A Phase I/II Trial of VR-CHOP in Lymphoma Patients

• Sponsor: Emory University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00634179
• Collaborator: Millennium Pharmaceuticals, Inc. (Industry)
• Enrollment: 37
• Location: 1
• Arm: 1
• Duration (Months): 93
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This is an open-label (doctors and patients know which drug will be given), single center, phase 1/2 clinical trial. The primary objective is to determine whether VR-CHOP provides benefit to patients with previously untreated indolent non-Hodgkin's lymphomas (NHL).

Condition or Disease	Intervention/Treatment	Phase
Lymphoma, B-Cell; Follicular Lymphoma	Drug: Bortezomib; Biological: Rituximab; Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Vincristine; Drug: Prednisone	Phase 1/Phase 2

Detailed Description

This study will assess whether adding bortezomib (Velcade) to R-CHOP (in a new combination called VR-CHOP) can further improve outcomes in patients with indolent NHL who have not previously received treatment.

Patients who are eligible to take part in the study will receive VR-CHOP at the doses of Velcade and vincristine established in phase 1. Patients will receive VR-CHOP for up to 8 cycles of treatment (each of 21 days duration). During treatment, patients will be assessed for their response to therapy and for possible side effects. All patients will go on to receive maintenance therapy after completion of their initial treatment as designed by the protocol.

Study Design

• Study Type: Interventional
• Actual Enrollment: 37 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Trial of VR-CHOP for Patients With Untreated Follicular Lymphoma and Other Low Grade B-Cell Lymphomas
• Study Start Date: Feb 1, 2008
• Actual Primary Completion Date: Nov 1, 2015
• Actual Study Completion Date: Nov 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (VR-CHOP regimen) INDUCTION: Patients receive bortezomib IV on days 1 and 8; rituximab IV, doxorubicin hydrochloride IV over 3-5 minutes, cyclophosphamide IV over 60 minutes, and vincristine sulfate IV over 10 minutes on day 1; and prednisone PO on days 1-5. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression. MAINTENANCE: Patients achieving complete response (CR) receive rituximab IV once every 12 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease or partial response (PR) receive rituximab IV and bortezomib once weekly for 4 weeks every 6 months for up to 2 years in the absence of disease progression or unacceptable toxicity.

Drug: Bortezomib; Bortezomib 1.6 mg/m² given on days 1 and 8; Other Names: Velcade ; Biological: Rituximab; Rituximab 375 mg/m²; Other Names: Rituxin MabThera ; Drug: Doxorubicin; Doxorubicin 50 mg/m²; Other Names: Adriamycin ; Drug: Cyclophosphamide; Cyclophosphamide 750 mg/m²; Other Names: Neosar ; Drug: Vincristine; Vincristine 1.4 mg/m² (capped at 1.5 mg maximum) given on day 1; Other Names: Oncovin ; Drug: Prednisone; Prednisone 100 mg/day given orally on days 1-5; Other Names: Deltasone

Outcome Measures

Primary Outcome Measures

1. Maximal Tolerated Doses of Bortezomib and Vincristine When Used in Combination of Bortezomib, Rituximab and the CHOP Chemotherapy Regimen (Phase I) [Cycle 1 for MTD, following completion of therapy for CR, up to 24 weeks]

   INDUCTION: Patients receive bortezomib IV on days 1 and 8; rituximab IV, doxorubicin hydrochloride IV over 3-5 minutes, cyclophosphamide IV over 60 minutes, and vincristine sulfate IV over 10 minutes on day 1; and prednisone PO on days 1-5. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression.

Secondary Outcome Measures

1. An Estimate of the Overall Response Rate (ORR)(Complete Response [CR] + CR Unconfirmed [CRu] + Partial Response [PR]) to Bortezomib and Rituximab (VR)-CHOP According to International Workshop to Standardize Response Criteria (IWRC) Criteria [Following completion of therapy, up to 2 years]

   Response was assessed by computerized tomography (CT) after every 2 cycles of induction therapy, one time at least 4 weeks after completing induction (i.e., prior to maintenance), and then every 3 months while on maintenance therapy. At the conclusion of maintenance therapy, patients underwent one post-treatment scan, with further scans completed at the discretion of the treating physician. Positron emission tomography was permitted but only CT measurements were used to determine response.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Tissue diagnosis of a previously untreated, cluster of differentiation antigen 20+ (CD20+), B-cell non-Hodgkin lymphoma.

• For the Phase 1 trial: patients with any of the following diagnoses are eligible:

• Follicular Lymphomas (Grade 1, 2, 3a, 3b)

• Small Lymphocytic Lymphoma

• Marginal Zone Lymphomas

• For the Phase 2 trial: patients with any of the following diagnoses are eligible:

• Follicular Lymphomas (Grade 1, 2, 3a)

• Small Lymphocytic Lymphoma

• Marginal Zone Lymphomas

• Patients with follicular or other low-grade lymphoma must have an indication for treatment based on modified Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria or a Follicular Lymphoma International Prognostic Index (FLIPI) score ≥ 3.

• Indications for treatment based on modified GELF criteria include any one of the following:

• B symptoms or other lymphoma-related symptoms

• Involvement of 3 nodal sites, each with a diameter of 3 cm

• Any nodal or extranodal tumor mass with a diameter of 7 cm

• Splenomegaly greater than 16 cm by CT scan.

• Pleural effusions or peritoneal ascites

• Cytopenias (leukocytes < 1.0 x 10 /L and/or platelets < 100 x 10/L)

• Leukemia (> 5.0 x 10 /L circulating malignant cells)

• Indications for treatment based on FLIPI criteria include any three of the following:

• Age ≥ 60 years

• Ann Arbor stage III or IV

• Hemoglobin level < 120 g/L

• Number of nodal areas involved > 4

• Serum lactate dehydrogenase (LDH) level > normal

• Only chemotherapy-naïve subjects are eligible. Subjects may have received prednisone (< 2 months of therapy) or radiation ≤ 2 sites of therapy.

• Voluntary written informed consent and Health Insurance Portability and Accountability Act (HIPAA) Authorization before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.

• Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study.

• Female patients of child bearing potential must have a negative β-human chorionic gonadotropin (β-hCG) test.

• Male subject agrees to use an acceptable method for contraception for the duration of the study.

• ≥ 18 years of age at the time of registration.

• Patients must have adequate renal function as demonstrated by a serum creatinine < 1.5 mg/dl unless felt to be secondary to lymphoma.

• Must have an alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ 3.5 the upper limit of normal and a total bilirubin ≤ 2.0 mg/dL unless secondary to lymphoma.

• Must have a cardiac left ventricular ejection fraction ≥ 50%.

• At least 1 measurable tumor mass (greater than 1.5 cm in the longest dimension and greater than 1.0 cm in the short axis).

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

Exclusion Criteria:

• Subject with primary or secondary central nervous system (CNS) lymphoma (current or previously treated) will not be eligible.

• A history of unrelated (non-lymphomatous) neoplasm within the past 10 years other than non-melanoma skin cancer or in-situ cervix cancer. Subjects with a prior diagnosis of malignancy more than 10 years may be entered into the study at the discretion of the Principal Investigator.

• Serious medical or psychiatric illness likely to interfere with participation in this clinical study.

• Patient has received other investigational drugs with 14 days before enrollment.

• Patient has hypersensitivity to boron or mannitol.

• Female subject is pregnant or breast-feeding. Chemotherapeutic agents are known to have teratogenic effects on developing embryos and to cause chromosomal damage to gametes. These agents also cause bone marrow suppression and can be excreted in milk. Confirmation that the subject is not pregnant must be established by a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women.

• Patient has ≥ Grade 2 peripheral neuropathy within 14 days before enrollment.

• Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.

• Patient has a platelet count of < 10 x 10¹⁰/L (unless due to bone marrow involvement with lymphoma documented within 14 days before enrollment).

• Patient has an absolute neutrophil count of < 1.0 x 10⁹/L (unless due to bone marrow involvement with lymphoma documented within 14 days before enrollment).

• Patient has a calculated or measured creatinine clearance of < 20 mL/minute within 14 days before enrollment.

• Presence of antibodies to HIV.

• Subject unwilling to give informed consent.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University Winship Cancer Institute	Atlanta	Georgia	United States	30322

Sponsors and Collaborators

• Emory University
• Millennium Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Christopher Flowers, MD, Emory University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Christopher R. Flowers, Principal Investigator, Emory University
• ClinicalTrials.gov Identifier: NCT00634179
• Other Study ID Numbers: IRB00002996; X05215
• First Posted: Mar 12, 2008
• Last Update Posted: Oct 27, 2016
• Last Verified: Sep 1, 2016

• Keywords provided by Christopher R. Flowers, Principal Investigator, Emory University: Lymphoma
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Follicular; Lymphoma, B-Cell; Prednisone; Cyclophosphamide; Rituximab; Doxorubicin; Vincristine; Bortezomib

Study Results

Participant Flow

Recruitment Details	All patients were recruited from Winship Cancer Institute of Emory University.
Pre-assignment Detail	A total of 37 patients were enrolled. However, not all patients participated in both phases of this study. For phase I, 19 patients were enrolled, and for phase II, 30 patients were enrolled.

Arm/Group Title	Treatment (VR-CHOP Regimen)
Arm/Group Description	Phase I will identify the maximal tolerated doses of bortezomib and vincristine when used in a combination of bortezomib, rituximab and the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy regimen. In Phase II, the trial will evaluate the efficacy and safety of the MTD combination of VELCADE and rituximab-CHOP in additional subjects who have untreated follicular B-cell non-Hodgkin's lymphoma (B-NHL)(Grade 1, 2, 3a), small lymphocytic lymphoma, or marginal zone lymphoma.
Period Title: Phase I: Induction
STARTED	19
COMPLETED	19
NOT COMPLETED	0
Period Title: Phase I: Induction
STARTED	30
COMPLETED	29
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Treatment (VR-CHOP Regimen)
Arm/Group Description	INDUCTION: Patients receive bortezomib IV on days 1 and 8; rituximab IV, doxorubicin hydrochloride IV over 3-5 minutes, cyclophosphamide IV over 60 minutes, and vincristine sulfate IV over 10 minutes on day 1; and prednisone PO on days 1-5. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression. MAINTENANCE: Patients achieving complete response (CR) receive rituximab IV once every 12 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease or partial response (PR) receive rituximab IV and bortezomib once weekly for 4 weeks every 6 months for up to 2 years in the absence of disease progression or unacceptable toxicity.
Overall Participants	37
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	58
Sex: Female, Male (Count of Participants)
Female	17 45.9%
Male	20 54.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	11 29.7%
White	26 70.3%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	37 100%

Outcome Measures

1. Primary Outcome

Title	Maximal Tolerated Doses of Bortezomib and Vincristine When Used in Combination of Bortezomib, Rituximab and the CHOP Chemotherapy Regimen (Phase I)
Description	INDUCTION: Patients receive bortezomib IV on days 1 and 8; rituximab IV, doxorubicin hydrochloride IV over 3-5 minutes, cyclophosphamide IV over 60 minutes, and vincristine sulfate IV over 10 minutes on day 1; and prednisone PO on days 1-5. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression.
Time Frame	Cycle 1 for MTD, following completion of therapy for CR, up to 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MTD of Bortezomib With Vincristine Capped at 1.5 mg
Arm/Group Description	Maximal tolerated dose (MTD) of bortezomib when vincristine is capped at 1.5 mg
Measure Participants	19
Number (95% Confidence Interval) [mg/m^2]	1.62

2. Secondary Outcome

Title	An Estimate of the Overall Response Rate (ORR)(Complete Response [CR] + CR Unconfirmed [CRu] + Partial Response [PR]) to Bortezomib and Rituximab (VR)-CHOP According to International Workshop to Standardize Response Criteria (IWRC) Criteria
Description	Response was assessed by computerized tomography (CT) after every 2 cycles of induction therapy, one time at least 4 weeks after completing induction (i.e., prior to maintenance), and then every 3 months while on maintenance therapy. At the conclusion of maintenance therapy, patients underwent one post-treatment scan, with further scans completed at the discretion of the treating physician. Positron emission tomography was permitted but only CT measurements were used to determine response.
Time Frame	Following completion of therapy, up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase I: Induction	Phase II: Maintenance
Arm/Group Description	INDUCTION: Patients receive bortezomib IV on days 1 and 8; rituximab IV, doxorubicin hydrochloride IV over 3-5 minutes, cyclophosphamide IV over 60 minutes, and vincristine sulfate IV over 10 minutes on day 1; and prednisone PO on days 1-5. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression.	INDUCTION: Patients receive bortezomib IV on days 1 and 8; rituximab IV, doxorubicin hydrochloride IV over 3-5 minutes, cyclophosphamide IV over 60 minutes, and vincristine sulfate IV over 10 minutes on day 1; and prednisone PO on days 1-5. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression. MAINTENANCE: Patients achieving CR receive rituximab IV once every 12 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients achieving stable disease or PR receive rituximab IV and bortezomib once weekly for 4 weeks every 6 months for up to 2 years in the absence of disease progression or unacceptable toxicity. Bortezomib: Bortezomib 1.6 mg/m² given on days 1 and 8 Rituximab: Rituximab 375 mg/m² Doxorubicin: Doxorubicin 50 mg/m² Cyclophosphamide: Cyclophosphamide 750 mg/m² Vincristine: Vincristine 1.4 mg/m² (capped at 1.5 mg maximum) given on day 1 Prednisone: Prednisone 100 mg/day given orally on
Measure Participants	19	29
Complete Response (CR)	13 35.1%	19 NaN
Partial Response (PR)	6 16.2%	10 NaN
Overall Response Rate (ORR)	19 51.4%	29 NaN

