Protocol for the Treatment of Patients With Previously Untreated Chronic Lymphocytic Leukemia

• Sponsor: University of Pittsburgh (Other)
• Overall Status: Completed
• CT.gov ID: NCT00280241
• Collaborator: Genentech, Inc. (Industry), Biogen (Industry)
• Enrollment: 65
• Location: 1
• Arm: 1
• Duration (Months): 103
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This research study will look at the effects (good or bad) of administering cyclophosphamide, fludarabine, and rituximab. Clinical studies with combination therapy have shown higher response rates than using single drugs, and this study will evaluate the side effects and effectiveness of this combination.

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

Detailed Description

This study is designed to expand on the highly successful combination of rituximab, fludarabine and cyclophosphamide for patients with previously untreated CLL. Responses in the range of 90-98% with 55% complete responses are reported. However, bone marrow toxicity has been a significant problem. This trial is designed to reduce the bone marrow toxicity by decreasing the doses of fludarabine and cyclophosphamide, but doubling the dose of rituximab with a maintenance dose of rituximab for up to two years, to maintain or even enhance efficacy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 65 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Clinical Protocol for the Treatment of Patients With Previously Untreated Chronic Lymphocytic Leukemia
• Study Start Date: Jun 1, 2004
• Actual Primary Completion Date: Feb 1, 2008
• Actual Study Completion Date: Jan 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: FLUDARABINE, CYCLOSPHOSPHAMIDE AND RITUXIMAB

Drug: Fludarabine; Fludarabine is usually administered by IV infusion over 30 minutes or longer.; Drug: Cyclophosphamide; The dosage is a solution of 20 mg/mI. IV infusion over 1 hour.; Drug: Rituximab; First Infusion: The rituximab solution for infusion should be administered intravenously at an initial rate of 50 mg/hr. Subsequent rituximab infusions can be administered at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr as tolerated.

Outcome Measures

Primary Outcome Measures

1. Tolerability of Rituximab, Cyclophosphamide and Fludarabine in Patients With Previously Untreated CLL/SLL [Duration of treatment on study]

   The number of patients who experience any grade 3-5 toxicity.

2. Efficacy of Rituximab, Cyclophosphamide and Fludarabine in Patients With Previously Untreated CLL/SLL [Three months after the sixth cycle (9 months)]

   The number of patients who experience a complete clinical response.

Secondary Outcome Measures

1. Overall Survival Rate [Five years after starting rituximab, cyclophosphamide and fludarabine]

   The percentage of participants who are still alive.

2. Duration of Response [From complete response to the time of progressive disease, death or last clinical examination]

   The length of time for which the complete response is maintained.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Diagnosis of CD20 + CLL

• Peripheral blood absolute lymphocyte count of > 5,000/mm3 obtained within 2 weeks prior to randomization.

• The lymphocytosis must consist of small to moderate size lymphocytes, with ≤55% (no greater than 55%) prolymphocytes, atypical lymphocytes, or lymphoblasts morphologically.

• Phenotypically characterized CD20 + CLL defined as: 1) the predominant population of cells share B-cell antigens with CD5 in the absence of other pan-T-celI markers (CD3, CD2, etc.); 2) B-cell expresses either kappa or lambda light chains; and 3) surface immunoglobulin (slg) with low-cell surface density expression.

• Splenomegaly, hepatomegaly or lymphadenopathy are not required for the diagnosis of CLL.

• Must require chemotherapy. Indications for chemotherapy are one or more of the following:

• One or more of the following disease-related symptoms

• Weight loss >10% within the previous 6 months.

• Fevers of greater than 100.0° F for 2 weeks without evidence of infection.

• Night sweats without evidence of infection.

• Evidence of progressive marrow failure as manifested by the development of or worsening of anemia (< 10 g/dl) and/or thrombocytopenia (< 100,000/mm3).

• Massive (i.e., > 6 cm below left costal margin) or progressive splenomegaly.

• Massive nodes or clusters (i.e., > 10 cm in longest diameter) or progressive

• adenopathy.

• Progressive lymphocytosis with an increase of> 50% over 2 month period, or an anticipated doubling time of less than 6 months.

• NOTE: Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease are not sufficient for protocol therapy.

• Serum creatinine <1.5 mg/dl.

• Bilirubin must be <2 mg/dl, unless secondary to tumor, obtained within 2 weeks prior to randomization.

• Age >18 years.

• Not pregnant (confirmed by serum pregnancy test in females of reproductive potential) or breast feeding, because it is unknown what effect these drugs will have on children.

• ECOG performance status 0-2.

• AST or ATL >2x upper limit of normal unless related to CLL.

