalgia	4/30 (13.3%)	4
Pain - knee	2/30 (6.7%)	2
Pain - thigh	4/30 (13.3%)	4
Nervous system disorders
Dizziness	3/30 (10%)	3
Paresthesia	4/30 (13.3%)	4
Weakness	3/30 (10%)	3
Skin and subcutaneous tissue disorders
Bruising	2/30 (6.7%)	3
Erythema	2/30 (6.7%)	3
Injection site reaction	30/30 (100%)	258
Pruritis	4/30 (13.3%)	5
Rash	6/30 (20%)	8
Xerosis	2/30 (6.7%)	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.