Smart Start: A Phase II Study of Rituximab, Lenalidomide, and Ibrutinib
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| ClinicalTrials.gov Identifier: NCT02636322 |
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Recruitment Status :
Completed
First Posted : December 21, 2015
Results First Posted : March 13, 2024
Last Update Posted : March 13, 2024
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Diffuse Large B-Cell Lymphoma Unclassifiable | Drug: Cyclophosphamide Drug: Doxorubicin Hydrochloride Drug: Etoposide Drug: Ibrutinib Drug: Lenalidomide Drug: Prednisone Biological: Rituximab Drug: Vincristine Sulfate | Phase 2 |
PRIMARY OBJECTIVES:
I. To determine the overall response rate at the end of 2 cycles of therapy with rituximab, lenalidomide, and ibrutinib in patients with high risk newly diagnosed non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB DLBCL).
II. To determine the complete response rate at the end of 6 cycles of therapy with rituximab, lenalidomide, and ibrutinib combined with chemotherapy (cyclophosphamide, doxorubicin hydrochloride [hydroxydaunorubicin hydrochloride], vincristine sulfate [Oncovin], prednisone [CHOP] or etoposide, prednisone, vincristine sulfate [Oncovin], cyclophosphamide, doxorubicin hydrochloride [hydroxydaunorubicin hydrochloride] [EPOCH]) in patients with high risk newly diagnosed non-GCB DLBCL.
SECONDARY OBJECTIVES:
I. To determine the overall response rate, landmark survival outcomes (progression free and overall survival), and safety of lenalidomide and ibrutinib with chemotherapy (CHOP or EPOCH) in patients with high risk newly diagnosed non-GCB DLBCL.
II. To evaluate descriptively the complete response rate in rituximab, lenalidomide, ibrutinib (RLI)-CHOP and in RLI-EPOCH.
EXPLORATORY OBJECTIVES:
I. To evaluate the baseline and therapy induced changes in the profile of mutations, gene expression, minimal residual disease clonotype levels, immune cell subsets, and tumor protein expression in tumor biopsy and blood samples in patients with high risk newly diagnosed non-GCB DLBCL.
OUTLINE:
SMART START: Patients receive rituximab intravenously (IV) over 4-6 hours on day 1, lenalidomide orally (PO) once daily (QD) on days 1-10, and ibrutinib PO QD on days 1-21. Treatment repeats every 21 days for 2 cycles in the absence of disease progression or unacceptable toxicity.
RLI WITH EPOCH: After SMART START therapy, patients receive rituximab IV over 4-6 hours on day 1, lenalidomide PO QD on days 1-10, and ibrutinib PO QD on days 1-21. Patients also receive etoposide IV over 24 hours on days 1-4, prednisone PO QD on days 1-5, vincristine sulfate IV over 24 hours on days 1-4, doxorubicin hydrochloride IV over 24 hours on days 1-4, and cyclophosphamide IV over 1 hour on day 5. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.
RLI WITH R-CHOP: After SMART START therapy, patients receive rituximab IV over 4-6 hours on day 1, lenalidomide PO QD on days 1-10, and ibrutinib PO QD on days 1-21. Patients also receive prednisone PO QD on days 1-5, vincristine sulfate IV over 1 hour on day 1, doxorubicin hydrochloride IV over 1 hour on day 1, and cyclophosphamide IV over 1 hour on day 1. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for 1 year, and then every 4 months for another year.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 60 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Parallel 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 29, 2016 |
| Actual Primary Completion Date : | October 24, 2022 |
| Actual Study Completion Date : | October 24, 2022 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: RLI WITH EPOCH
SMART START: Patients receive rituximab IV over 4-6 hours on day 1, lenalidomide PO QD on days 1-10, and ibrutinib PO QD on days 1-21. Treatment repeats every 21 days for 2 cycles in the absence of disease progression or unacceptable toxicity. After SMART START therapy, patients receive rituximab IV over 4-6 hours on day 1, lenalidomide PO QD on days 1-10, and ibrutinib PO QD on days 1-21. Patients also receive etoposide IV over 24 hours on days 1-4, prednisone PO QD on days 1-5, vincristine sulfate IV over 24 hours on days 1-4, doxorubicin hydrochloride IV over 24 hours on days 1-4, and cyclophosphamide IV over 1 hour on day 5. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. |
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Drug: Etoposide Given IV
Other Names:
Drug: Ibrutinib Given PO
Other Names:
Drug: Lenalidomide Given PO
Other Names:
Drug: Prednisone Given PO
Other Names:
Biological: Rituximab Given IV
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
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Experimental: RLI WITH R-CHOP
SMART START: Patients receive rituximab IV over 4-6 hours on day 1, lenalidomide PO QD on days 1-10, and ibrutinib PO QD on days 1-21. Treatment repeats every 21 days for 2 cycles in the absence of disease progression or unacceptable toxicity. After SMART START therapy, patients receive rituximab IV over 4-6 hours on day 1, lenalidomide PO QD on days 1-10, and ibrutinib PO QD on days 1-21. Patients also receive prednisone PO QD on days 1-5, vincristine sulfate IV over 1 hour on day 1, doxorubicin hydrochloride IV over 1 hour on day 1, and cyclophosphamide IV over 1 hour on day 1. Treatment repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. |
