Phase I/II study of bortezomib (VELCADE) plus rituximab-hyperCVAD alternating with bortezomib plus rituximab-high dose methotrexate/cytarabine in patients with untreated aggressive mantle cell lymphoma
The goal of this clinical research study is to learn if bortezomib (in combination with rituximab plus 2 different intensive chemotherapy regimens) can help to control the disease in patients with mantle cell lymphoma. The safety of these drug combinations will also be studied.
Disease Group: Lymphoma
Treatment Agent: Bortezomib
Treatment Location: Independent Multicenter Arrangements
Estimatated Length of Stay in Houston: Four days every 6 weeks. Occasionally additional 5 days every 3 weeks.
Return Visit: The study patients who start therapy at MDACC will remain in Houston to receive all of their therapy.
Home Care: N/A
Phase I: The primary objective of this study is to: · Determine the safety and the maximum tolerated dose (MTD) of bortezomib when added to the combination of rituximab, methotrexate, and cytarabine alternating with bortezomib, rituximab-hyperCVAD in patients with untreated aggressive mantle cell lymphoma. The secondary objectives of this study are to: · Evaluate overall response rate, complete remission rate, overall survival, and duration of remission. Phase II: The primary objective of this phase of the study is to: Evaluate the time to failure (TTF) rate following therapy with bortezomib plus rituximab-hyperCVAD alternating with bortezomib plus rituximab-high dose methotrexate/cytarabine in patients between 18 and 79 years of age with untreated aggressive mantle cell lymphoma. The secondary objective of this phase of the study is to: · Evaluate overall response rate, overall survival, and duration of remission. · Evaluate toxicity of the combination regimen. · Correlate outcome with pretreatment markers.
IRB Review and Approval Date: 11/16/2006
Recruitment Status: Closed
Projected Accrual: 110
1) Confirmed diagnosis of previously untreated nodular or diffuse mantle
cell lymphoma and their blastoid cytologic variant.
2) ECOG Performance status of 0, 1, or 2.
3) Serum bilirubin <1.5mg/dl and serum creatinine < 2.0 mg/dl within 14 dyas before enrollment (unless higher levels are due to lymphoma)
4) Platelet count>100,000/mm^3 and absolute neutrophil count (ANC)>1,000/mm^3 within 14 days before enrollment (unless due to lymphoma).
5) Cardiac ejection fraction >/= 50% by ECHO or MUGA.
6) Age 18 years to 79 years.
7) Patients must be willing to receive transfusions of blood products.
8) Voluntary written IRB-approved informed consent 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.
9) Female subject is either post-menopausal for at least 1 year before the Screening visit or surgically sterilized or if they are of childbearing potential, agree to practice 2 effective methods of birth control, at the same time (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) from the time of signing the informed consent through 30 days after the last dose of study treatment, or agree to completely abstain from heterosexual intercourse.
10) Male subject, even if surgically sterilized (ie, status post vasectomy) agrees to practice effective barrier contraception during the entire study treatment period and through 30 days after the last dose of study treatment, or agree to completely abstain from heterosexual intercourse.
1) HIV infection.
2) CNS involvement.
3) Co-morbid medical or psychiatric illnesses that preclude treatment with intense dose chemotherapy.
4) Concurrent or previous malignancy with < 90% probability of survival at 5 years.
5) Patient has >/= Grade 2 peripheral neuropathy within 14 days before enrollment.
6) 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.
7) Patient has hypersensitivity to bortezomib, boron or mannitol.
8) Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum B-human chorionic gonadotropin (B-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women.
9) Participating in clinical trials with other investigational agents not included in this trial within 14 days of the start of this trial and throughout the duration of this trial.
10) Radiation therapy within 3 weeks before randomization. Enrollment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy.