High Dose Rituximab for Initial Treatment of Indolent B-Cell Lymphomas

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00895661
• Collaborator: Dana-Farber Cancer Institute (Other), Brigham and Women's Hospital (Other), Genentech, Inc. (Industry)
• Enrollment: 40
• Locations: 2
• Arm: 1
• Actual Duration (Months): 73
• Patients Per Site: 20
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this clinical trial is to see if increased doses of rituximab are safe and effective for the initial treatment of indolent B-cell lymphomas. Rituximab (Rituxan) is a type of drug called an "antibody" that specifically targets B-cell lymphoma cells, and is approved by the FDA for the treatment of indolent B-cell non-hodgkin lymphomas and certain other types of non-hodgkin lymphomas. Standard doses currently used may not be achieving maximal efficacy. Higher doses have been shown to be safe in other clinical trials, and may offer superior efficacy to the current standard dose. This trial also employs intermittent maintenance doses of rituximab at the standard dose, which has been shown to prolong remissions and survival in patients with relapsed indolent B-cell lymphomas. This trial is designed to show that higher dose rituximab plus maintenance rituximab can achieve similarly good results to chemotherapy approaches, but without chemotherapy-related toxicity.

Condition or Disease	Intervention/Treatment	Phase
B-cell Lymphoma; Indolent B-cell Lymphoma	Drug: rituximab	Phase 2

Detailed Description

• All participants will receive increased-dose rituximab through a vein in the arm once a week for 4 weeks (on Days 1, 8, 15, and 22 of the initial 28-day study cycle). This first cycle of study treatment is called the Induction Phase. If the participant responds well to the Induction Phase, they then may continue to the Maintenance Therapy Phase, where they will receive a lower dose of rituximab once every three months for up to 2 years.

• During the Induction Phase, the following procedures will take place before the participant receives each dose of rituximab: medical review, physical exam, performance status, and ECG. Blood tests will be drawn about 30-60 minutes after the first dose of rituximab on Day 1. Samples will be drawn immediately before each dose and again 30-60 minutes after each dose on Days 1, 8, 15 and 22.

• During the Maintenance Therapy Phase, the following procedures will take place before the participant receives each dose of rituximab: medical review, physical exam, performance status, ECG, blood tests and response assessments by CT scan.

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Increased Dose Rituximab Plus Maintenance Rituximab for Initial Systemic Treatment of Indolent B-Cell Lymphomas
• Actual Study Start Date: Jul 1, 2009
• Actual Primary Completion Date: Oct 1, 2010
• Actual Study Completion Date: Aug 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Other: rituximab single-arm, open-label, interventional	Drug: rituximab; Increased dose (750 mg/m2) intravenously for 4 weekly doses followed by maintenance dosing once every three months for up to 2 years. Maintenance dose is standard (375 mg/m2).; Other Names: Rituxan

Outcome Measures

Primary Outcome Measures

1. Determine Complete Response Rate (CRR) of Increased Dose Rituximab in Indolent B-cell Lymphomas [after a median number of 8 maintenance cycles, up to 24 weeks]

   CR requires all of the following: Regression to normal size on CT (≤ 1.5 cm in their greatest transverse diameter for nodes ≥ 1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in their greatest transverse diameter before treatment must have decreased to <1 cm in their greatest transverse diameter after treatment, or by more than 75% in the sum of the products of the greatest diameters (SPD). The spleen, if considered to be enlarged before therapy on the basis of a CT scan, must have regressed in size and must not be palpable on physical examination. If bone marrow is known to be involved at the beginning, then repeat biopsy documents clearance

Secondary Outcome Measures

1. Overall Response Rate (ORR) [after a median number of 8 maintenance cycles, up to 24 weeks]

   Complete Response (CR): see definition in primary outcome Partial Response (PR): ≥50% decrease in SPD of up to 6 largest dominant masses No new sites of disease or increase in the size of the other nodes, liver, or spleen. Splenic and hepatic nodules must regress by at least 50% in the SPD. Overall Response (OR) = CR + PR.

2. Progression-free Survival (PFS) [5 years]

   Progressive Disease (PD) or Relapsed Disease (RD): Appearance of a new lesion(s) > 1.5 cm in any axis, ≥ 50% increase in SPD of more than one node, or ≥50% increase in longest diameter of a previously identified node > 1 cm in short axis. >50% increase from nadir in the SPD of any previous lesions PFS is number of participants who have not died or had PD or RD.