• Subject has provided written informed consent.

Exclusion criteria:

• Subjects with autoimmune anemia or thrombocytopenia are not eligible.

• No prior cytotoxic chemotherapy. Patients with a history of steroid treatment for CLL, autoimmune hemolytic anemia, or autoimmune thrombocytopenia are not eligible.

• Subjects with active infections requiring oral or intravenous antibiotics until resolution of the infection and completion of therapeutic antibiotics.

• Women of childbearing potential and sexually active males who refuse to use an accepted and effective method of contraception.

• Subjects with a second malignancy other than basal cell carcinoma of the skin or in situ carcinoma of the cervix are not eligible unless the tumor was treated with curative intent at least two years previously.

• History of HIV

• CNS disease

• History of psychiatric disorder that would make it difficult to enroll and follow the patient on trial.

• New York Heart Classification III or IV heart disease.

• Hepatitis BsAg or Hepatitis C positive.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hillman Cancer Center	Pittsburgh	Pennsylvania	United States	15232

Sponsors and Collaborators

• University of Pittsburgh
• Genentech, Inc.
• Biogen

Investigators

• Principal Investigator: Micahel Boyiadzis, MD, University of Pittsburgh Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Michael Boyiadzis, Study Principal Investigator, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT00280241
• Other Study ID Numbers: 03-136
• First Posted: Jan 20, 2006
• Last Update Posted: Feb 4, 2016
• Last Verified: Jan 1, 2016

• Keywords provided by Michael Boyiadzis, Study Principal Investigator, University of Pittsburgh: Chronic; Lymphocytic; Leukemia; Fludarabine; Cyclophosphamide; Rituximab
• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Cyclophosphamide; Rituximab; Fludarabine

Study Results

Participant Flow

Arm/Group Title	FLUDARABINE, CYCLOSPHOSPHAMIDE AND RITUXIMAB
Arm/Group Description	Fludarabine: Fludarabine is usually administered by IV infusion over 30 minutes or longer. Cyclophosphamide: The dosage is a solution of 20 mg/mI. IV infusion over 1 hour. Rituximab: First Infusion: The rituximab solution for infusion should be administered intravenously at an initial rate of 50 mg/hr. Subsequent rituximab infusions can be administered at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr as tolerated.
Period Title: Overall Study
STARTED	65
COMPLETED	55
NOT COMPLETED	10

Baseline Characteristics

Arm/Group Title	FLUDARABINE, CYCLOSPHOSPHAMIDE AND RITUXIMAB
Arm/Group Description	Fludarabine: Fludarabine is usually administered by IV infusion over 30 minutes or longer. Cyclophosphamide: The dosage is a solution of 20 mg/mI. IV infusion over 1 hour. Rituximab: First Infusion: The rituximab solution for infusion should be administered intravenously at an initial rate of 50 mg/hr. Subsequent rituximab infusions can be administered at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr as tolerated.
Overall Participants	65
Age, Customized (years) [Median (Full Range) ]
Median (Full Range) [years]	58
Sex: Female, Male (Count of Participants)
Female	15 23.1%
Male	50 76.9%

Outcome Measures

1. Primary Outcome

Title	Tolerability of Rituximab, Cyclophosphamide and Fludarabine in Patients With Previously Untreated CLL/SLL
Description	The number of patients who experience any grade 3-5 toxicity.
Time Frame	Duration of treatment on study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	FLUDARABINE, CYCLOSPHOSPHAMIDE AND RITUXIMAB
Arm/Group Description	Fludarabine: Fludarabine is usually administered by IV infusion over 30 minutes or longer. Cyclophosphamide: The dosage is a solution of 20 mg/mI. IV infusion over 1 hour. Rituximab: First Infusion: The rituximab solution for infusion should be administered intravenously at an initial rate of 50 mg/hr. Subsequent rituximab infusions can be administered at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr as tolerated.
Measure Participants	65
Number [participants]	42 64.6%

2. Secondary Outcome

Title	Overall Survival Rate
Description	The percentage of participants who are still alive.
Time Frame	Five years after starting rituximab, cyclophosphamide and fludarabine

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	FLUDARABINE, CYCLOSPHOSPHAMIDE AND RITUXIMAB
Arm/Group Description	Fludarabine: Fludarabine is usually administered by IV infusion over 30 minutes or longer. Cyclophosphamide: The dosage is a solution of 20 mg/mI. IV infusion over 1 hour. Rituximab: First Infusion: The rituximab solution for infusion should be administered intravenously at an initial rate of 50 mg/hr. Subsequent rituximab infusions can be administered at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr as tolerated.
Measure Participants	65
Number (95% Confidence Interval) [percentage of participants]	85.5 131.5%

