TREC: Bendamustine Hydrochloride, Rituximab, Etoposide, and Carboplatin in Treating Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma or Hodgkin Lymphoma

• Sponsor: University of Washington (Other)
• Overall Status: Completed
• CT.gov ID: NCT01165112
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 48
• Location: 1
• Arm: 1
• Actual Duration (Months): 57
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

This phase I/II trial is studying the side effects and best dose of bendamustine hydrochloride when given together with carboplatin, etoposide, and rituximab in treating patients with diffuse large B cell lymphoma or Hodgkin lymphoma that has come back after a period of improvement or has not responded to previous treatment. Drugs used in chemotherapy, such as bendamustine hydrochloride, etoposide, and carboplatin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, may block cancer growth by targeting certain cells. Giving bendamustine hydrochloride together with carboplatin, etoposide, and rituximab may kill more cancer cells.

Condition or Disease	Intervention/Treatment	Phase
Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Hodgkin Lymphoma	Drug: Bendamustine Hydrochloride; Drug: Carboplatin; Biological: Rituximab; Drug: Etoposide; Other: Laboratory Biomarker Analysis	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To estimate the maximally tolerated dose of bendamustine (bendamustine hydrochloride) that can be combined with rituximab, carboplatin, and etoposide chemotherapy in patients with relapsed or refractory lymphoid malignancies.

2. To determine the safety and toxicity of the above regimen.

SECONDARY OBJECTIVES:

1. To gain a preliminary assessment of the efficacy of the above regimen.

2. To determine the ability to proceed to peripheral blood stem cell collection following the above regimen (the impact of above regimen on stem cell reserve).

3. To investigate whether findings from laboratory, radiographic or pathologic studies have any prognostic impact on the response to treatment.

OUTLINE: This is a phase I, dose-escalation study of bendamustine hydrochloride followed by a phase II study.

Patients receive bendamustine hydrochloride intravenously (IV) over 30-60 minutes on days 1 and 2, etoposide IV over 60 minutes on days 1-3, and carboplatin IV over 60 minutes on day 1. Patients with cluster of differentiation (CD)20+ T-cell lymphoma disease also receive rituximab IV on day 2 or 3. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months for 4 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Trial of Bendamustine/Treanda®, Rituximab, Etoposide, and Carboplatin for Patients With Relapsed or Refractory Lymphoid Malignancies and Select Untreated Lymphomas (TREC)
• Actual Study Start Date: Sep 1, 2010
• Actual Primary Completion Date: Jun 1, 2015
• Actual Study Completion Date: Jun 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (chemotherapy and monoclonal antibody therapy) Patients receive bendamustine hydrochloride IV over 30-60 minutes on days 1 and 2, etoposide IV over 60 minutes on days 1-3, and carboplatin IV over 60 minutes on day 1. Patients with CD20+ T-cell lymphoma disease also receive rituximab IV on day 2 or 3. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity.

Drug: Bendamustine Hydrochloride; Given IV; Other Names: Ribomustin SyB L-0501 Treanda ; Drug: Carboplatin; Given IV; Biological: Rituximab; Given IV; Other Names: MOAB IDEC-C2B8 ; Drug: Etoposide; Given IV; Other Names: Lastet ; Other: Laboratory Biomarker Analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Maximally Tolerated Dose of Bendamustine Hydrochloride That Can be Combined With Rituximab, Carboplatin, and Etoposide Chemotherapy in Patients With Relapsed or Refractory Lymphoid Malignancies [Up to 5 weeks after the last course]

   Defined as dose at which approximately =< 25% of patients experience a DLT. Following completed observation of final patient, two-parameter logistic model fit to data, generating dose-response curve based on observed toxicity rate at dose levels visited. Based on this fitted model, MTD is estimated to be dose that is associated with toxicity rate of 25%. If estimate of slope parameter for fitted curve is not positive and finite, geometric mean of dose level used for last cohort and dose level that would have been assigned to next cohort is taken as MTD.

2. Safety and Toxicity of This Regimen [Up to 5 weeks after the last course]

   Count of participants experiencing a dose limiting toxicity. The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 will be used to classify and grade toxicities.

Secondary Outcome Measures

1. Preliminary Assessment of the Efficacy of This Regimen [Up to 5 weeks after the last course]

   Response will be defined by standard NCI criteria (Cheson et al) for lymphoid malignancies.

2. Ability to Proceed to Peripheral Blood Stem Cell (PBSC) Collection Following Treatment (Impact of This Regimen on Stem Cell Reserve) [Up to 5 weeks after the last course]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients must have relapsed or primary refractory lymphomas: diffuse large B cell lymphoma (DLBCL) or Hodgkin's lymphoma (HL); patients with other lymphoid malignancies such as T- cell, or lymphomas that are not curable with anthracycline based therapy (e.g. mantle cell lymphoma [MCL], follicular lymphoma [FL], marginal zone lymphoma [MZL], lymphoplasmacytic lymphoma [LPL]) are eligible with protocol Chair review and approval; Note: as of 11/1/12 only patients with typical DLBCL and HL are eligible for enrollment; unusual pathology for DLBCL and HL will require Study Chair approval; the goal is to have 20 patients with DLBCL and 20 patients with HL enrolled

• World Health Organization (WHO) classification of patient's malignancies must be provided

• Patients must have measurable disease defined as lesions that can be accurately measured in two dimensions by computed tomography (CT), magnetic resonance imaging (MRI), medical photograph (skin or oral lesion), plain x-ray, or other conventional technique and a greatest transverse diameter of 1 cm or greater; or palpable lesions with both diameters >= 2 cm; Note: CT scans remain the standard for evaluation of nodal disease

• Patients must have a CT of chest, abdomen, and pelvis within 28 days of enrollment; patients with evidence of lymphadenopathy in the neck must have a CT of neck

• Patients should not have evidence of active central nervous system lymphoma

• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

• Absolute neutrophil count (ANC) >= 1,500/mm^3 (without transfusion or growth factor support); exception: patients with cytopenias due to disease, that do not meet these criteria, will be considered eligible with review and approval by the principal investigator (PI) or Co-PI prior to study entry

• Platelets >= 100,000/mm^3 (without transfusion or growth factor support); exception: patients with cytopenias due to disease, that do not meet these criteria, will be considered eligible with review and approval by the PI or Co-PI prior to study entry

• Serum creatinine < 1.5 mg/dl or creatinine clearance greater than 50/ml per minute

• Total bilirubin < 1.5 times upper limit of normal

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 times upper limit of normal

• Patients must have a serum lactate dehydrogenase (LDH) performed within 14 days prior to registration

• All patients must be informed of the investigational nature of this study and have given written consent in accordance with institutional and federal guidelines

• Patients must be anticipated to complete at least 2 cycles of chemotherapy

Exclusion Criteria:

• Patients known positive for human immunodeficiency virus (HIV), or infectious hepatitis type B or C

• Pregnant or nursing women; men or women of reproductive potential may not participate unless they have agreed to use an effective contraceptive method

• Patients with other prior malignancies except for adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, breast or cervical cancer in situ, or other cancer from which the patient has been disease-free for 5 years or greater, unless approved by the protocol Chair

• Patients who are refractory (i.e. not responded or progressed within 6 months) to a carboplatin, cisplatin, bendamustine, or etoposide-based regimen

• Patients who have other medical conditions that would contraindicate treatment with aggressive chemotherapy (including active infection, uncontrolled hypertension, congestive heart failure, unstable angina pectoris, or myocardial infarction within the past 6 months, uncontrolled arrhythmia); if the patient's cardiac history is questionable, a measurement of left ventricular ejection fraction should be obtained within 42 days prior to registration; patients with left ventricular ejection fraction < 50% are not eligible

• Autologous or allogeneic transplantation within 12 months or radioimmunotherapy within 6 months of registration; prior failed (< 5 x 10^6 CD34/kg) peripheral blood stem cell (PBSC) collection

• Patients who had pelvic radiation within 12 months or received more than 2 prior therapies with myelotoxic regimens; single agent monoclonal antibody treatment is not considered as one therapy; radiation treatment following chemotherapy is not considered as one separated therapy; consolidative therapy will be considered one regimen e.g. salvage therapy followed by conditioning regimen and transplant

• Previous chemotherapy/immunotherapy within 3 weeks before study entry

• Concurrent use of other anti-cancer agents or experimental treatments

• Known hypersensitivity to bendamustine, mannitol, etoposide, carboplatin, or rituximab

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington	United States	98109

Sponsors and Collaborators

• University of Washington
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Ajay Gopal, Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ajay Gopal, Principal Investigator, University of Washington
• ClinicalTrials.gov Identifier: NCT01165112
• Other Study ID Numbers: PSOC 2502; NCI-2010-00907; PSOC 2502; P30CA015704
• First Posted: Jul 19, 2010
• Last Update Posted: Dec 5, 2018
• Last Verified: Nov 1, 2018

• Additional relevant MeSH terms: Lymphoma; Hodgkin Disease; Lymphoma, Large B-Cell, Diffuse; Recurrence; Rituximab; Carboplatin; Etoposide; Bendamustine Hydrochloride

Study Results

Participant Flow

Arm/Group Title	Treatment (Chemotherapy and Monoclonal Antibody Therapy)
Arm/Group Description	Patients receive bendamustine hydrochloride IV over 30-60 minutes on days 1 and 2, etoposide IV over 60 minutes on days 1-3, and carboplatin IV over 60 minutes on day 1. Patients with CD20+ T-cell lymphoma disease also receive rituximab IV on day 2 or 3. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Bendamustine Hydrochloride: Given IV Carboplatin: Given IV Rituximab: Given IV Etoposide: Given IV Laboratory Biomarker Analysis: Correlative studies
Period Title: Overall Study
STARTED	48
COMPLETED	48
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Chemotherapy and Monoclonal Antibody Therapy)
Arm/Group Description	Patients receive bendamustine hydrochloride IV over 30-60 minutes on days 1 and 2, etoposide IV over 60 minutes on days 1-3, and carboplatin IV over 60 minutes on day 1. Patients with CD20+ T-cell lymphoma disease also receive rituximab IV on day 2 or 3. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Bendamustine Hydrochloride: Given IV Carboplatin: Given IV Rituximab: Given IV Etoposide: Given IV Laboratory Biomarker Analysis: Correlative studies
Overall Participants	48
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	56
Sex: Female, Male (Count of Participants)
Female	19 39.6%
Male	29 60.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 10.4%
Not Hispanic or Latino	39 81.3%
Unknown or Not Reported	4 8.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 4.2%
Native Hawaiian or Other Pacific Islander	1 2.1%
Black or African American	1 2.1%
White	43 89.6%
More than one race	0 0%
Unknown or Not Reported	1 2.1%

Outcome Measures

1. Primary Outcome

Title	Maximally Tolerated Dose of Bendamustine Hydrochloride That Can be Combined With Rituximab, Carboplatin, and Etoposide Chemotherapy in Patients With Relapsed or Refractory Lymphoid Malignancies
Description	Defined as dose at which approximately =< 25% of patients experience a DLT. Following completed observation of final patient, two-parameter logistic model fit to data, generating dose-response curve based on observed toxicity rate at dose levels visited. Based on this fitted model, MTD is estimated to be dose that is associated with toxicity rate of 25%. If estimate of slope parameter for fitted curve is not positive and finite, geometric mean of dose level used for last cohort and dose level that would have been assigned to next cohort is taken as MTD.
Time Frame	Up to 5 weeks after the last course

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Chemotherapy and Monoclonal Antibody Therapy)
Arm/Group Description	Patients receive bendamustine hydrochloride IV over 30-60 minutes on days 1 and 2, etoposide IV over 60 minutes on days 1-3, and carboplatin IV over 60 minutes on day 1. Patients with CD20+ T-cell lymphoma disease also receive rituximab IV on day 2 or 3. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Bendamustine Hydrochloride: Given IV Carboplatin: Given IV Rituximab: Given IV Etoposide: Given IV Laboratory Biomarker Analysis: Correlative studies
Measure Participants	48
Number [mg/m2 x 2]	120

2. Primary Outcome

Title	Safety and Toxicity of This Regimen
Description	Count of participants experiencing a dose limiting toxicity. The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0 will be used to classify and grade toxicities.
Time Frame	Up to 5 weeks after the last course