3. Incidence of Severity of Infusion Reactions, Infections and Neutropenia [24 months]

   Toxicity grades: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Indolent B-Cell NHL of the following histologies:

1. Follicular lymphoma (grades 1-3A);

2. marginal zone lymphoma (extranodal, nodal or splenic):

• Extranodal marginal zone lymphomas (MALT lymphomas) may not be candidates for cure with antibiotics or local radiotherapy. Patients who have failed antibiotics or local therapy are eligible for the protocol as long as they have measurable disease and are naive to chemotherapy and monoclonal antibody;

• splenic marginal zone lymphoma patients may have received prior splenectomy as long as they have measureable disease and are naive to chemotherapy and monoclonal antibody therapy;

1. Small lymphocytic lymphoma (must have less than 5000 circulating clonal B-lymphocytes);

2. Indolent CD20+ B-cell lymphoma not otherwise specified with CD20+ expression

• Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as 20mm or greater with conventional techniques or as 10mm or greater with spiral CT scan

• No previous chemotherapy, antibody therapy or radioimmunotherapy for NHL. Patients previously treated with external bean radiation alone, surgery, or with antibiotics are eligible

• 18 years of age or older

• Life expectancy of greater than 3 months

• ECOG performance status of 2 or less

• Adequate bone marrow function

• Use of adequate contraception

Exclusion Criteria:

• Prior chemotherapy, monoclonal antibody therapy or radioimmunotherapy for lymphoma

• Receiving any other investigational agent

• Known brain metastases

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to rituximab

• HIV positivity

• Active hepatitis B infection

• Candidate for curative radiotherapy, unless radiation therapy is considered too toxic (as in abdominal disease), or is refused by the patient

• NYHA Classification III or IV disease

• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection that is not optimally treated with antibiotics, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements

• Pregnant women

• Individuals with a history of a different malignancy except for the following circumstances:

1. disease-free for at least 1 year and are deemed by the investigator to be at low risk for recurrence of that malignancy;

2. localized prostate cancer, prostate cancer with elevated PSA but no measurable disease on CT scans or bone scan, cervical cancer in situ; and

3. non-melanoma skin cancers

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
2	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Massachusetts General Hospital
• Dana-Farber Cancer Institute
• Brigham and Women's Hospital
• Genentech, Inc.

Investigators

• Principal Investigator: Jeremy Abramson, MD, Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Jeremy Abramson, MD, Director, Lymphoma Program, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT00895661
• Other Study ID Numbers: 09-054
• First Posted: May 8, 2009
• Last Update Posted: Jun 9, 2017
• Last Verified: May 1, 2017

• Keywords provided by Jeremy Abramson, MD, Director, Lymphoma Program, Massachusetts General Hospital: rituximab
• Additional relevant MeSH terms: Lymphoma; Lymphoma, B-Cell; Rituximab

Study Results

Participant Flow

Arm/Group Title	Rituximab
Arm/Group Description	single-arm, open-label, interventional rituximab: Increased dose (750 mg/m2) intravenously for 4 weekly doses followed by maintenance dosing once every three months for up to 2 years. Maintenance dose is standard (375 mg/m2).
Period Title: Overall Study
STARTED	40
COMPLETED	37
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Rituximab
Arm/Group Description	single-arm, open-label, interventional rituximab: Increased dose (750 mg/m2) intravenously for 4 weekly doses followed by maintenance dosing once every three months for up to 2 years. Maintenance dose is standard (375 mg/m2).
Overall Participants	40
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60
Sex: Female, Male (Count of Participants)
Female	27 67.5%
Male	13 32.5%
Region of Enrollment (participants) [Number]
United States	40 100%
Lymphoma type (Count of Participants)
Follicular	31 77.5%
Marginal zone	4 10%
Small lymphocytic	3 7.5%
Indolent B cell, not otherwise specified	2 5%
Involvement of >4 nodal sites (Count of Participants)
Count of Participants [Participants]	17 42.5%
Hgb<12 g/dL (Count of Participants)
Count of Participants [Participants]	9 22.5%
elevated LDH (Lactate dehydrogenase) (Count of Participants)
Count of Participants [Participants]	11 27.5%
Follicular lymphoma prognostic index (FLIPI) (Count of Participants)
Low risk	6 15%
Intermediate risk	15 37.5%
High risk	17 42.5%
FLIPI score not available	2 5%

