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Phase II Randomized Study With R-DHAP +/- Bortezomib as Induction Therapy in Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL) Patients Before High-Dose Chemotherapy BEAM With Autologous Stem Cell Transplantation (ASCT).


Phase 2/Phase 3
18 Years
65 Years
Open (Enrolling)
Both
Diffuse Large B-cell Lymphoma Refractory, Diffuse Large B-cell Lymphoma Recurrent

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Trial Information

Phase II Randomized Study With R-DHAP +/- Bortezomib as Induction Therapy in Relapsed/Refractory Diffuse Large B-cell Lymphoma (DLBCL) Patients Before High-Dose Chemotherapy BEAM With Autologous Stem Cell Transplantation (ASCT).


This is a prospective, multicenter, two-arm randomized phase II screening trial34 in young
patients (18-65 years) affected by relapsed/refractory Diffuse Large B-cell Lymphoma (DLBCL)
at diagnosis, eligible to high-dose therapy.

Aim of the study is to to assess whether the addition of Bortezomib to R-DHAP is more
promising than standard R-DHAP, as induction therapy before high dose chemotherapy with ASCT
with respect to response and safety. Patients will be randomized at first relapse between:
a) the standard salvage therapy Rituximab in association to DHAP every 28 days (R-DHAP) for
4 cycles and b) Bortezomib in association to the same regimen (BR-DHAP). In both arms the
induction therapy is followed by autologous stem cell transplantation or, if indicated, by
allogeneic stem cell transplant.

A patient is considered evaluable if it is possible to assess response by PET after 4 cycle
or, if a patient withdraws from the study for PD, before completion of study treatment.

After providing written informed consent, patients will be evaluated for eligibility during
a 21-day screening period. If they continue to meet eligibility criteria, they will be
randomized to receive the first dose of BR-DHAP or R-DHAP .


Inclusion Criteria:



1. Age 18-65

2. Relapsed/refractory disease after receiving one line of standard R-CHOP like
chemotherapy

3. Diffuse Large B-cell Lymphoma at relapse. Patient has to be re-biopsied prior to
study entry. If this is harmful for the patient, the patient can be enrolled if
archival tumor sample and block from first diagnosis are available.

4. No prior Bortezomib therapy

5. Measurable and/or evaluable disease

6. Any Ann Arbor stage and IPI group at relapse

7. Performance status < 2 according to ECOG scale unless due to lymphoma

8. No Central Nervous System (CNS) disease (meningeal and/or brain involvement by
lymphoma)

9. Adequate haematological counts: ANC > 1.5 x 109/L, Hgb > 10.5 g/dl (transfusion
independent), Platelet count > 75 x 109/L (transfusion independent), with the
exception of cytopenia due to lymphoma bone marrow involvement

10. HIV negativity, HCV negativity, HBV negativity or patients with HBcAb +, HBsAg -, HBs
Ab+/- with HBV-DNA negativity (in these patients Lamivudine prophylaxis is mandatory)

11. Normal liver function (ALP, AST, ALT, GGT, conjugated bilirubin total < 2 x ULN) if
not related to lymphoma

12. Normal kidney function (creatinine clearance > 45 ml/min)

13. Cardiac ejection fraction > 50% (MUGA scan or echocardiography)

14. Normal lung function

15. Absence of active opportunistic infections

16. Non peripheral neuropathy or active neurological non neoplastic disease of CNS

17. Non major surgical intervention prior 3 months to randomization if not due to
lymphoma and/or no other disease life-threatening that can compromise chemotherapy
treatment

18. Disease free of prior malignancies other than lymphoma for > 3 years with exception
of currently treated squamous cell and basal cell carcinoma of the skin or carcinoma
in situ of the cervix or breast

19. Life expectancy > 6 months

20. No psychiatric illness that precludes understanding concepts of the trial or signing
informed consent

21. Written informed consent

22. Women must be:

- postmenopausal for at least 1 year (must not have had a natural menses for at
least 12 months)

- surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal
ligation, or otherwise be incapable of pregnancy),

- abstinent (at the discretion of the investigator/per local regulations), or

- if sexually active, be practicing a highly effective method of birth control
(eg, prescription oral contraceptives, contraceptive injections, contraceptive
patch, intrauterine device, double-barrier method (eg, condoms, diaphragm, or
cervical cap, with spermicidal foam, cream, or gel, male partner sterilization)
as local regulations permit, before entry, and must agree to continue to use the
same method of contraception throughout the study. They must also be prepared to
continue birth control measures for at least 12 months after terminating
treatment.