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Chemotherapy and Monoclonal Antibody Therapy)
Arm/Group Description	Patients receive bendamustine hydrochloride IV over 30-60 minutes on days 1 and 2, etoposide IV over 60 minutes on days 1-3, and carboplatin IV over 60 minutes on day 1. Patients with CD20+ T-cell lymphoma disease also receive rituximab IV on day 2 or 3. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Bendamustine Hydrochloride: Given IV Carboplatin: Given IV Rituximab: Given IV Etoposide: Given IV Laboratory Biomarker Analysis: Correlative studies
Measure Participants	48
Count of Participants [Participants]	0 0%

3. Secondary Outcome

Title	Preliminary Assessment of the Efficacy of This Regimen
Description	Response will be defined by standard NCI criteria (Cheson et al) for lymphoid malignancies.
Time Frame	Up to 5 weeks after the last course

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Chemotherapy and Monoclonal Antibody Therapy)
Arm/Group Description	Patients receive bendamustine hydrochloride IV over 30-60 minutes on days 1 and 2, etoposide IV over 60 minutes on days 1-3, and carboplatin IV over 60 minutes on day 1. Patients with CD20+ T-cell lymphoma disease also receive rituximab IV on day 2 or 3. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Bendamustine Hydrochloride: Given IV Carboplatin: Given IV Rituximab: Given IV Etoposide: Given IV Laboratory Biomarker Analysis: Correlative studies
Measure Participants	47
Count of Participants [Participants]	33 68.8%

4. Secondary Outcome

Title	Ability to Proceed to Peripheral Blood Stem Cell (PBSC) Collection Following Treatment (Impact of This Regimen on Stem Cell Reserve)
Time Frame	Up to 5 weeks after the last course

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Chemotherapy and Monoclonal Antibody Therapy)
Arm/Group Description	Patients receive bendamustine hydrochloride IV over 30-60 minutes on days 1 and 2, etoposide IV over 60 minutes on days 1-3, and carboplatin IV over 60 minutes on day 1. Patients with CD20+ T-cell lymphoma disease also receive rituximab IV on day 2 or 3. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Bendamustine Hydrochloride: Given IV Carboplatin: Given IV Rituximab: Given IV Etoposide: Given IV Laboratory Biomarker Analysis: Correlative studies
Measure Participants	32
Count of Participants [Participants]	30 62.5%

Adverse Events

Arm/Group Title	Treatment (Chemotherapy and Monoclonal Antibody Therapy)
Arm/Group Description	Patients receive bendamustine hydrochloride IV over 30-60 minutes on days 1 and 2, etoposide IV over 60 minutes on days 1-3, and carboplatin IV over 60 minutes on day 1. Patients with CD20+ T-cell lymphoma disease also receive rituximab IV on day 2 or 3. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Bendamustine Hydrochloride: Given IV Carboplatin: Given IV Rituximab: Given IV Etoposide: Given IV Laboratory Biomarker Analysis: Correlative studies
All Cause Mortality
	Treatment (Chemotherapy and Monoclonal Antibody Therapy)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Chemotherapy and Monoclonal Antibody Therapy)
	Affected / at Risk (%)	# Events
Total	14/48 (29.2%)
Blood and lymphatic system disorders
Febrile neutropenia	4/48 (8.3%)
Cardiac disorders
Atrial fibrillation	1/48 (2.1%)
Gastrointestinal disorders
Obstruction gastric	2/48 (4.2%)
General disorders
Fever	2/48 (4.2%)
Immune system disorders
Allergic reaction	2/48 (4.2%)
Infections and infestations
Catheter related infection	1/48 (2.1%)
Aseptic Meningitis	1/48 (2.1%)
Metabolism and nutrition disorders
Dehydration	2/48 (4.2%)
Respiratory, thoracic and mediastinal disorders
Asthma exacerbation	1/48 (2.1%)
Upper respiratory infection	1/48 (2.1%)
Vascular disorders
Hypotension	1/48 (2.1%)
Vascular access complication	1/48 (2.1%)
Other (Not Including Serious) Adverse Events
	Treatment (Chemotherapy and Monoclonal Antibody Therapy)
	Affected / at Risk (%)	# Events
Total	46/48 (95.8%)
Blood and lymphatic system disorders
Anemia	6/48 (12.5%)
Neutropenia	24/48 (50%)
Thrombocytopenia	30/48 (62.5%)
Febrile neutropenia	4/48 (8.3%)
Infections and infestations
Infection	3/48 (6.3%)
Metabolism and nutrition disorders
Dehydration	4/48 (8.3%)

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.