Outcome Measures

1. Primary Outcome

Title	Determine Complete Response Rate (CRR) of Increased Dose Rituximab in Indolent B-cell Lymphomas
Description	CR requires all of the following: Regression to normal size on CT (≤ 1.5 cm in their greatest transverse diameter for nodes ≥ 1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in their greatest transverse diameter before treatment must have decreased to <1 cm in their greatest transverse diameter after treatment, or by more than 75% in the sum of the products of the greatest diameters (SPD). The spleen, if considered to be enlarged before therapy on the basis of a CT scan, must have regressed in size and must not be palpable on physical examination. If bone marrow is known to be involved at the beginning, then repeat biopsy documents clearance
Time Frame	after a median number of 8 maintenance cycles, up to 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rituximab
Arm/Group Description	single-arm, open-label, interventional rituximab: Increased dose (750 mg/m2) intravenously for 4 weekly doses followed by maintenance dosing once every three months for up to 2 years. Maintenance dose is standard (375 mg/m2).
Measure Participants	40
Count of Participants [Participants]	21 52.5%

2. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	Complete Response (CR): see definition in primary outcome Partial Response (PR): ≥50% decrease in SPD of up to 6 largest dominant masses No new sites of disease or increase in the size of the other nodes, liver, or spleen. Splenic and hepatic nodules must regress by at least 50% in the SPD. Overall Response (OR) = CR + PR.
Time Frame	after a median number of 8 maintenance cycles, up to 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rituximab
Arm/Group Description	single-arm, open-label, interventional rituximab: Increased dose (750 mg/m2) intravenously for 4 weekly doses followed by maintenance dosing once every three months for up to 2 years. Maintenance dose is standard (375 mg/m2).
Measure Participants	40
Count of Participants [Participants]	32 80%

3. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	Progressive Disease (PD) or Relapsed Disease (RD): Appearance of a new lesion(s) > 1.5 cm in any axis, ≥ 50% increase in SPD of more than one node, or ≥50% increase in longest diameter of a previously identified node > 1 cm in short axis. >50% increase from nadir in the SPD of any previous lesions PFS is number of participants who have not died or had PD or RD.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rituximab
Arm/Group Description	single-arm, open-label, interventional rituximab: Increased dose (750 mg/m2) intravenously for 4 weekly doses followed by maintenance dosing once every three months for up to 2 years. Maintenance dose is standard (375 mg/m2).
Measure Participants	40
Count of Participants [Participants]	19 47.5%

4. Secondary Outcome

Title	Incidence of Severity of Infusion Reactions, Infections and Neutropenia
Description	Toxicity grades: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rituximab
Arm/Group Description	single-arm, open-label, interventional rituximab: Increased dose (750 mg/m2) intravenously for 4 weekly doses followed by maintenance dosing once every three months for up to 2 years. Maintenance dose is standard (375 mg/m2).
Measure Participants	40
Grade 3/4 neutropenia	3 7.5%
Any allergic reactions with infusions	19 47.5%
Grade 3 allergic reactions with infusions	2 5%

