Phase 1 and 2 Study of Combination Treatment of Bortezomib, Fludarabine and Cyclophosphamide in Patients With Recurrent Mantle Cell Lymphoma
18 Years
N/A
Both
Mantle Cell Lymphoma Recurrent
Trial Information
Phase 1 and 2 Study of Combination Treatment of Bortezomib, Fludarabine and Cyclophosphamide in Patients With Recurrent Mantle Cell Lymphoma
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.
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.
Type of Study:
Interventional
Study Design:
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Clinical efficacy will be assessed according to the CT scan and bone marrow aspirate and biopsy
Outcome Description:
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.
Outcome Time Frame:
2cycle,28-day/cycle
Safety Issue:
Yes
Authority:
China: Food and Drug Administration
Study ID:
Vel-FC-4003
NCT ID:
NCT01322776
Start Date:
March 2011
Completion Date:
October 2013
Related Keywords:
- Mantle Cell Lymphoma Recurrent
- Mantle Cell Lymphoma
- Recurrent
- Bortezomib
- Combination Treatment
- Lymphoma
- Lymphoma, Mantle-Cell
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