Adverse Events

Arm/Group Title	Phase I: Induction		Phase II: Maintenance
Arm/Group Description	Phase I will identify the maximal tolerated doses of bortezomib and vincristine when used in a combination of bortezomib, rituximab and the CHOP chemotherapy regimen.		In Phase II, the trial will evaluate the efficacy and safety of the MTD combination of VELCADE and rituximab-CHOP in additional subjects who have untreated follicular B-NHL. (Grade 1, 2, 3a), small lymphocytic lymphoma, or marginal zone lymphoma.
All Cause Mortality
	Phase I: Induction		Phase II: Maintenance
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Phase I: Induction		Phase II: Maintenance
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/19 (15.8%)		1/29 (3.4%)
Blood and lymphatic system disorders
Thrombosis	1/19 (5.3%)		0/29 (0%)
Febrile Neutropenia	1/19 (5.3%)		0/29 (0%)
Extravasation	1/19 (5.3%)		0/29 (0%)
Cardiac disorders
Prolonged QT Interval	0/19 (0%)		1/29 (3.4%)
Gastrointestinal disorders
Vomiting	0/19 (0%)		1/29 (3.4%)
Diarrhea	0/19 (0%)		1/29 (3.4%)
General disorders
Fatigue	0/19 (0%)		1/29 (3.4%)
Infections and infestations
Urinary Tract Infection	0/19 (0%)		1/29 (3.4%)
Metabolism and nutrition disorders
Dehydration	0/19 (0%)		1/29 (3.4%)
Nervous system disorders
Pain	0/19 (0%)		1/29 (3.4%)
Psychiatric disorders
Anxiety/Depression	0/19 (0%)		1/29 (3.4%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/19 (0%)		1/29 (3.4%)
Skin and subcutaneous tissue disorders
Cellulitis	0/19 (0%)		1/29 (3.4%)
Other (Not Including Serious) Adverse Events
	Phase I: Induction		Phase II: Maintenance
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/19 (84.2%)		22/29 (75.9%)
Blood and lymphatic system disorders
Neutropenia	13/19 (68.4%)		14/29 (48.3%)
Thrombocytopenia	4/19 (21.1%)		3/29 (10.3%)
Anemia	0/19 (0%)		1/29 (3.4%)
Febrile Neutropenia	0/19 (0%)		1/29 (3.4%)
Extravasation	0/19 (0%)		1/29 (3.4%)
Cardiac disorders
Tachycardia	0/19 (0%)		1/29 (3.4%)
Gastrointestinal disorders
Vomiting	9/19 (47.4%)		2/29 (6.9%)
Diarrhea	7/19 (36.8%)		1/29 (3.4%)
Dyspepsia	4/19 (21.1%)		0/29 (0%)
General disorders
Nausea	13/19 (68.4%)		2/29 (6.9%)
Fatigue	11/19 (57.9%)		1/29 (3.4%)
Weakness	0/19 (0%)		1/29 (3.4%)
Immune system disorders
Fever	0/19 (0%)		1/29 (3.4%)
Parotitis	0/19 (0%)		1/29 (3.4%)
Metabolism and nutrition disorders
Low Potassium	4/19 (21.1%)		2/29 (6.9%)
Hyperglycemia	0/19 (0%)		2/29 (6.9%)
Nervous system disorders
Neuropathy	16/19 (84.2%)		22/29 (75.9%)
Pain	12/19 (63.2%)		1/29 (3.4%)
Respiratory, thoracic and mediastinal disorders
Hypoxia	0/19 (0%)		1/29 (3.4%)
Skin and subcutaneous tissue disorders
Rash	4/19 (21.1%)		0/29 (0%)

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.