Clinical trial NCT02213913: Lenalidomide and Combination Chemotherapy (DA-EPOCH-R) in Treating Patients With MYC-Associated B-Cell Lymphomas
Official title: Prospective, Multi-center Phase I/II Trial of Lenalidomide and Dose-Adjusted EPOCH-R in MYC-Associated B-Cell Lymphomas
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Adult Grade III Lymphomatoid Granulomatosis
B-cell Chronic Lymphocytic Leukemia
Contiguous Stage II Adult Diffuse Large Cell Lymphoma
Contiguous Stage II Adult Diffuse Mixed Cell Lymphoma
Contiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma
Contiguous Stage II Adult Immunoblastic Large Cell Lymphoma
Contiguous Stage II Grade 1 Follicular Lymphoma
Contiguous Stage II Grade 2 Follicular Lymphoma
Contiguous Stage II Grade 3 Follicular Lymphoma
Contiguous Stage II Mantle Cell Lymphoma
Contiguous Stage II Marginal Zone Lymphoma
Contiguous Stage II Small Lymphocytic Lymphoma
Cutaneous B-cell Non-Hodgkin Lymphoma
Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
Intraocular Lymphoma
Nodal Marginal Zone B-cell Lymphoma
Noncontiguous Stage II Adult Diffuse Large Cell Lymphoma
Noncontiguous Stage II Adult Diffuse Mixed Cell Lymphoma
Noncontiguous Stage II Adult Diffuse Small Cleaved Cell Lymphoma
Noncontiguous Stage II Adult Immunoblastic Large Cell Lymphoma
Noncontiguous Stage II Grade 1 Follicular Lymphoma
Noncontiguous Stage II Grade 2 Follicular Lymphoma
Noncontiguous Stage II Grade 3 Follicular Lymphoma
Noncontiguous Stage II Mantle Cell Lymphoma
Noncontiguous Stage II Marginal Zone Lymphoma
Noncontiguous Stage II Small Lymphocytic Lymphoma
Progressive Hairy Cell Leukemia, Initial Treatment
Small Intestine Lymphoma
Splenic Marginal Zone Lymphoma
Stage 0 Chronic Lymphocytic Leukemia
Stage I Adult Diffuse Large Cell Lymphoma
Stage I Adult Diffuse Mixed Cell Lymphoma
Stage I Adult Diffuse Small Cleaved Cell Lymphoma
Stage I Adult Hodgkin Lymphoma
Stage I Adult Immunoblastic Large Cell Lymphoma
Stage I Chronic Lymphocytic Leukemia
Stage I Grade 1 Follicular Lymphoma
Stage I Grade 2 Follicular Lymphoma
Stage I Grade 3 Follicular Lymphoma
Stage I Mantle Cell Lymphoma
Stage I Marginal Zone Lymphoma
Stage I Small Lymphocytic Lymphoma
Stage II Adult Hodgkin Lymphoma
Stage II Chronic Lymphocytic Leukemia
Stage II Small Lymphocytic Lymphoma
Stage III Adult Diffuse Large Cell Lymphoma
Stage III Adult Diffuse Mixed Cell Lymphoma
Stage III Adult Diffuse Small Cleaved Cell Lymphoma
Stage III Adult Hodgkin Lymphoma
Stage III Adult Immunoblastic Large Cell Lymphoma
Stage III Chronic Lymphocytic Leukemia
Stage III Grade 1 Follicular Lymphoma
Stage III Grade 2 Follicular Lymphoma
Stage III Grade 3 Follicular Lymphoma
Stage III Mantle Cell Lymphoma
Stage III Marginal Zone Lymphoma
Stage III Small Lymphocytic Lymphoma
Stage IV Adult Diffuse Large Cell Lymphoma
Stage IV Adult Diffuse Mixed Cell Lymphoma
Stage IV Adult Diffuse Small Cleaved Cell Lymphoma
Stage IV Adult Hodgkin Lymphoma
Stage IV Adult Immunoblastic Large Cell Lymphoma
Stage IV Chronic Lymphocytic Leukemia
Stage IV Grade 1 Follicular Lymphoma
Stage IV Grade 2 Follicular Lymphoma
Stage IV Grade 3 Follicular Lymphoma
Stage IV Mantle Cell Lymphoma
Stage IV Marginal Zone Lymphoma
Stage IV Small Lymphocytic Lymphoma
Testicular Lymphoma
Untreated Hairy Cell Leukemia
Waldenström Macroglobulinemia
Lead sponsor: University of Chicago
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2014-08-12
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase I/II trial studies the side effects and best dose of lenalidomide when given together with combination chemotherapy and to see how well they work in treating patients with v-myc myelocytomatosis viral oncogene homolog (avian) (MYC)-associated B-cell lymphomas. Lenalidomide may stop the growth of B-cell lymphomas by blocking the growth of new blood vessels necessary for cancer growth and by blocking some of the enzymes needed for cell growth. Biological therapies, such as lenalidomide, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Drugs used in chemotherapy, such as etoposide, prednisone, vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as rituximab, may block cancer growth in different ways by targeting certain cells. Giving lenalidomide together with combination chemotherapy may be an effective treatment in patients with B-cell lymphoma.

Detailed description: PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of lenalidomide when added to dose-adjusted (DA)-etoposide, prednisone, vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, rituximab (EPOCH-R) (hereby termed "DA-EPOCH-RR") in patients with double hit lymphoma (DHL) lymphomas. (Phase I) II. To determine the 1- and 2-year progression free survival (PFS) of DA-EPOCH-RR in patients with DHL lymphomas. (Phase II)

SECONDARY OBJECTIVES:

I. Overall response rate, complete response, and duration of response. II. Quality of life (QOL) measures using standardized scales. III. Toxicity assessment using version 4.0 of the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) criteria.

IV. Overall survival (OS) at 1 and 2 years.

OUTLINE: This is a phase I, dose-escalation study of lenalidomide followed by a phase II study.

INDUCTION PHASE: Patients receive lenalidomide orally (PO) daily on days 1-14. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

DA-EPOCH-R: Patients receive etoposide intravenously (IV) continuously on days 1-4, prednisone PO twice daily (BID) on days 1-5, vincristine sulfate IV continuously on days 1-4, doxorubicin hydrochloride IV continuously on days 1-4, cyclophosphamide IV over 15 minutes on day 5, and rituximab IV over 4 hours on day 1 (per institutional guidelines). Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION PHASE: Patients who are transplantation (hematopoietic stem cell transplant \[HSCT\])-eligible receive BCNU, etoposide, cytarabine, and melphalan (BEAM)-conditioning regimen followed by autologous (auto)-HSCT or HSCT at the discretion of the treating physician. Patients who do not undergo HSCT in first remission receive lenalidomide maintenance for 12 months.

After completion of study treatment, patients are followed up for every 3 months for 1 year, every 4 months for 1 year, and then periodically for 1 year.

Eligibility criteria: Inclusion Criteria

1. B-cell lymphoma with comprehensive immunohistochemistry (IHC) panel establishing lineage (CD20, CD3) and cell of origin (CD10, BCL6 and MUM1) in addition to proliferative/prognostic markers (Ki-67, C-myc and BCL2). DHL will be identified using cytogenetics and/or immunohistochemistry as detailed in section 4.1.2 below.
2. To define DHL, patients must have evidence of C-myc \[defined as: Cytogenetic evidence (FISH or karyotype) of C-myc breaks (Increased copy number in itself is not considered positivity for C-myc) OR Positive IHC defined as \>40% of the lymphoma cells staining for C-myc\] PLUS either:

   1. Breaks in BCL-2 via cytogenetic studies or
   2. BCL-2 immunopositivity in \>70% of lymphoma cells.
3. Patients are allowed to have received radiotherapy before enrollment if radiation was given to alleviate pain and/or neurologic compromise as long as there remains areas of measurable disease present. Further, at the investigator's discretion and for patients who are unstable, one cycle of R-CHOP is allowed prior to enrollment but no more than one cycle. For purposes of this trial, prednisone or other corticosteroids used for non-lymphomatous conditions will be allowed. In addition, a prior/recent short course (\< 2 weeks) of steroids for symptom relief of lymphoma-related symptoms will be allowed.
4. AST and ALT \< 3 x upper limit of normal (ULN), and total bilirubin \<1.5 x ULN (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver involvement with NHL or stable chronic liver disease per investigator assessment).
5. Patients must have adequate renal function by virtue of GFR \> 50 ml/minute using Cockroft-Gault formula.
6. Patients must have adequate bone marrow function (platelets \>100,000 and ANC \>1,200). Patients with bone marrow involvement are allowed at the investigator's discretion regardless of cytopenias.
7. ECOG PS 0-2.
8. Age ≥ 18 years.
9. All study participants must be registered into the mandatory lenalidomide REMS® program, and be willing and able to comply with the requirements of the REMS® program.
10. Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the lenalidomide REMS® program. (Please see study schema for further details)
11. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin).
12. Ability to read, understand, and sign a written informed consent approved by each institutional IRB. Alternatively, patients with legal guardians who can read, understand, and sign written informed consent may also enroll.

Exclusion Criteria

1. Prior therapy for lymphoma
2. Known CNS involvement
3. Known HIV positive status
4. Pregnant females
5. Burkitt and/or precursor lymphoblastic leukemia/lymphoma.
6. Prior pomalidomide exposure
7. Known hypersensitivity to lenalidomide or thalidomide
8. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.
9. Subjects who have currently active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver involvement with NHL or stable chronic liver disease per investigator assessment).
10. Treatment with any known non-marketed drug substance or experimental therapy within 4 weeks prior to enrollment, or currently participating in any other interventional clinical study for NHL or any other illness (except observational, prevention, and/or registry trials).
11. No current malignancy. Subjects who have been free of malignancy for at least 2 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma (any site) are eligible. Women with a history of cervical cancers are allowed.
12. Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis and active Hepatitis C.
13. History of significant cerebrovascular disease in the past 3 months or ongoing event with active symptoms or sequelae.
14. Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB DNA test will be performed and if positive, the subject will be excluded if unable to tolerate and/or receive anti-Hepatitis-B therapy. Positive serology because of prior vaccination is allowed.
15. Positive serology for hepatitis C (HC) defined as a positive test for HCAb.
16. Inability to comply with study or follow-up testing and procedures.

Primary outcomes:
measure: PFS
timeFrame: Time elapsed between treatment initiation and tumor progression or death from any cause (whichever occurs first), assessed up to 3 years
measure: MTD of adding lenalidomide to the DA-EPOCH-R regimen as a front-line therapy in patients with DHL lymphomas (using CTCAE v 4.0) (Phase I)
timeFrame: Up to 21 days
measure: PFS (Phase II)
timeFrame: Time elapsed between treatment initiation and tumor progression or death from any cause (whichever occurs first), assessed at 1 year
measure: PFS (Phase II)
timeFrame: Time elapsed between treatment initiation and tumor progression or death from any cause (whichever occurs first), assessed at 2 years
Secondary outcomes:
measure: Add lenalidomide to the DA-EPOCH-R regimen as a front-line therapy in patients with DHL lymphomas (Phase I)
timeFrame: Up to 18 weeks
measure: Overall response rate defined as the sum of partial response (PR) and complete response (CR) by computed tomography (CT) of positron emission tomography/CT and/or resolution of marrow-only involvement (if originally involved) (Phase I)
timeFrame: Up to 18 weeks
measure: Anti-tumor activity, calculated as the sum of stable disease, PR, and CR according to the Revised Response Criteria for Malignant Lymphoma and Cheson et al (Phase I)
timeFrame: Up to 18 weeks
measure: Duration of response, calculated as the duration from detecting any objective response until progression or death from any cause, according to the Revised Response Criteria for Malignant Lymphoma and Cheson et al (Phase I)
timeFrame: Time elapsed between initial documented PR or CR and first progression event, assessed up to 18 weeks
measure: Incidence of adverse events, defined as the occurrence of all grades of toxicity (using CTCAE version 4.0)
timeFrame: Up to 21 days from last treatment
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital Cancer Care Institute
state: Illinois
city: Evanston
country: United States
facility: NorthShore University HealthSystem
state: Illinois
city: Peoria
country: United States
facility: Illinois Cancer Care
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
Study officials:
affiliation: University of Chicago
name: Sonali Smith
role: PRINCIPAL_INVESTIGATOR
References: