E1412: Randomized Phase II Open Label Study of Lenalidomide R-CHOP (R2CHOP) vs RCHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone) in Patients with Newly Diagnosed Diffuse Large B Cell Lymphoma

Study ID
STU 102013-031

Study Sites

  • UT Southwestern Ambulatory Services

Contact
James Pond
214/648-7030
BLAKE.POND@UTSouthwestern.edu

Principal Investigator
Robert Collins

Summary

This study is a multicenter randomized phase 2 study of lenalidomide and RCHoP (R2CHoP) vs. RCHoP in patients with newly diagnosed DLBCL to evaluate the efficacy of this combination.

arm a:experimental arm
R2CHoP repeated every 3 weeks (+/- 3days) for total of 6 cycles
[?] Lenalidomide
[?] Rituximab
[?] Cyclophosphamide
[?] Doxorubicin
[?] Vincristine
[?] Prednisone

arm B:Control arm
RCHoP repeated every 3 weeks (+/- 3days) for total of 6 cycles
[?] Rituximab
[?] Cyclophosphamide
[?] Doxorubicin
[?] Vincristine
[?] Prednisone

Participant Eligibility

(1) Age >= 18 years. DLBCL is rare in children and the R2CHOP regimen
has not been tested in that group.
(2) Histologically confirmed DLBCL expressing CD20 antigen (J Clin
Oncol 17(4):1244-53, 1999). Patients with transform lymphoma are
excluded. In this regard, patients with composite lymphoma in the
diagnostic tissue (concomitant DLBCL and follicular or other low-
grade lymphoma component) are excluded. However, patients with
DLBCL in primary diagnostic tissue but a bone marrow that shows low
grade or indeterminate lymphoma are eligible. Patients with known
primary mediastinal large B-cell lymphoma (PMLBCL) are
excluded because contemporary data suggest patients with this
entity may be best served with the dose adjusted EPOCH-R regimen
or with R-CHOP followed by consolidative XRT. Similarly, patients
with known c-myc translocation (by fluorescence in situ hybridization)
positive DLBCL are encouraged to participate trials specifically design
for these patients, since contemporary data suggest patients with this
entity may be best served more intensive chemotherapy, however
patients with known c-myc positive are NOT excluded from this study.
C-myc testing prior to study enrollment is NOT required.
(3) Stages II bulky disease (defined as mass size of more than 10 cm),
stage III, or IV (Ann Arbor Staging). Patients with stage I and stage II
non-bulky disease frequently are treated with abbreviated
chemoimmunotherapy followed by involved field radiation and may be
eligible for other protocols and are thus excluded from this study.
(4) A tumor tissue specimen from the initial diagnostic biopsy has been
located and ready to ship to the ECOG-ACRIN Central Biorepository
and Pathology Facility within 30 days following registration.
Patients must have paraffin-embedded tumor specimen available for
central pathology review and defined laboratory research studies.
Archived formalin fixed paraffin embedded (FFPE) tumor tissue block
is required. If the block is unavailable for submission, please submit
the below alternative requirements:

* One (1) H&E slide, and

* Twenty (20) 4 [MICRO-SYMBOL]m unstained air-dried plus slides, and

* One (1) or more core punches (minimum of 4mm diameter)
(5) IPI of 2 or greater
(6) ECOG performance status 0-2
(7) Patients must have measurable disease (at least 1 lesion of >= 1.5 cm in one diameter) as detected by CT or the CT images of the PET/CT
(8) Previously untreated and not receiving any other agent that would be considered as a treatment for the lymphoma
(9) No known CNS lymphoma or cerebrospinal fluid involvement with
malignant lymphoma cells. These patients are usually treated with
CNS directed therapy. Screening for CSF/CNS involvement is NOT
required but can be performed per treating MD discretion. IT
methotrexate or IT cytarabine prophylaxis in patients with negative
CSF who are felt to be at high risk of CNS relapse is allowed per local
MD discretion. This should be noted on the treatment form.
(10) Adequate organ function
-ANC >= 1500;
-PLT >= 100,000;
-Total bilirubin <= 1.5 x upper limit of normal (ULN) or if total
bilirubin is >1.5 x ULN, the direct bilirubin must be normal;
-Alk. phosphatase <= 3 x ULN unless evidence of the direct liver
involvement by lymphoma x then <= 5xULN;
-AST <= 3 x ULN unless evidence of the direct liver involvement
by lymphoma x then <= 5xULN
Creatinine <= 2 x ULN or CrCl > 30 ml/min.
(11) Ejection fraction of >=45% by either MUGA or ECHO.
(12) Absence of co-morbid systemic illnesses or other severe concurrent
disease which, in the judgment of the investigator, would make the
patient inappropriate for entry into this study or interfere significantly
with the proper assessment of safety and toxicity of the prescribed
regimens, including, but not limited to, ongoing or active infection,
symptomatic congestive heart failure, unstable angina pectoris,
cardiac arrhythmia, or psychiatric illness/social situations that would
limit compliance with study requirements.
(13) Absence of history of myocardial infarction <= 6 months, or congestive
heart failure requiring use of ongoing maintenance therapy for life-
threatening ventricular arrhythmias.
(14) Absence of history of deep venous thrombosis/embolism, threatening
thromboembolism or known thrombophilia. Patients with a history of
DVT/PE or thrombophilia may still participate if they are willing to be
on full anticoagulation during the treatment if randomized to
R2CHOP arm A. Full anticoagulation is defined as Warfarin, factor X
inhibitors, or low molecular weight heparin at therapeutic doses. The
rationale for this requirement is that Lenalidomide therapy is
associated with an increased risk of thrombosis.
(15) Patient must be able and willing to receive anticoagulation therapy
with aspirin 70-325 mg daily prophylaxis, low molecular weight
heparin, factor X inhibitors or Warfarin. This is due to an increased
risk of thrombosis in patients treated with lenalidomide without
prophylaxis. Patients unable or unwilling to take any prophylaxis are
NOT eligible.
(16) Absence of history of AIDS-related conditions (other than the
presenting DLBCL) or posttransplant lymphoproliferative disorder
(PTLD) in immunocompromised patients. Patients with HIV on
antiretroviral therapy other than AZT and/or stavudine and without
prior AIDS defining conditions and adequate CD4 count (>400) are
eligible. The safety of lenalidomide-RCHOP (R2CHOP) in patients
with HIV infection and advanced immunosuppression and in patients
with organ transplants requiring immunosuppression has not been
established.
(17) No other active malignancy requiring therapy such as radiation,
chemotherapy, or immunotherapy. Exceptions to this are as follows:
localized nonmelanotic skin cancer and any cancer that in the
judgment of the investigator has been treated with curative intent and
will not interfere with the study treatment plan and response
assessment.
(18) No history of radiation therapy to >= 25% of the bone marrow for other
diseases or history of anthracycline therapy.
(19) Patients must not be receiving erythroid stimulating agents (EPO:
Procrit, Aranesp).
(20) Patient must be willing to provide informed written consent and to
return to enrolling institution for follow-up.
(21) Women must not be pregnant or breast-feeding because this study
involves an investigational agent whose genotoxic, mutagenic
and teratogenic effects on the developing fetus and newborn are
unknown.
(22) Females of childbearing potential (FCBP) must have a negative
serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL
within 10 x 14 days prior to and again within 24 hours of starting
lenalidomide and must either commit to continued abstinence from
heterosexual intercourse or begin TWO acceptable methods of birth
control, one highly effective method and one additional effective
method AT THE SAME TIME, at least 28 days before she starts
taking lenalidomide. FCBP must also agree to ongoing pregnancy
testing. A female of childbearing potential is any woman, regardless
of sexual orientation or whether they have undergone tubal ligation,
who meets the following criteria: 1) has not undergone a hysterectomy
or bilateral oophorectomy; or 2) has not been naturally
postmenopausal for at least 24 consecutive months (i.e., has had
menses at any time in the preceding 24 consecutive months).
Female? ______ (Yes or No)
Date of blood test or urine study: ____________________
(23) Men must agree to use a latex condom during sexual contact with a
FCBP even if they have had a successful vasectomy. All patients
must be counseled at a minimum of every 28 days about pregnancy
precautions and risks of fetal exposure.