23. Women of childbearing potential must have a negative serum or urine beta-human
chorionic gonadotropin (beta-hCG) pregnancy test at screening

24. Men must agree to use an acceptable method of contraception (for themselves or female
partners as listed above) for the duration of the study. Men must agree to use a
double barrier method of birth control and to not donate sperm during the study and
for 3 months after receiving the last dose of study drug.

Exclusion Criteria:

1. Diagnosis of Lymphoblastic Lymphoma, Burkitt Lymphoma, Non Hodgkin Lymphoma CD20
negative, Mantle Cell Lymphoma, Follicular Lymphoma g I-II-IIIa-IIIb, Primary
Mediastinal Lymphoma

2. Age > 65 years

3. Patients ineligible to high-dose chemotherapy

4. Performance status > 2 according to ECOG scale if not due to lymphoma

5. Patient has known or suspected hypersensitivity or intolerance to Rituximab

6. Patient has received an experimental drug or used an experimental medical device
within 4 weeks before the planned start of treatment. Concurrent participation in
non-treatment studies is allowed, if it will not interfere with participation in this
study.

7. CNS disease (meningeal and/or brain involvement by lymphoma)

8. History of clinically relevant liver or renal insufficiency; significant cardiac,
vascular, pulmonary, gastrointestinal, endocrine, neurologic, rheumatologic,
hematologic, psychiatric, or metabolic disturbances

9. Uncontrolled diabetes (if receiving antidiabetic agents, subjects must be on a stable
dose for at least 3 months before first dose of study drug

10. Uncontrolled or severe cardiovascular disease including myocardial infarction within
six months of enrollment, New York Heart Association (NYHA) Class III or IV heart
failure, uncontrolled angina, clinically significant pericardial disease, or cardiac
amyloidosis

11. Cardiac ejection fraction < 45% (MUGA scan or echocardiography)

12. Creatinine clearance < 45 ml/min

13. Presence of major neurological disorders

14. HIV positivity, HCV positivity, HBV positivity with the exception of patients with
HBcAb +, HbsAg -, HBs Ab+/- with HBV-DNA negative

15. Active opportunistic infection

16. Major surgical intervention prior 3 months to randomization if not due to lymphoma
and/or other disease life-threatening that can compromise chemotherapy treatment

17. Prior malignancies other than lymphoma in the last 3 years with exception of
currently treated squamous cell and basal cell carcinoma of the skin or carcinoma in
situ of the cervix or breast

18. Life expectancy < 6 months

19. Any other coexisting medical or psychological condition that would preclude
participation in the study or compromise ability to give informed consent.

20. If female, the patient is pregnant or breast-feeding.

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Complete Response (CR) Rate

Outcome Description:

Proportion of CR according to the Cheson 2007 response criteria, evaluated by PET scan

Outcome Time Frame:

At the end of the induction phase (6 months)

Safety Issue:

No

Principal Investigator

Umberto Vitolo, MD

Investigator Role:

Study Director

Investigator Affiliation:

S.C. Ematologia 2 - Azienda Ospedaliera Città della Salute e della Sienza - Presidio Molinette

Authority:

Italy: The Italian Medicines Agency

Study ID:

FIL_VERAL12

NCT ID:

NCT01805557

Start Date:

February 2013

Completion Date:

February 2018

Related Keywords:

  • Diffuse Large B-cell Lymphoma Refractory
  • Diffuse Large B-cell Lymphoma Recurrent
  • Diffuse Large B-cell Lymphoma (DLBCL)
  • Bortezomib
  • Lymphoma
  • Lymphoma, B-Cell
  • Lymphoma, Large B-Cell, Diffuse

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