Genes in Predicting Outcome of Patients With DLBCL Treated With Rituximab and Combination Chemotherapy (R-CHOP)

• Sponsor: University of Miami (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00450385
• Collaborator: (none)
• Enrollment: 57
• Locations: 5
• Arm: 1
• Actual Duration (Months): 108.3
• Patients Per Site: 11.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The investigators hypothesize that survival of newly diagnosed DLBCL (diffuse large B-cell lymphoma) patients treated with R-CHOP can be predicted by RNA or protein gene expression or by presence of biomarkers associated with the anti-tumor effects of Rituximab.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma	Drug: Rituximab; Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Prednisone; Drug: Vincristine	Phase 2

Detailed Description

In this phase II multi-institutional trial, the investigators will identify genes associated with either good or bad outcome in DLBCL patients treated with R-CHOP, will construct a robust predictive models based on RNA extracted from or paraffin specimens as well on immunohistochemistry and will examine the predictive power of new biomarkers associated with the anti-tumor effects of rituximab. The acquisition of fixed tissue as a component of this uniformly treated prospective study will also afford future studies with this informative dataset.

Study Design

• Study Type: Interventional
• Actual Enrollment: 57 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study to Establish Gene Expression Models Predicting Survival of Diffuse Large B-Cell Lymphoma Patients Treated With R-CHOP
• Actual Study Start Date: Apr 24, 2007
• Actual Primary Completion Date: May 1, 2016
• Actual Study Completion Date: May 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: R-CHOP Patients will receive R-CHOP for 6 to 8 cycles: Rituximab 375 mg/m2 on day 1 Cyclophosphamide 750 mg/m2 IV on day 1 Doxorubicin 50 mg/m2 on day 1 Vincristine 1.4 mg/m2 (maximum = 2 mg) IV on day 1 Prednisone 100 mg orally days 1-5, repeated every 21 days.

Drug: Rituximab; Rituximab 375 mg/m2 on day 1 for 6 to 8 cycles; Other Names: Rituxan ; Drug: Cyclophosphamide; Cyclophosphamide 750 mg/m2 IV on day 1 for 6 to 8 cycles; Other Names: Cytoxan ; Drug: Doxorubicin; Doxorubicin 50 mg/m2 on day 1 for 6 to 8 cycles; Other Names: Adriamycin ; Drug: Prednisone; Prednisone 40 mg/m2 orally days 1-5, repeated every 21 days for 6 to 8 cycles.; Other Names: Deltasone ; Drug: Vincristine; Vincristine 1.4 mg/m2 (maximum = 2 mg) IV on day 1 for 6 to 8 cycles; Other Names: Oncovin

Outcome Measures

Primary Outcome Measures

1. Determination of a List of Genes and Construction of Survival Prediction Models That Will Predict Overall Survival at 30 Months in DLBCL Patients Receiving R-CHOP Therapy. [30 months]

   The investigators aim to determine a list of genes and construct survival prediction model(s) that will predict the overall survival at 30 months in DLBCL patients prospectively treated with R-CHOP chemotherapy. Overall survival time will be calculated from the date of the diagnosis until death or last follow-up examination.

2. Usefulness of Biomarkers Associated With Anti-Tumor Effects of Rituximab in Predicting Overall Survival in DLBCL Patients Receiving R-CHOP Therapy [24 Months]

   The investigators aim to determine the usefulness of biomarkers associated with the antitumor effects of rituximab (e.g. immunoglobulin GFc receptor genotypes, CD20 protein expression and gene expression profiles) to predict overall survival of DLBCL patients treated with R-CHOP therapy and followed for at least 24 months or until death.

3. Comparison of the Ability of Constructed Survival Models to Predict Overall Survival in DLBCL Patients Receiving R-CHOP Therapy [2 Years]

   The investigators will compare the ability of constructed survival models to predict survival in DLBCL patients receiving R-CHOP therapy

Secondary Outcome Measures

1. Determination of the Ability of Models and/or Biomarkers Associated With Anti-Tumor Effects of Rituximab to Predict 24-month Time to Treatment Failure in DLBCL Patients Receiving R-CHOP Therapy [24 Months]

   The investigators aim to determine the ability of the models and/or biomarkers associated with the anti-tumor effects of rituximab to predict 24-month time to treatment failure, defined as disease progression, death or initiation of new treatment.

2. Overall Response Rate of Study Participants at the End of Protocol Therapy [Up to 8 cycles, about 24 weeks]

   Rate of participants achieving complete response (CR), complete response/unconfirmed (CRu) partial response (PR) according to Non-Hodgkin's Lymphoma response criteria.

3. Number of Participants From Whom Fixed Tissue Samples Were Collected for Future Studies. [Baseline]

   Number of participants from whom paraffin-embedded DLBCL tissue samples were collected for future studies.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• 1. Diagnosis of diffuse large B-cell lymphoma, CD20-positive, according to the World Health Organization Classification, stages II-IV or limited stage I disease that is bulky (more than 10 cm) or with International Prognostic Index (IPI) score > 1.
• 1. Patients must not have had prior chemotherapy, radiotherapy or immunotherapy. A short course (< 2 weeks) of corticosteroids is allowed.
• 1. Adequate paraffin-embedded tumor specimen must be available for gene expression analysis and immunohistochemistry prior to initiation of therapy. (If the specimen is deemed inadequate, the subject can be retroactively screen failed, as this does not change the treatment regimen).
• 1. Baseline measurements and evaluation must be obtained within 4 weeks before first treatment.
• 1. Age >18 years.
• 1. Eastern Cooperative Oncology Group (ECOG) performance status 0-3.
• 1. Adequate organ function:

• White Blood Cells count (WBC) >2500/µL

• Absolute Neutrophil Count (ANC) > 1000/µL (unless due to disease in marrow)

• platelet count >100,000/µL (unless due to disease in marrow)

• creatinine < 2.0 mg/dL,

• bilirubin < 1.5 mg/dL (may be 1.5-3.0 mg/dl if due to liver involvement by lymphoma)

• Serum Glutamic Oxaloacetic Transaminase (SGOT)/ Serum Glutamic Pyruvic Transaminase (SGPT) <3 x upper limit of normal.

• 1. Female patients must not be pregnant or breast feeding.
• 1. Women of childbearing potential and men must be strongly advised to use an accepted and effective method of contraception.
• 1. Patients must have left ventricular ejection fraction of >45%.
• 1. Provision of written informed consent.

Exclusion Criteria:

• 1. Patients with a second malignancy other than basal cell carcinoma of the skin or in situ carcinoma of the cervix unless the tumor was treated with curative intent at least two years previously; and; the patient continue to be free of evidence of recurrence.
• 1. Patients with HIV infection as these patients are managed on dedicated protocols.
• 1. Patients with active central nervous system (CNS) lymphoma.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University	Stanford	California	United States	94305
2	University of Miami	Miami	Florida	United States	33136
3	University of Rochester Medical Center - Wilmot Cancer Institute	Rochester	New York	United States	14642
4	Cleveland Clinic	Cleveland	Ohio	United States	44195
5	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232

Sponsors and Collaborators

• University of Miami

Investigators

• Study Chair: Izidore S. Lossos, MD, University of Miami

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Izidore Lossos, Professor, University of Miami
• ClinicalTrials.gov Identifier: NCT00450385
• Other Study ID Numbers: 20061138; SCCC-2006069; WIRB-20070073
• First Posted: Mar 22, 2007
• Last Update Posted: Jun 23, 2017
• Last Verified: May 1, 2017

• Keywords provided by Izidore Lossos, Professor, University of Miami: recurrent adult diffuse large cell lymphoma; stage III adult diffuse large cell lymphoma; stage IV adult diffuse large cell lymphoma; contiguous stage II adult diffuse large cell lymphoma; noncontiguous stage II adult diffuse large cell lymphoma; stage I adult diffuse large cell lymphoma
• Additional relevant MeSH terms: Lymphoma; Prednisone; Cyclophosphamide; Rituximab; Doxorubicin; Vincristine

Study Results

Participant Flow

Recruitment Details	A total of 60 patients were consented, however, only 57 of these patients were found to be eligible for enrollment per the protocol.

Arm/Group Title	R-CHOP
Arm/Group Description	Patients will receive R-CHOP for 6 to 8 cycles: Rituximab 375 mg/m2 on day 1 Cyclophosphamide 750 mg/m2 IV on day 1 Doxorubicin 50 mg/m2 on day 1 Vincristine 1.4 mg/m2 (maximum = 2 mg) IV on day 1 Prednisone 100 mg orally days 1-5, repeated every 21 days.
Period Title: Overall Study
STARTED	57
COMPLETED	44
NOT COMPLETED	13

Baseline Characteristics

Arm/Group Title	R-CHOP
Arm/Group Description	Patients will receive R-CHOP for 6 to 8 cycles: Rituximab 375 mg/m2 on day 1 Cyclophosphamide 750 mg/m2 IV on day 1 Doxorubicin 50 mg/m2 on day 1 Vincristine 1.4 mg/m2 (maximum = 2 mg) IV on day 1 Prednisone 100 mg orally days 1-5, repeated every 21 days.
Overall Participants	57
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	25 43.9%
>=65 years	32 56.1%
Sex: Female, Male (Count of Participants)
Female	30 52.6%
Male	27 47.4%
Region of Enrollment (Count of Participants)
United States	57 100%

Outcome Measures

1. Primary Outcome

Title	Determination of a List of Genes and Construction of Survival Prediction Models That Will Predict Overall Survival at 30 Months in DLBCL Patients Receiving R-CHOP Therapy.
Description	The investigators aim to determine a list of genes and construct survival prediction model(s) that will predict the overall survival at 30 months in DLBCL patients prospectively treated with R-CHOP chemotherapy. Overall survival time will be calculated from the date of the diagnosis until death or last follow-up examination.
Time Frame	30 months

Outcome Measure Data

Analysis Population Description

The study required a minimum of 90 participants for gene expression analyses from which survival prediction model(s) could be derived. Due to actual participant accrual (57) being far below the minimum number of participants required, no data were collected on gene expression, and no survival prediction models were constructed.

Arm/Group Title	R-CHOP
Arm/Group Description	Patients will receive R-CHOP for 6 to 8 cycles: Rituximab 375 mg/m2 on day 1 Cyclophosphamide 750 mg/m2 IV on day 1 Doxorubicin 50 mg/m2 on day 1 Vincristine 1.4 mg/m2 (maximum = 2 mg) IV on day 1 Prednisone 100 mg orally days 1-5, repeated every 21 days.
Measure Participants	0

2. Primary Outcome

Title	Usefulness of Biomarkers Associated With Anti-Tumor Effects of Rituximab in Predicting Overall Survival in DLBCL Patients Receiving R-CHOP Therapy
Description	The investigators aim to determine the usefulness of biomarkers associated with the antitumor effects of rituximab (e.g. immunoglobulin GFc receptor genotypes, CD20 protein expression and gene expression profiles) to predict overall survival of DLBCL patients treated with R-CHOP therapy and followed for at least 24 months or until death.
Time Frame	24 Months

Outcome Measure Data

Analysis Population Description

The study required a minimum of 90 participants for associated biomarker analyses. Due to actual participant accrual (57) being far below the minimum number of participants required, no biomarker data were collected.

Arm/Group Title	R-CHOP
Arm/Group Description	Patients will receive R-CHOP for 6 to 8 cycles: Rituximab 375 mg/m2 on day 1 Cyclophosphamide 750 mg/m2 IV on day 1 Doxorubicin 50 mg/m2 on day 1 Vincristine 1.4 mg/m2 (maximum = 2 mg) IV on day 1 Prednisone 100 mg orally days 1-5, repeated every 21 days.
Measure Participants	0

3. Primary Outcome

Title	Comparison of the Ability of Constructed Survival Models to Predict Overall Survival in DLBCL Patients Receiving R-CHOP Therapy
Description	The investigators will compare the ability of constructed survival models to predict survival in DLBCL patients receiving R-CHOP therapy
Time Frame	2 Years

Outcome Measure Data

Analysis Population Description

The comparison could not be made because the study required a minimum of 90 participants for initial gene expression analyses from which survival prediction model(s) would be derived. Due to actual participant accrual (57) being far below the minimum number of participants required, no gene expression or survival prediction data were collected.

Arm/Group Title	R-CHOP
Arm/Group Description	Patients will receive R-CHOP for 6 to 8 cycles: Rituximab 375 mg/m2 on day 1 Cyclophosphamide 750 mg/m2 IV on day 1 Doxorubicin 50 mg/m2 on day 1 Vincristine 1.4 mg/m2 (maximum = 2 mg) IV on day 1 Prednisone 100 mg orally days 1-5, repeated every 21 days.
Measure Participants	0

4. Secondary Outcome

Title	Determination of the Ability of Models and/or Biomarkers Associated With Anti-Tumor Effects of Rituximab to Predict 24-month Time to Treatment Failure in DLBCL Patients Receiving R-CHOP Therapy
Description	The investigators aim to determine the ability of the models and/or biomarkers associated with the anti-tumor effects of rituximab to predict 24-month time to treatment failure, defined as disease progression, death or initiation of new treatment.
Time Frame	24 Months

Outcome Measure Data

Analysis Population Description

The determination could not be made because the study required a minimum of 90 participants for biomarker analyses and derivation of survival prediction model(s). Due to actual participant accrual (57) being far below the minimum required, no data were collected on the ability of models and/or biomarkers to predict time to treatment failure.

Arm/Group Title	R-CHOP
Arm/Group Description	Patients will receive R-CHOP for 6 to 8 cycles: Rituximab 375 mg/m2 on day 1 Cyclophosphamide 750 mg/m2 IV on day 1 Doxorubicin 50 mg/m2 on day 1 Vincristine 1.4 mg/m2 (maximum = 2 mg) IV on day 1 Prednisone 100 mg orally days 1-5, repeated every 21 days.
Measure Participants	0

5. Secondary Outcome

Title	Overall Response Rate of Study Participants at the End of Protocol Therapy
Description	Rate of participants achieving complete response (CR), complete response/unconfirmed (CRu) partial response (PR) according to Non-Hodgkin's Lymphoma response criteria.
Time Frame	Up to 8 cycles, about 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R-CHOP
Arm/Group Description	Patients will receive R-CHOP for 6 to 8 cycles: Rituximab 375 mg/m2 on day 1 Cyclophosphamide 750 mg/m2 IV on day 1 Doxorubicin 50 mg/m2 on day 1 Vincristine 1.4 mg/m2 (maximum = 2 mg) IV on day 1 Prednisone 100 mg orally days 1-5, repeated every 21 days.
Measure Participants	57
Complete Response (CR)	40 70.2%
Complete Response unconfirmed (CRu)	0 0%
Partial Response (PR)	7 12.3%
Progressive Disease (PD)	2 3.5%
Unknown	8 14%

6. Secondary Outcome

Title	Number of Participants From Whom Fixed Tissue Samples Were Collected for Future Studies.
Description	Number of participants from whom paraffin-embedded DLBCL tissue samples were collected for future studies.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	R-CHOP
Arm/Group Description	Patients will receive R-CHOP for 6 to 8 cycles: Rituximab 375 mg/m2 on day 1 Cyclophosphamide 750 mg/m2 IV on day 1 Doxorubicin 50 mg/m2 on day 1 Vincristine 1.4 mg/m2 (maximum = 2 mg) IV on day 1 Prednisone 100 mg orally days 1-5, repeated every 21 days. Rituximab: Rituximab 375 mg/m2 on day 1 for 6 to 8 cycles Cyclophosphamide: Cyclophosphamide 750 mg/m2 IV on day 1 for 6 to 8 cycles Doxorubicin: Doxorubicin 50 mg/m2 on day 1 for 6 to 8 cycles Prednisone: Prednisone 40 mg/m2 orally days 1-5, repeated every 21 days for 6 to 8 cycles. Vincristine: Vincristine 1.4 mg/m2 (maximum = 2 mg) IV on day 1 for 6 to 8 cycles
Measure Participants	57
Count of Participants [Participants]	57 100%

Adverse Events

Arm/Group Title	R-CHOP
Arm/Group Description	Patients will receive R-CHOP for 6 to 8 cycles: Rituximab 375 mg/m2 on day 1 Cyclophosphamide 750 mg/m2 IV on day 1 Doxorubicin 50 mg/m2 on day 1 Vincristine 1.4 mg/m2 (maximum = 2 mg) IV on day 1 Prednisone 100 mg orally days 1-5, repeated every 21 days.
All Cause Mortality
	R-CHOP
	Affected / at Risk (%)	# Events
Total	3/57 (5.3%)
Serious Adverse Events
	R-CHOP
	Affected / at Risk (%)	# Events
Total	4/57 (7%)
Blood and lymphatic system disorders
Febrile neutropenia	1/57 (1.8%)	1
Gastrointestinal disorders
Abdominal pain	2/57 (3.5%)	2
Diarrhea	1/57 (1.8%)	1
General disorders
Fever	1/57 (1.8%)	1
Infections and infestations
Infection - Other	1/57 (1.8%)	1
Musculoskeletal and connective tissue disorders
Muscle weakness, generalized or specific area (not due to neuropathy)	1/57 (1.8%)	1
Renal and urinary disorders
Urinary frequency	1/57 (1.8%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/57 (3.5%)	2
Other (Not Including Serious) Adverse Events
	R-CHOP
	Affected / at Risk (%)	# Events
Total	3/57 (5.3%)
Blood and lymphatic system disorders
Edema: limb	1/57 (1.8%)	1
Febrile neutropenia	1/57 (1.8%)	1
Leukocytes (total WBC)	2/57 (3.5%)	3
Platelet count decreased	2/57 (3.5%)	3
Gastrointestinal disorders
Anorexia	1/57 (1.8%)	1
Constipation	2/57 (3.5%)	4
Gastritis	1/57 (1.8%)	1
Nausea	1/57 (1.8%)	1
Taste alteration (dysgeusia)	1/57 (1.8%)	1
General disorders
Constitutional Symptoms - Other	1/57 (1.8%)	1
Fatigue	2/57 (3.5%)	2
Injection site reaction	1/57 (1.8%)	1
Pain	1/57 (1.8%)	2
Sweating (diaphoresis)	1/57 (1.8%)	2
Metabolism and nutrition disorders
Cholesterol, serum-high (hypercholestremia)	1/57 (1.8%)	1
Uric acid, serum-high (hyperuricemia)	1/57 (1.8%)	1
Musculoskeletal and connective tissue disorders
Myalgia	1/57 (1.8%)	1
Nervous system disorders
Dizziness	1/57 (1.8%)	2
Extrapyramidal disorder	1/57 (1.8%)	1
Headache	2/57 (3.5%)	2
Mood alteration	1/57 (1.8%)	1
Psychiatric disorders
Insomnia	1/57 (1.8%)	1
Skin and subcutaneous tissue disorders
Alopecia	1/57 (1.8%)	1
Rash/desquamation	1/57 (1.8%)	1
Vascular disorders
Hypertension	1/57 (1.8%)	1

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.