Adverse Events

Arm/Group Title	Rituximab
Arm/Group Description	single-arm, open-label, interventional rituximab: Increased dose (750 mg/m2) intravenously for 4 weekly doses followed by maintenance dosing once every three months for up to 2 years. Maintenance dose is standard (375 mg/m2).
All Cause Mortality
	Rituximab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Rituximab
	Affected / at Risk (%)	# Events
Total	4/40 (10%)
Gastrointestinal disorders
Small bowel obstruction	1/40 (2.5%)	1
Infections and infestations
Cellulitis (toe)	1/40 (2.5%)	1
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/40 (2.5%)	1
Skin and subcutaneous tissue disorders
Decubitus ulcer	1/40 (2.5%)	1
Other (Not Including Serious) Adverse Events
	Rituximab
	Affected / at Risk (%)	# Events
Total	40/40 (100%)
Blood and lymphatic system disorders
Neutrophils	40/40 (100%)	495
Hemoglobin	13/40 (32.5%)	38
Leukocytes	11/40 (27.5%)	32
Lymphopenia	7/40 (17.5%)	15
Platelets	5/40 (12.5%)	6
Edema head and neck	3/40 (7.5%)	5
Hematologic-other	3/40 (7.5%)	5
Edema limb	2/40 (5%)	2
Cardiac disorders
Palpitations	3/40 (7.5%)	3
Sinus bradycardia	2/40 (5%)	9
Sinus tachycardia	2/40 (5%)	7
Ear and labyrinth disorders
Hearing-other	3/40 (7.5%)	6
Otitis- middle ear (non-infectious)	2/40 (5%)	3
Endocrine disorders
Hyopthyroidism	2/40 (5%)	3
Eye disorders
Ocular-other	2/40 (5%)	2
Gastrointestinal disorders
Diarrhea w/o prior colostomy	11/40 (27.5%)	32
Nausea	9/40 (22.5%)	21
Anorexia	5/40 (12.5%)	13
Dyspepsia	5/40 (12.5%)	7
Vomiting	4/40 (10%)	6
Constipation	3/40 (7.5%)	7
GI-other	3/40 (7.5%)	6
Dysphagia	2/40 (5%)	8
Muco/stomatitis (symptom) oral cavity	2/40 (5%)	5
Dry mouth	2/40 (5%)	3
Esophagitis	2/40 (5%)	3
Taste disturbance	2/40 (5%)	3
Dehydration	2/40 (5%)	2
General disorders
Fatigue	24/40 (60%)	97
Fever w/o neutropenia	10/40 (25%)	12
Abdomen- pain	9/40 (22.5%)	21
Head/headache	8/40 (20%)	20
Sweating	8/40 (20%)	19
Back-pain	8/40 (20%)	10
Pain-other	7/40 (17.5%)	11
Insomnia	6/40 (15%)	27
Pelvic-pain	6/40 (15%)	15
Joint-pain	6/40 (15%)	14
Rigors/chills	5/40 (12.5%)	5
Extremity-limb- pain	4/40 (10%)	10
Neck- pain	4/40 (10%)	6
Chest/thoracic pain NOS	3/40 (7.5%)	4
Muscle- pain	3/40 (7.5%)	4
Flu-like syndrome	3/40 (7.5%)	3
Chest wall- pain	2/40 (5%)	2
Weight gain	2/40 (5%)	2
Weight loss	2/40 (5%)	2
Hepatobiliary disorders
Cholecystitis	2/40 (5%)	6
Immune system disorders
Allergic reaction	40/40 (100%)	493
Allergic rhinitis	8/40 (20%)	20
Infections and infestations
Infection-other	40/40 (100%)	493
Infection Gr0-2 neut- upper airway	10/40 (25%)	14
Infection Gr0-2 neut- bronchus	5/40 (12.5%)	5
Infection Gr0-2 neut- sinus	4/40 (10%)	6
Infection Gr0-2 neut- skin	2/40 (5%)	3
Infection Gr0-2 neut- urinary tract	2/40 (5%)	3
Infection Gr0-2 neut- lung	2/40 (5%)	2
Metabolism and nutrition disorders
Tumor lysis syndrome	40/40 (100%)	493
Hyperglycemia	14/40 (35%)	52
AST- SGOT	5/40 (12.5%)	8
Alkaline phosphatase	4/40 (10%)	13
ALT- SGPT	4/40 (10%)	10
Hyperuricemia	3/40 (7.5%)	9
Creatinine	3/40 (7.5%)	6
Hypokalemia	3/40 (7.5%)	3
Hypocalcemia	2/40 (5%)	5
Hypoglycemia	2/40 (5%)	3
Hypoalbuminemia	2/40 (5%)	2
Hyponatremia	2/40 (5%)	2
Metabolic/Laboratory-other	2/40 (5%)	2
Musculoskeletal and connective tissue disorders
Musculoskeletal/soft tissue-other	3/40 (7.5%)	3
Arthritis	2/40 (5%)	9
Nervous system disorders
Dizziness	8/40 (20%)	21
Anxiety	5/40 (12.5%)	18
Neuropathy-sensory	4/40 (10%)	18
Renal and urinary disorders
Urinary frequency/urgency	3/40 (7.5%)	8
Respiratory, thoracic and mediastinal disorders
Cough	15/40 (37.5%)	34
Dyspnea	9/40 (22.5%)	19
Pulmonary/Upper Respiratory-other	3/40 (7.5%)	5
Bronchospasm- wheezing	3/40 (7.5%)	4
Voice changes/dysarthria	2/40 (5%)	2
Skin and subcutaneous tissue disorders
Rash/desquamation	10/40 (25%)	19
Skin-other	8/40 (20%)	16
Rash: acne/acneiform	4/40 (10%)	9

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.