3. Primary Outcome

Title	Efficacy of Rituximab, Cyclophosphamide and Fludarabine in Patients With Previously Untreated CLL/SLL
Description	The number of patients who experience a complete clinical response.
Time Frame	Three months after the sixth cycle (9 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	FLUDARABINE, CYCLOSPHOSPHAMIDE AND RITUXIMAB
Arm/Group Description	Fludarabine: Fludarabine is usually administered by IV infusion over 30 minutes or longer. Cyclophosphamide: The dosage is a solution of 20 mg/mI. IV infusion over 1 hour. Rituximab: First Infusion: The rituximab solution for infusion should be administered intravenously at an initial rate of 50 mg/hr. Subsequent rituximab infusions can be administered at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr as tolerated.
Measure Participants	63
Number [participants]	46 70.8%

4. Secondary Outcome

Title	Duration of Response
Description	The length of time for which the complete response is maintained.
Time Frame	From complete response to the time of progressive disease, death or last clinical examination

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	FLUDARABINE, CYCLOSPHOSPHAMIDE AND RITUXIMAB
Arm/Group Description	Fludarabine: Fludarabine is usually administered by IV infusion over 30 minutes or longer. Cyclophosphamide: The dosage is a solution of 20 mg/mI. IV infusion over 1 hour. Rituximab: First Infusion: The rituximab solution for infusion should be administered intravenously at an initial rate of 50 mg/hr. Subsequent rituximab infusions can be administered at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr as tolerated.
Measure Participants	37
Median (Full Range) [Months]	22.3

Adverse Events

Arm/Group Title	FLUDARABINE, CYCLOSPHOSPHAMIDE AND RITUXIMAB
Arm/Group Description	Fludarabine: Fludarabine is usually administered by IV infusion over 30 minutes or longer. Cyclophosphamide: The dosage is a solution of 20 mg/mI. IV infusion over 1 hour. Rituximab: First Infusion: The rituximab solution for infusion should be administered intravenously at an initial rate of 50 mg/hr. Subsequent rituximab infusions can be administered at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr as tolerated.
All Cause Mortality
	FLUDARABINE, CYCLOSPHOSPHAMIDE AND RITUXIMAB
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	FLUDARABINE, CYCLOSPHOSPHAMIDE AND RITUXIMAB
	Affected / at Risk (%)	# Events
Total	26/65 (40%)
Blood and lymphatic system disorders
Hemoglobin	5/65 (7.7%)
Blood/Bone Marrow-Other	1/65 (1.5%)
Prothrombin time (PT)	1/65 (1.5%)
Febrile neutropenia	2/65 (3.1%)
Cardiac disorders
Supraventricular arrhythmias (SVT/atrial fibrillation/flutter)	1/65 (1.5%)
Cardiac-ischemia/infarction	2/65 (3.1%)
Cardiovascular/General-Other	1/65 (1.5%)
Gastrointestinal disorders
Diarrhea	2/65 (3.1%)
Ileus (or neuroconstipation)	1/65 (1.5%)
General disorders
Edema	1/65 (1.5%)
Rigors, chills	2/65 (3.1%)
Infections and infestations
Infection without neutropenia	1/65 (1.5%)
Infection/Febrile Neutropenia-Other	3/65 (4.6%)
Investigations
Leukocytes (total WBC)	7/65 (10.8%)
Neutrophils/granulocytes (ANC/AGC)	20/65 (30.8%)
Platelets	2/65 (3.1%)
Metabolism and nutrition disorders
Hypokalemia	1/65 (1.5%)
Skin and subcutaneous tissue disorders
Rash/desquamation	1/65 (1.5%)
Other (Not Including Serious) Adverse Events
	FLUDARABINE, CYCLOSPHOSPHAMIDE AND RITUXIMAB
	Affected / at Risk (%)	# Events
Total	65/65 (100%)
Blood and lymphatic system disorders
Hemoglobin	28/65 (43.1%)
Blood/Bone Marrow-Other	1/65 (1.5%)
Hemorrhage-Other	1/65 (1.5%)
Lymphatics-Other	1/65 (1.5%)
Cardiac disorders
Cardiovascular/General-Other	2/65 (3.1%)
Ear and labyrinth disorders
Inner ear/hearing	1/65 (1.5%)
Endocrine disorders
Hypothyroidism	1/65 (1.5%)
Eye disorders
Conjunctivitis	1/65 (1.5%)
Vision-blurred vision	3/65 (4.6%)
Ocular/Visual-Other	1/65 (1.5%)
Gastrointestinal disorders
Constipation	14/65 (21.5%)
Diarrhea	15/65 (23.1%)
Dyspepsia/heartburn	5/65 (7.7%)
Flatulence	1/65 (1.5%)
Nausea	39/65 (60%)
Taste disturbance (dysgeusia)	2/65 (3.1%)
Gastrointestinal-Other	5/65 (7.7%)
Gastritis	1/65 (1.5%)
Stomatitis/pharyngitis (oral/pharyngeal mucositis)	8/65 (12.3%)
Vomiting	14/65 (21.5%)
Melena/GI bleeding	1/65 (1.5%)
Abdominal pain or cramping	7/65 (10.8%)
General disorders
Edema	6/65 (9.2%)
Fatigue (lethargy, malaise, asthenia)	53/65 (81.5%)
Constitutional Symptoms-Other	3/65 (4.6%)
Fever (in the absence of neutropenia, where neutropenia is defined as AGC<1.0 x 10e9/L)	16/65 (24.6%)
Rigors, chills	19/65 (29.2%)
Injection site reaction	1/65 (1.5%)
Pain-Other	13/65 (20%)
Chest pain (non-cardiac and non-pleuritic)	2/65 (3.1%)
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever)	7/65 (10.8%)
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	5/65 (7.7%)
Infections and infestations
Infection without neutropenia	23/65 (35.4%)
Infection with unknown ANC	3/65 (4.6%)
Infection with grade 3 or 4 neutropenia	2/65 (3.1%)
Wound-infectious	1/65 (1.5%)
Injury, poisoning and procedural complications
Wound-non-infectious	2/65 (3.1%)
Investigations
Lymphopenia	1/65 (1.5%)
Leukocytes (total WBC)	41/65 (63.1%)
Neutrophils/granulocytes (ANC/AGC)	25/65 (38.5%)
Platelets	25/65 (38.5%)
Weight gain	2/65 (3.1%)
Weight loss	3/65 (4.6%)
SGOT (AST) (serum glutamic oxaloacetic transaminase)	3/65 (4.6%)
SGPT (ALT) (serum glutamic pyruvic transaminase)	3/65 (4.6%)
Alkaline phosphatase	1/65 (1.5%)
Creatinine	1/65 (1.5%)
Metabolism and nutrition disorders
Anorexia	20/65 (30.8%)
Dehydration	1/65 (1.5%)
Hypercalcemia	1/65 (1.5%)
Hyperglycemia	7/65 (10.8%)
Hyperkalemia	1/65 (1.5%)
Musculoskeletal and connective tissue disorders
Muscle weakness (not due to neuropathy)	1/65 (1.5%)
Musculoskeletal-Other	6/65 (9.2%)
Arthralgia	9/65 (13.8%)
Myalgia	9/65 (13.8%)
Arthritis	1/65 (1.5%)
Bone pain	4/65 (6.2%)
Nervous system disorders
Memory loss	1/65 (1.5%)
Neuropathy - motor	6/65 (9.2%)
Neurology-Other	3/65 (4.6%)
Dizziness/lightheadedness	7/65 (10.8%)
Headache	14/65 (21.5%)
Neuropathy-sensory	8/65 (12.3%)
Speech impairment (e.g., dysphasia or aphasia)	1/65 (1.5%)
Neuropathic pain	1/65 (1.5%)
Psychiatric disorders
Insomnia	15/65 (23.1%)
Mood alteration-anxiety, agitation	4/65 (6.2%)
Mood alteration-depression	4/65 (6.2%)
Renal and urinary disorders
Dysuria (painful urination)	2/65 (3.1%)
Urinary frequency/urgency	4/65 (6.2%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/65 (1.5%)
Cough	22/65 (33.8%)
Dyspnea (shortness of breath)	8/65 (12.3%)
Hiccoughs (hiccups, singultus)	2/65 (3.1%)
Pulmonary-Other	6/65 (9.2%)
Voice changes/stridor/larynx (e.g., hoarseness, loss of voice, laryngitis)	1/65 (1.5%)
Skin and subcutaneous tissue disorders
Sweating (diaphoresis)	12/65 (18.5%)
Pigmentation changes (e.g., vitiligo)	1/65 (1.5%)
Pruritus	10/65 (15.4%)
Erythema multiforme (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis)	1/65 (1.5%)
Urticaria (hives, welts, wheals)	5/65 (7.7%)
Dermatology/Skin-Other	3/65 (4.6%)
Alopecia	1/65 (1.5%)
Rash/desquamation	13/65 (20%)
Vascular disorders
Hypotension	2/65 (3.1%)
Hypertension	2/65 (3.1%)
Hot flashes/flushes	5/65 (7.7%)
Flushing	2/65 (3.1%)

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.