Drug: Cyclophosphamide
Given IV
Other Names:
Drug: Doxorubicin Hydrochloride Given IV
Other Names:
Drug: Ibrutinib Given PO
Other Names:
Drug: Lenalidomide Given PO
Other Names:
Drug: Prednisone Given PO
Other Names:
Biological: Rituximab Given IV
Other Names:
Drug: Vincristine Sulfate Given IV
Other Names:
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- Overall Response Rate [ Time Frame: Up to 42 days ]After two cycles of RLI
- Overall Response Rate [ Time Frame: up to 84 days ]After two cycles of RLI plus two cycles of RLI-chemotherapy
- Progression Free Survival at 2 Years [ Time Frame: 2 years ]
- Overall Survival for 2 Years [ Time Frame: 2 years ]
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Histopathologically confirmed diagnosis of previously untreated DLBCL of the non-GCB DLBCL subtype
- No prior treatment except a prior limited-field radiotherapy, a short course of glucocorticoids =< 25 mg 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)
- Patient or durable power of attorney (DPA) for healthcare must be able to understand and voluntarily sign an Institutional Review Board (IRB) -approved informed consent form
- Patients must have bi-dimensional measurable disease, as defined as radiographically apparent disease with the longest dimension of >= 1.5 cm
- 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)
- Serum bilirubin < 1.5 x upper limit of normal (ULN) except in patients with Gilbert's syndrome as defined by > 80% unconjugated bilirubin
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN or < 5 x ULN if hepatic metastases are present
- Absolute neutrophil count (ANC) > 1000/mm^3 unless deemed related to lymphoma involvement in the bone marrow and felt potentially reversible by the treating physician
- Platelets > 100,000/mm^3 unless deemed related to lymphoma involvement in the bone marrow and felt potentially reversible by the treating physician
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Renal function assessed by calculated creatinine clearance:
- Calculated creatinine clearance >=30 ml/min by Cockcroft-Gault formula
- Patients must be willing to receive transfusions of blood products
- All study participants must be registered into the mandatory Revlimid Risk Evaluation and Mitigation Strategy (REMS) program, and be willing and able to comply with the requirements of the REMS program
- 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
- 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
- Able to take aspirin (81 mg) daily or alternative therapy as prophylactic anticoagulation
Exclusion Criteria:
- 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, chronic obstructive pulmonary disease (COPD), left ventricular ejection fraction (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
- Pregnant or lactating females
- Known hypersensitivity to lenalidomide or thalidomide, ibrutinib, rituximab, etoposide, vincristine, doxorubicin, cyclophosphamide, or prednisone
- Known human immunodeficiency virus (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 gastrointestinal (GI) consultation
- All patients with central nervous system involvement with lymphoma
- 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
- Significant neuropathy (grades 2 or grade 1 with pain) within 14 days prior to enrollment
- 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
- Patients with active pulmonary embolism or deep vein thrombosis (diagnosed within 30 days of study enrollment)
- Patients with severe bradycardia (heart rate < 40 beats per minute [bpm], hypotension, light-headedness, syncope)
- Major surgery within 4 weeks of study entry, or wound that is not healed from prior surgery or trauma
- History of stroke or intracranial hemorrhage within 6 months prior to study entry
- Requires anticoagulation with warfarin or equivalent vitamin K antagonists
- Requires chronic treatment with strong cytochrome P450, family 3, subfamily A (CYP3A) inhibitors
- Vaccinated with live, attenuated vaccines within 4 weeks of study entry
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
| United States, Texas | |
| M D Anderson Cancer Center | |
| Houston, Texas, United States, 77030 | |
| Principal Investigator: | Jason Westin | M.D. Anderson Cancer Center |
Documents provided by M.D. Anderson Cancer Center:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | M.D. Anderson Cancer Center |
| ClinicalTrials.gov Identifier: | NCT02636322 |
| Other Study ID Numbers: |
2015-0147 NCI-2016-00017 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) 2015-0147 ( Other Identifier: M D Anderson Cancer Center ) |
| First Posted: | December 21, 2015 Key Record Dates |
| Results First Posted: | March 13, 2024 |
| Last Update Posted: | March 13, 2024 |
| Last Verified: | February 2024 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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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 Prednisone Cortisone Cyclophosphamide Rituximab Doxorubicin |
Liposomal doxorubicin Etoposide Vincristine Lenalidomide Etoposide phosphate Podophyllotoxin Antineoplastic Agents, Immunological Antibodies Immunoglobulins Antibodies, Monoclonal Ibrutinib Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antirheumatic Agents |