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Combination of Bortezomib, Fludarabine and Cyclophosphamide Treat Recurrent Mantle Cell Lymphoma

The recruitment status of this study is unknown because the information has not been verified recently.
Verified March 2011 by Sun Yat-sen University.
Recruitment status was  Recruiting
Sponsor:
Collaborators:
Fudan University
Zhejiang University
West China Hospital
Rui Jin Hospital
Tianjin Medical University Cancer Institute and Hospital
Beijing Cancer Hospital
Jiangsu Cancer Institute & Hospital
Information provided by:
Sun Yat-sen University
ClinicalTrials.gov Identifier:
NCT01322776
First received: March 24, 2011
Last updated: NA
Last verified: March 2011
History: No changes posted
  Purpose

This is a multi-center, single arm, open-label, prospective IIS study, which will enroll 40 recurrent MCL patients.The aim is to evaluate the efficacy and safety of bortezomib, fludarabine and cyclophosphamide treatment and also analyze the relationship between NF-kB activity and efficacy of bortezomib treatment and whether NF-kB activity can predict MCL progression.


Condition Intervention Phase
Mantle Cell Lymphoma Recurrent
Drug: Combination of Bortezomib, Fludarabine and Cyclophosphamide
Phase 1
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase 1 and 2 Study of Combination Treatment of Bortezomib, Fludarabine and Cyclophosphamide in Patients With Recurrent Mantle Cell Lymphoma

Resource links provided by NLM:


Further study details as provided by Sun Yat-sen University:

Primary Outcome Measures:
  • Clinical efficacy will be assessed according to the CT scan and bone marrow aspirate and biopsy [ Time Frame: 2cycle,28-day/cycle ] [ Designated as safety issue: Yes ]
    The International Working Group (IWG) published the guidelines for response criteria for lymphoma in 1999. These response criteria are based on the reduction in the size of the enlarged lymph node as measured by CT scan and the extent of bone marrow involvement that is determined by bone marrow aspirate and biopsy.


Secondary Outcome Measures:
  • Maximum Tolerated Dose(MTD)of Cyclophosphamide [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    Maximum tolerated dose (MTD) of cyclophosphamide will be determined in accordance with the standard "3+3" method, testing three dose levels, 150mg/m^2, 200mg/m^2 and 250mg/m^2. Cyclophosphamide dose escalation test will be conducted in the first cycle, with every three patients in a group. Patients' enrollment will be competed among different sites, but futher step should be taken only after the 3 patients in one group complete the first cycle, their efficacy and safety have been completely evaluated, and the notification of going to next step by a CRO company.


Estimated Enrollment: 40
Study Start Date: March 2011
Estimated Study Completion Date: October 2013
Estimated Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Bortezomib,Fludarabine,Cyclophosphamide Drug: Combination of Bortezomib, Fludarabine and Cyclophosphamide
bortezomib 1.3mg/m^2 i.v. on days 1, 4, 8 and 11 of each 28-day cycle fludarabine 25mg/m^2 i.v. on days 1~3 of each 28-day cycle cyclophosphamide i.v. on days 1~2 of each 28-day cycle

Detailed Description:

This is a multi-center, single arm, open-label, prospective IIS study, which will enroll 40 recurrent MCL patients.The aim is to evaluate the efficacy and safety of bortezomib, fludarabine and cyclophosphamide treatment and also analyze the relationship between NF-kB activity and efficacy of bortezomib treatment and whether NF-kB activity can predict MCL progression.

This study consists of three phases: screening/baseline phase, treatment phase and follow-up phase after the end of treatment.

At screening/baseline phase, investigators obtain informed consent form, check the inclusion/exclusion criteria and then collect the following data: demographics, medical history data, vital signs, ECG, MRI/CT/B-ultrasound/X-ray examinations, physical examination, laboratory examinations, pregnancy test (only female) and bone marrow biopsy and aspiration. Pathological diagnosis of mantle cell lymphoma should be established by lymph node biopsy or other tumor histopathological examination and immunophenotyping. At the same time, ECOG-performance status, Fact/GOG-Ntx questionnaire and NF-κB activity will be assessed.

During treatment period, patients will be treated with bortezomib, fludarabine and cyclophosphamide in a 28-day cycle. Patients achieve complete response (CR) or partial response (PR) can receive up to six cycles of VF (C) treatment, while those continue stable disease (SD) will be stopped after 4-cycle treatment and those with progressive disease (PD) will also be stopped after 2-cycle treatment. Due to adverse events, patients may receive reductions or deviate from the intended dose and duration of VF (C) treatment. These adjustments must be in accordance with the regulations in the protocol about the dose and time adjustment.

Maximum tolerated dose (MTD) of cyclophosphamide will be determined in accordance with the standard "3+3" method, testing three dose levels, 150mg/m2, 200mg/m2 and 250mg/m2. Cyclophosphamide dose escalation test will be conducted in the first cycle, with every three patients in a group. Patients' enrollment will be competed among different sites, but further step should be taken only after the 3 patients in one group complete the first cycle, their efficacy and safety have been completely evaluated, and the notification of going to next step by a CRO company. Subjects involved in the cyclophosphamide dose escalation test will continue initial cyclophosphamide dose during the entire study, except for possible dose adjustment determined by investigators due to DLT. After ascertaining MTD, new patients will be administrated with cyclophosphamide at the MTD. According to the dose escalation diagram, up to 18 patients will be involved in dose escalation phase. Subjects who discontinue the treatment due to causes other than DLT in the first cycle should be replaced by new participants to enter dose escalation test. DLT is defined as: a grade 4 neutropenia lasting longer than 7 days, a grade 4 thrombocytopenia, a neutropenic fever, or a grade 3 or above non-hematological toxicity (except for nausea, vomiting and alopecia); a grade 3 or above nausea, vomiting or diarrhea is considered as DLT only if still observed after treatment. Please refer to dose escalation diagram to conduct dose escalation trial.

Subjects will be followed up for 24 weeks after the end of chemotherapy. In this study, the primary efficacy endpoints are maximum tolerated dose (MTD) of cyclophosphamide in combination treatment with bortezomib and fludarabine, complete response rate (CR + CRu), overall response rate (ORR). Main indicators will be evaluated every 2 cycles in the treatment period and every 12 weeks in follow-up period.

Concomitant medications within 2 week before enrollment and during the study process need to be documented. All adverse events will be reported from the time a signed and dated informed consent form is obtained until 30 days following the last dose of study drug.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female patients 18 years or older;
  • Histologically confirmed MCL (Initial diagnosis in hospitals other than sites must be reconfirmed;
  • Recurrent patients after first-line or second-line chemotherapy;
  • At least including the following characteristic immunophenotype confirmed by immunohistochemistry: CD 20+, CD5+ and cyclin D1+;
  • At least 1 measurable site of tumor(long diameter > 2.0 cm by physical examination or > 1.5cm on CT;
  • No involvement of central nervous system;
  • ECOG performance status ≤ 2,life expectancy>6 months;
  • Within 14 days before enrollment,WBC > 3×10^9/L,neutrophils > 1.5×10^9/L,platelets > 75×10^9/L;
  • ALT ≤ 2 × upper limit of normal (ULN),AST ≤ 2×ULN,total bilirubin ≤ 2×ULN,serum creatinine ≤ 1.5×ULN,calculated creatinine clearance > 50ml/min;
  • Female patients must be post menopausal, surgically sterile, or practicing an effective method of birth control;
  • Male patients must agree to use an acceptable method of contraception for the duration of the study;
  • All patients must have signed an informed consent document indicating that they understand the purpose and procedures required for the study and are willing to participate in the study.

Exclusion Criteria:

  • Peripheral neuropathy or neuropathic pain of grade 2 or worse according to CTC AE 3.0;
  • Prior treatment with bortezomib;
  • Diagnosed as a malignancy other than MCL(Patients with completely resected basal cell carcinoma, squamous cell carcinoma of the skin, or in situ malignancy are not excluded;
  • Any experimental or anti-cancer therapy within 4 weeks before the first dose of study drug (including rituximab, alemtuzumab or unconjugated therapeutic antibodies, radiation therapy, etc.);
  • Fludarabine resistance or intolerance,exposure to fludarabine within 6 months before screening;History of allergic reaction to compounds containing boron, mannitol, fludarabine or cyclophosphamide;
  • Patients with known diagnosis of active systemic infection, HIV or active hepatitis B (carriers of hepatitis B are permitted to enter study);
  • Serious medical (e.g., cardiac failure [New York Heart Association: NYHA Class III or IV, or left ventricular ejection fraction: LVEF < 50%], active peptic ulceration, or uncontrolled diabetes mellitus) or psychiatric illness likely to interfere with participation in this clinical study;
  • Pregnancy or lactation;
  • Female or male patients of child-bearing potential who will not use adequate contraception during the course of the study;
  • Other condition likely to interfere with participation in this clinical study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01322776

Contacts
Contact: Huiqiang Huang huanghq@sysucc.org.cn

Locations
China, Guang Dong
SunYat-sen University Cancer Centre Recruiting
Guang Zhou, Guang Dong, China
Contact: Huiqiang Huang       huanghq@sysucc.org.cn   
Principal Investigator: Huiqiang Huang         
Sub-Investigator: Xiaoxiao Wang         
Sponsors and Collaborators
Sun Yat-sen University
Fudan University
Zhejiang University
West China Hospital
Rui Jin Hospital
Tianjin Medical University Cancer Institute and Hospital
Beijing Cancer Hospital
Jiangsu Cancer Institute & Hospital
  More Information

No publications provided

Responsible Party: Huiqiang Huang, Sun Yat-sen University Cancer Centre
ClinicalTrials.gov Identifier: NCT01322776     History of Changes
Other Study ID Numbers: Vel-FC-4003
Study First Received: March 24, 2011
Last Updated: March 24, 2011
Health Authority: China: Food and Drug Administration

Keywords provided by Sun Yat-sen University:
Mantle Cell Lymphoma
Recurrent
Bortezomib
Combination Treatment

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Mantle-Cell
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoma, Non-Hodgkin
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Bortezomib
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Vidarabine
Alkylating Agents
Anti-Infective Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Antiviral Agents
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 27, 2014