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Smart Start: Study of Rituximab, Lenalidomide, and Ibrutinib Combined With Chemotherapy For Patients With High Risk Diffuse Large B-Cell Lymphoma

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ClinicalTrials.gov Identifier: NCT02636322
Recruitment Status : Recruiting
First Posted : December 21, 2015
Last Update Posted : July 2, 2018
Sponsor:
Collaborators:
Celgene
Janssen Scientific Affairs, LLC
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:

The goal of this clinical research study is to learn if the combination of rituximab, lenalidomide, and ibrutinib, when given alone and with standard chemotherapy (called either "EPOCH" - Etoposide, Prednisone, Oncovin [vincristine], Cyclophosphamide, and Hydrodaunorubicin [doxorubicin]; or "R-CHOP" - Rituximab, Cyclophosphamide, Hydrodaunorubicin [doxorubicin], Oncovin [vincristine], and Prednisone), can help to control diffuse large B cell lymphoma. The safety of this drug combination will also be studied.

This is an investigational study. Ibrutinib is FDA approved and commercially available for the treatment of certain types of patients (patients with mantle cell lymphoma [MCL] or chronic lymphocytic leukemia [CLL] who have received at least 1 earlier therapy, CLL patients with certain genetic mutations, and patients with Waldenstrom's macroglobulinemia [WM]).

Lenalidomide is FDA approved and commercially available for the treatment of MCL in patients who have received 2 therapies before, multiple myeloma (MM), and myelodysplastic syndrome (MDS). Rituximab is FDA approved and commercially available for the treatment of non-Hodgkin's lymphoma and certain types of leukemia. EPOCH and R-CHOP are FDA approved and commercially available for their use on this study. The use of all these drugs in combination is investigational.

Up to 60 participants will be enrolled in this study. All will take part at MD Anderson.


Condition or disease Intervention/treatment Phase
Lymphoma Drug: Rituximab Drug: Ibrutinib Drug: Lenalidomide Drug: Etoposide Drug: Prednisone Drug: Vincristine Drug: Cyclophosphamide Drug: Doxorubicin Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Rituximab, Lenalidomide, and Ibrutinib Combined With Chemotherapy For Patients With High Risk Diffuse Large B-Cell Lymphoma
Actual Study Start Date : March 2016
Estimated Primary Completion Date : March 2023
Estimated Study Completion Date : March 2024


Arm Intervention/treatment
Experimental: Rituximab, Lenalidomide, and Ibrutinib + EPOCH or R-CHOP

The selection of R-DA-EPOCH or R-CHOP made by the treating physician.

Smart Start: Rituximab by vein on Day 1. Ibrutinib by mouth 1 time every day. Lenalidomide by mouth 1 time every day on Days 1-10 of each cycle.

At completion of Smart Start Participants on R-EPOCH: Rituximab IV on Day 1. Ibrutinib by mouth 1 time every day. Lenalidomide by mouth 1 time every day on Days 1 - 10 of each cycle. Etoposide IV on Days 1 - 4 of each cycle. Prednisone by mouth 2 times each day on Days 1 - 5 of each cycle. Vincristine IV Days 1 - 4 of each cycle. Cyclophosphamide IV Day 5 of each cycle. Doxorubicin IV on Days 1 - 4 of each cycle.

At completion of Smart Start Participants on R-CHOP: Rituximab IV on Day 1. Cyclophosphamide IV on Day 1 of each cycle. Doxorubicin IV on Day 1 of each cycle. Vincristine IV on Day 1 of each cycle. Prednisone by mouth on Days 1 - 5 of each cycle.

Drug: Rituximab

Smart Start: Rituximab 375 mg/m2 by vein once.

At completion of Smart Start Participants on R-EPOCH: Rituximab 375 mg/m2 by vein on Day 1 of a 21 day cycle for 6 cycles.

At completion of Smart Start Participants on R-CHOP: Rituximab 375 mg/m2 by vein on Day 1 of a 21 day cycle for 6 cycles.

Other Name: Rituxan

Drug: Ibrutinib

Smart Start: Ibrutinib 560 mg by mouth 1 time every day in a 21 day cycle for 2 cycles.

At completion of Smart Start Participants on R-EPOCH: Ibrutinib 560 mg by mouth 1 time every day in a 21 day cycle for 6 cycles.

Other Names:
  • PCI-32765
  • Imbruvica

Drug: Lenalidomide

Smart Start: Lenalidomide 25 mg by mouth 1 time every day on Days 1-10 of each 21 day cycle for 2 cycles.

At completion of Smart Start Participants on R-EPOCH: Lenalidomide 25 mg by mouth 1 time every day on Days 1 - 10 of each 21 day cycle for 6 cycles.

Other Names:
  • CC-5013
  • Revlimid

Drug: Etoposide
At completion of Smart Start Participants on R-EPOCH: Etoposide 50 mg/m2 by vein on Days 1 - 4 of each 21 day cycle for 6 cycles.
Other Name: VePesid

Drug: Prednisone

At completion of Smart Start Participants on R-EPOCH: Prednisone 100 mg by mouth on Days 1 - 5 of each 21 day cycle for 6 cycles.

At completion of Smart Start Participants on R-CHOP: Prednisone 100 mg by mouth on Days 1 - 5 of each 21 day cycle for 6 cycles.


Drug: Vincristine

At completion of Smart Start Participants on R-EPOCH: Vincristine 0.4 mg/m2 by vein on Days 1 - 4 of each 21 day cycle for 6 cycles.

At completion of Smart Start Participants on R-CHOP: Vincristine 1.4 mg/m2 by vein on Days 1 of each 21 day cycle for 6 cycles.

Other Name: Oncovin

Drug: Cyclophosphamide

At completion of Smart Start Participants on R-EPOCH: Cyclophosphamide 750 mg/m2 by vein on Day 5 of each 21 day cycle for 6 cycles.

At completion of Smart Start Participants on R-CHOP: Cyclophosphamide 750 mg/m2 by vein on Day 1 of each 21 day cycle for 6 cycles.

Other Names:
  • Cytoxan
  • Neosar

Drug: Doxorubicin

At completion of Smart Start Participants on R-EPOCH: Doxorubicin 10 mg/m2 by vein on Days 1 - 4 of each 21 day cycle for 6 cycles.

At completion of Smart Start Participants on R-CHOP: Doxorubicin 50mg/m2 by vein on Day 1 of each 21 day cycle for 6 cycles.

Other Names:
  • Hydroxydaunorubicin
  • Adriamycin PFS
  • Adriamycin RDF
  • Adriamycin
  • Rubex




Primary Outcome Measures :
  1. Overall Response Rate (ORR) of Rituximab, Lenalidomide, and Ibrutinib in Participants With High Risk Diffuse Large B-Cell Lymphoma [ Time Frame: 42 days, Following Cycle 2 ]
    ORR, complete response (CR) or partial response (PR) using Lugano criteria: CR: PET/CT Based Response: Complete metabolic response Score 1, 2, or 3 with/without residual mass on 5 point scale; or CT-Based Responses: Target nodes/nodal masses regress to <= 1.5 cm in longest dimension. No extralymphatic sites of disease. PET-CT response assessment in FDG-avid histologies, CT preferred for low/variable FDG avidity using 5-point scale. PR: decrease >50% in sum product perpendicular diameters up to 6 representative nodes or extranodal lesions. Progressive disease by CT criteria only requires increase in perpendicular diameters (PPDs) of single node by 50%, Partial Metabolic Response Score 4 or 5 with reduced uptake compared to baseline & residual masses of any size; At interim, findings suggest responding disease, as end of treatment, findings indicate residual disease. Partial Remission: >=50% decrease in sum product diameters up to 6 target measureable nodes & extranodal sites

  2. Complete Response Rate (CRR) of Rituximab, Lenalidomide, and Ibrutinib combined with CHOP or EPOCH in Participants With High Risk Diffuse Large B-Cell Lymphoma [ Time Frame: 126 days ]
    PET/CT scan using Lugano criteria for CR: PET-CT Based Response: Complete metabolic response has Score 1, 2, or 3 with/without residual mass on 5 point scale; or CT-Based Responses: Target nodes/nodal masses regress to <= 1.5 cm in longest dimension. No extralymphatic sites of disease.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histopathologically confirmed diagnosis of previously untreated DLBCL of the non-GCB DLBCL subtype.
  2. No prior treatment except a prior limited-field radiotherapy, a short course of glucocorticoids </= 25mg daily of prednisone equivalent which must cease prior to day 1 of cycle 1, and/or cyclophosphamide for an urgent lymphoma related problem at diagnosis (e.g. epidural cord compression, superior vena cava syndrome).
  3. Patient or durable power of attorney (DPA) for healthcare must be able to understand and voluntarily sign an IRB-approved informed consent form.
  4. Age >/=18 years at the time of signing the informed consent.
  5. Patients must have bi-dimensional measurable disease, as defined as radiographically apparent disease with the longest dimension of >/= 1.5cm.
  6. Patients with performance status of </=3 (3 only allowed if decline in status is deemed related to lymphoma and felt potentially reversible by the treating physician)
  7. Serum bilirubin <1.5x ULN except in patients with Gilbert's syndrome as defined by > 80% unconjugated bilirubin; AST (SGOT) and ALT (SGPT) </= 3x ULN or < 5x ULN if hepatic metastases are present; ANC >1000/mm^3 and platelets >100,000/mm^3 unless deemed related to lymphoma involvement in the bone marrow and felt potentially reversible by the treating physician.
  8. Renal function assessed by calculated creatinine clearance: a. Calculated creatinine clearance >/=30ml/min by Cockcroft-Gault formula. See section below, Dosing Regimen, regarding lenalidomide dose adjustment for calculated creatinine clearance >/=30ml/min and < 60ml/min.
  9. Patients must be willing to receive transfusions of blood products.
  10. All study participants must be registered into the mandatory Revlimid REMS® program, and be willing and able to comply with the requirements of the REMS® program.
  11. Women of childbearing potential must have a negative serum (Beta-human chorionic gonadotropin [Beta-hCG]) or urine pregnancy test at screening and must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program.
  12. Women of childbearing potential and men who are sexually active with a woman of childbearing potential must be practicing a highly effective method of birth control during and after the study (12 months for women and 3 months for men), consistent with local regulations regarding the use of birth control methods for subjects participating in this clinical study. Men must agree to not donate sperm during and for up to 3 months after their conclusion of therapy on study.
  13. Able to take aspirin (81mg) daily or alternative therapy as prophylactic anticoagulation.

Exclusion Criteria:

  1. 1. Any serious medical condition including but not limited to uncontrolled hypertension, uncontrolled congestive heart failure within past 6 months prior to screening (Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification), uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, COPD, LVEF less than 40%, renal failure, active infection, history of invasive fungal infection, moderate to severe hepatic disease (Child Pugh Class B or C), active hemorrhage, laboratory abnormality, or psychiatric illness that, in the investigators opinion places the patient at unacceptable risk and would prevent the subject from signing the informed consent form. Patients with history of cardiac arrhythmias should have cardiac evaluation and clearance.
  2. Pregnant or lactating females.
  3. Known hypersensitivity to lenalidomide or thalidomide, ibrutinib, rituximab, etoposide, vincristine, doxorubicin, cyclophosphamide, or prednisone.
  4. Known HIV infection. Patients with active hepatitis B infection (not including patients with prior hepatitis B vaccination; or positive serum Hepatitis B antibody). Known hepatitis C infection is allowed as long as there is no active disease and is cleared by GI consultation.
  5. All patients with central nervous system involvement with lymphoma.
  6. Diagnosis of prior malignancy within the past 2 years with the exception of successfully treated basal cell carcinoma, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or breast. History of other malignancies are allowed if in remission (including prostate cancer patients in remission from radiation therapy, surgery or brachytherapy), not actively being treated, with a life expectancy > 3 years.
  7. Significant neuropathy (Grades 2 or Grade 1 with pain) within 14 days prior to enrollment
  8. Contraindication to any of the required concomitant drugs or supportive treatments or intolerance to hydration due to preexisting pulmonary or cardiac impairment including pleural effusion requiring thoracentesis or ascites requiring paracentesis not due to lymphoma.
  9. Patients with active pulmonary embolism or deep vein thrombosis (diagnosed within 30 days of study enrollment).
  10. Patients with severe bradycardia (heart rate <40 bpm, hypotension, light-headedness, syncope).
  11. Major surgery within 4 weeks of study entry, or wound that is not healed from prior surgery or trauma.
  12. History of stroke or intracranial hemorrhage within 6 months prior to study entry.
  13. Requires anticoagulation with warfarin or equivalent vitamin K antagonists.
  14. Requires chronic treatment with strong CYP3A inhibitors
  15. Vaccinated with live, attenuated vaccines within 4 weeks of study entry

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02636322


Contacts
Contact: Jason R. Westin, MD 713-792-2860

Locations
United States, Texas
University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Celgene
Janssen Scientific Affairs, LLC
Investigators
Principal Investigator: Jason R. Westin, MD M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT02636322     History of Changes
Other Study ID Numbers: 2015-0147
NCI-2016-00017 ( Registry Identifier: NCI CTRP )
First Posted: December 21, 2015    Key Record Dates
Last Update Posted: July 2, 2018
Last Verified: June 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by M.D. Anderson Cancer Center:
Lymphoma
High Risk Diffuse Large B-Cell Lymphoma
DLBCL
Rituximab
Rituxan
Ibrutinib
PCI-32765
Imbruvica
Lenalidomide
CC-5013
Revlimid
Etoposide
VePesid
Prednisone
Vincristine
Oncovin
Cyclophosphamide
Cytoxan
Neosar
Doxorubicin
Hydroxydaunorubicin
Adriamycin PFS
Adriamycin RDF
Adriamycin
Rubex

Additional relevant MeSH terms:
Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Cyclophosphamide
Thalidomide
Rituximab
Liposomal doxorubicin
Lenalidomide
Etoposide phosphate
Doxorubicin
Prednisone
Etoposide
Vincristine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic