Fludarabine, Cyclophosphamide, and Rituximab - High Dose Frontline

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00794820
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 66
• Location: 1
• Arm: 1
• Duration (Months): 132
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

Primary Objective:

• To evaluate the efficacy (combined morphologic and flow remissions) of a combination of fludarabine, cyclophosphamide and multiple dose rituximab as frontline therapy for CLL.

Secondary Objective:

• To evaluate remission duration and survival.

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia	Drug: Fludarabine Phosphate; Drug: Cyclophosphamide; Drug: Rituximab	Phase 2

Detailed Description

DESCRIPTION OF RESEARCH

Fludarabine and cyclophosphamide are chemotherapy drugs that are used in the treatment of CLL. Rituximab is a monoclonal antibody that binds to lymphoma cells and causes cell death.

Before treatment starts, you will have a complete physical exam and routine blood tests (about 2 teaspoons). A bone marrow sample will be collected. To collect a bone marrow sample, an area of the hip or chest bone is numbed with anesthetic and a small amount of bone marrow is withdrawn through a large needle. Women who are able to have children must have a negative blood or urine pregnancy test.

Rituximab will be given through a needle (IV) in a vein on Days 1, 2, and 3. One day after the first dose of rituximab (Day 2), fludarabine and cyclophosphamide will be given through a needle (IV) in a vein daily for 3 days (Days 2, 3, 4). After the first month, all the drugs will be given on Days 1, 2, 3. Other IV fluids such as saline will be given on all of the treatment days for hydration, which means that the daily visit will take about six hours. The combination will be repeated once every 4 to 6 weeks for a total of 6 courses.

The drugs acetaminophen (Tylenol) and diphenhydramine hydrochloride (Benadryl) will be given before the dose of rituximab. This will be done to decrease the risk of side effects. If side effects do occur during rituximab treatment, the drug may have to be stopped until the side effects go away and then restarted so the time in the outpatient area may be longer.

The first treatment will be given at M. D. Anderson. The other 5 courses can be performed ether at M. D. Anderson or at home with your regular physician.

The same doses of all three drugs will be used throughout the study unless side effects become severe. In that case, the dose may be lowered or the treatment may be stopped. You will be taken off study if the disease gets worse.

During treatments, patients will have blood samples (about 1 teaspoon each) taken once every 1-2 weeks. Bone marrow studies will be done at the end of the 3rd and 6th chemotherapy courses.

After treatment is completed, you will have blood tests (about 2 teaspoons each) done every 3 months for as long as you are in remission.

This is an investigational study. The FDA has approved all of the drugs used in this study and they are commercially available. However, their use in this study is investigational. As many as 64 patients will take part in the study. All will be enrolled at M. D. Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 66 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Fludarabine, Cyclophosphamide, and Multiple Dose Rituximab as Frontline Therapy in Chronic Lymphocytic Leukemia (CLL)
• Study Start Date: Dec 1, 2003
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: FCR-Multiple Dose Rituximab Fludarabine phosphate + Cyclophosphamide + Rituximab	Drug: Fludarabine Phosphate; 25 mg/m^2 by vein over 5-30 minutes daily for 3 days (days 2-4); Other Names: Fludara® Fludarabine ; Drug: Cyclophosphamide; 250 mg/m^2 by vein over 60 minutes daily for 3 days (days 2-4); Other Names: Cytoxan® Neosar® ; Drug: Rituximab; 375 mg/m^2 by vein for dose 1 (given 1 day prior to chemotherapy) and then 500 mg/m^2 on days 2-3; Other Names: Rituxan®

Outcome Measures

Primary Outcome Measures

1. Complete Remission (CR) Rate of FCR3 in Treatment-naïve Participants With Chronic Lymphocytic Leukemia (CLL) at 6 Months [6 months]

   CR Rate is defined as number of all treated participants with CR as defined by 2008 IWCLL update of NCI-WG response criteria: Complete remission (CR), requiring absence of peripheral blood clonal lymphocytes by immunophenotyping, absence of lymphadenopathy, absence of hepatomegaly or splenomegaly, absence of constitutional symptoms and satisfactory blood counts; Complete remission with incomplete marrow recovery (CRi), defined as CR above, but without normal blood counts; Partial remission (PR), defined as ≥ 50% fall in lymphocyte count, ≥ 50% reduction in lymphadenopathy or ≥ 50% reduction in liver or spleen, together with improvement in peripheral blood counts; Progressive disease (PD): ≥ 50% rise in lymphocyte count to > 5 x109/L, ≥ 50% increase in lymphadenopathy, ≥ 50% increase in liver or spleen size, Richter's transformation, or new cytopenias due to CLL; Stable disease, defined as not meeting criteria for CR, CRi, PR or PD.

Secondary Outcome Measures

1. Remission Duration/Time to Progression (TTP) [6 months to disease progression, period covered up to 12 years following treatment; Data cutoff for analysis was October 2014.]

   TTP was defined as time from initiation of treatment to primary refractory disease or CLL progression. TTP was censored for therapy-related myelodysplastic syndrome (t-MDS) or acute myelogenous leukemia (t-AML) and death in remission. TTP calculated using Kaplan-Meier estimates.

2. Overall Survival (OS) Rate [6 months to disease progression, period covered up to 12 years following treatment; Data cutoff for analysis was October 2014.]

   OS was defined as the time from the initiation of treatment to last follow-up date or death. OS were calculated using Kaplan-Meier estimates.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. 16 years or older

2. Untreated CLL with indication for therapy or minimally treated (e.g. less than 1 month of steroids or chemotherapy) are eligible

3. Performance status of 3 or better (Appendix A)

4. Adequate renal and hepatic function (creatinine <2 mg%, bilirubin <2mg%). Patient with renal or liver dysfunction due to organ infiltration by lymphocytes may be eligible after discussion with the study chairman but upper limits for creatinine even under these circumstances would be creatinine < 3 mg% and bilirubin < 6 mg%. Patients with Gilbert's Syndrome may be entered on study with bilirubin 2-7 mg%..

5. A signed informed consent in keeping with policies of the hospital

Exclusion Criteria:

1. None

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center
• Genentech, Inc.

Investigators

• Principal Investigator: Susan O'Brien, M.D., M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• University of Texas MD Anderson Cancer Center Website

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT00794820
• Other Study ID Numbers: 2003-0591; NCI-2010-01220
• First Posted: Nov 20, 2008
• Last Update Posted: May 8, 2018
• Last Verified: Apr 1, 2018

• Keywords provided by M.D. Anderson Cancer Center: Chronic Lymphocytic Leukemia; CLL; Leukemia; Fludarabine phosphate; Cyclophosphamide; Rituximab; FCR; Cytoxan®; Neosar®; Rituxan®
• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Vidarabine; Cyclophosphamide; Rituximab; Fludarabine; Fludarabine phosphate

Study Results

Participant Flow

Recruitment Details	Recruitment Period: All recruitment done at The University of Texas MD Anderson Cancer Center.

Arm/Group Title	FCR-Multiple Dose Rituximab
Arm/Group Description	Fludarabine phosphate 25 mg/m^2 intravenous (IV) daily for 3 days (days 2-4) + Cyclophosphamide 250 mg/m^2 IV daily for 3 days (days 2-4)+ Rituximab 375 mg/m^2 IV for dose 1 (given 1 day prior to chemotherapy) then 500 mg/m^2 on days 2-3
Period Title: Overall Study
STARTED	66
COMPLETED	50
NOT COMPLETED	16

Baseline Characteristics

Arm/Group Title	FCR-Multiple Dose Rituximab
Arm/Group Description	Fludarabine phosphate 25 mg/m^2 intravenous (IV) daily for 3 days (days 2-4) + Cyclophosphamide 250 mg/m^2 IV daily for 3 days (days 2-4)+ Rituximab 375 mg/m^2 IV for dose 1 (given 1 day prior to chemotherapy) then 500 mg/m^2 on days 2-3
Overall Participants	66
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	58
Sex: Female, Male (Count of Participants)
Female	13 19.7%
Male	53 80.3%
Region of Enrollment (participants) [Number]
United States	66 100%

Outcome Measures

1. Primary Outcome

Title	Complete Remission (CR) Rate of FCR3 in Treatment-naïve Participants With Chronic Lymphocytic Leukemia (CLL) at 6 Months
Description	CR Rate is defined as number of all treated participants with CR as defined by 2008 IWCLL update of NCI-WG response criteria: Complete remission (CR), requiring absence of peripheral blood clonal lymphocytes by immunophenotyping, absence of lymphadenopathy, absence of hepatomegaly or splenomegaly, absence of constitutional symptoms and satisfactory blood counts; Complete remission with incomplete marrow recovery (CRi), defined as CR above, but without normal blood counts; Partial remission (PR), defined as ≥ 50% fall in lymphocyte count, ≥ 50% reduction in lymphadenopathy or ≥ 50% reduction in liver or spleen, together with improvement in peripheral blood counts; Progressive disease (PD): ≥ 50% rise in lymphocyte count to > 5 x109/L, ≥ 50% increase in lymphadenopathy, ≥ 50% increase in liver or spleen size, Richter's transformation, or new cytopenias due to CLL; Stable disease, defined as not meeting criteria for CR, CRi, PR or PD.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Of the 66 participants registered, one participant failed screening and therefore was not evaluable for toxicity or response. One of the 65 participants was not assessed for response to therapy therefore is not included in analysis. The participant went off study after two months of treatment and was not evaluable for response.

Arm/Group Title	FCR-Multiple Dose Rituximab
Arm/Group Description	Fludarabine phosphate 25 mg/m^2 intravenous (IV) daily for 3 days (days 2-4) + Cyclophosphamide 250 mg/m^2 IV daily for 3 days (days 2-4)+ Rituximab 375 mg/m^2 IV for dose 1 (given 1 day prior to chemotherapy) then 500 mg/m^2 on days 2-3
Measure Participants	64
Number [Percentage of Participants]	75 113.6%

2. Secondary Outcome

Title	Remission Duration/Time to Progression (TTP)
Description	TTP was defined as time from initiation of treatment to primary refractory disease or CLL progression. TTP was censored for therapy-related myelodysplastic syndrome (t-MDS) or acute myelogenous leukemia (t-AML) and death in remission. TTP calculated using Kaplan-Meier estimates.
Time Frame	6 months to disease progression, period covered up to 12 years following treatment; Data cutoff for analysis was October 2014.

Outcome Measure Data

Analysis Population Description

Of the 66 participants registered, one participant failed screening and therefore was not evaluable for toxicity or response. One of the 65 participants was not assessed for response to therapy therefore is not included in analysis. The participant went off study after two months of treatment and was not evaluable for response.

Arm/Group Title	FCR-Multiple Dose Rituximab
Arm/Group Description	Fludarabine phosphate 25 mg/m^2 intravenous (IV) daily for 3 days (days 2-4) + Cyclophosphamide 250 mg/m^2 IV daily for 3 days (days 2-4)+ Rituximab 375 mg/m^2 IV for dose 1 (given 1 day prior to chemotherapy) then 500 mg/m^2 on days 2-3
Measure Participants	64
Median (Full Range) [Months]	81

3. Secondary Outcome

Title	Overall Survival (OS) Rate
Description	OS was defined as the time from the initiation of treatment to last follow-up date or death. OS were calculated using Kaplan-Meier estimates.
Time Frame	6 months to disease progression, period covered up to 12 years following treatment; Data cutoff for analysis was October 2014.

Outcome Measure Data

Analysis Population Description

Of the 66 participants registered, one participant failed screening and therefore was not evaluable for toxicity or response. One of the 65 participants is not included in analysis, the participant went off study after two months of treatment.

Arm/Group Title	FCR-Multiple Dose Rituximab
Arm/Group Description	Fludarabine phosphate 25 mg/m^2 intravenous (IV) daily for 3 days (days 2-4) + Cyclophosphamide 250 mg/m^2 IV daily for 3 days (days 2-4)+ Rituximab 375 mg/m^2 IV for dose 1 (given 1 day prior to chemotherapy) then 500 mg/m^2 on days 2-3
Measure Participants	64
Number [Percentage of Participants]	58 87.9%

Adverse Events

Time Frame	Adverse events collected through 6 courses; courses repeated every 4-6 weeks, up to 36 weeks.
Adverse Event Reporting Description	Of the 66 participants registered, one participant failed screening and therefore was not evaluable for toxicity or response.
Arm/Group Title	FCR-Multiple Dose Rituximab
Arm/Group Description	Fludarabine phosphate 25 mg/m^2 intravenous (IV) daily for 3 days (days 2-4) + Cyclophosphamide 250 mg/m^2 IV daily for 3 days (days 2-4)+ Rituximab 375 mg/m^2 IV for dose 1 (given 1 day prior to chemotherapy) then 500 mg/m^2 on days 2-3
All Cause Mortality
	FCR-Multiple Dose Rituximab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	FCR-Multiple Dose Rituximab
	Affected / at Risk (%)	# Events
Total	30/65 (46.2%)
Gastrointestinal disorders
Vomiting	1/65 (1.5%)	1
General disorders
Chills	1/65 (1.5%)	1
Pain	2/65 (3.1%)	2
Infections and infestations
Infection	24/65 (36.9%)	31
Pneumonia	2/65 (3.1%)	2
Bacteria Infection	1/65 (1.5%)	1
Vascular disorders
Thromboembolic event	1/65 (1.5%)	1
Other (Not Including Serious) Adverse Events
	FCR-Multiple Dose Rituximab
	Affected / at Risk (%)	# Events
Total	63/65 (96.9%)
Blood and lymphatic system disorders
Anemia	7/65 (10.8%)	8
Neutropenia	18/65 (27.7%)	20
Gastrointestinal disorders
Nausea	46/65 (70.8%)	97
Vomiting	6/65 (9.2%)	7
Diarrhea	8/65 (12.3%)	11
General disorders
Fatigue	42/65 (64.6%)	68
Edema	7/65 (10.8%)	9
Fever	41/65 (63.1%)	66
Chills	21/65 (32.3%)	25
Pain	18/65 (27.7%)	25
Infections and infestations
Other Infection	4/65 (6.2%)	4
Skin and subcutaneous tissue disorders
Rash	7/65 (10.8%)	8
Vascular disorders
Thromboembolic event	6/65 (9.2%)	6

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.