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R-ICE and Lenalidomide in Treating Patients With First-Relapse/Primary Refractory Diffuse Large B-Cell Lymphoma

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ClinicalTrials.gov Identifier: NCT02628405
Recruitment Status : Recruiting
First Posted : December 11, 2015
Last Update Posted : July 2, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Academic and Community Cancer Research United

Brief Summary:
This phase I/II trial studies the side effects and best dose of lenalidomide when given together with rituximab-ifosfamide-carboplatin-etoposide (R-ICE) and to see how well they work in treating patients with diffuse large B-cell lymphoma that has returned after a period of improvement and that has not responded to previous treatment. Drugs used in chemotherapy, such as rituximab, ifosfamide, carboplatin, etoposide, and lenalidomide, 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. Giving lenalidomide with R-ICE may be a better treatment for patients with diffuse large B-cell lymphoma.

Condition or disease Intervention/treatment Phase
CD20 Positive Recurrent B-Cell Non-Hodgkin Lymphoma Recurrent Diffuse Large B-Cell Lymphoma Recurrent Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma Recurrent Transformed Non-Hodgkin Lymphoma Refractory B-Cell Non-Hodgkin Lymphoma Refractory Diffuse Large B-Cell Lymphoma Refractory Primary Mediastinal (Thymic) Large B-Cell Cell Lymphoma Refractory Transformed Non-Hodgkin Lymphoma Drug: Carboplatin Drug: Etoposide Drug: Ifosfamide Other: Laboratory Biomarker Analysis Drug: Lenalidomide Biological: Rituximab Phase 1 Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To assess the safety and maximum tolerated dose (MTD) of the addition of lenalidomide to the R-ICE chemoimmunotherapy regimen (lenalidomide-rituximab-ifosfamide-carboplatin-etoposide [R2ICE]) for the treatment of primary-refractory/first-relapse B-cell lymphoma. (Phase I) II. To determine if the addition of lenalidomide (based on dose determination from phase I) to the R-ICE chemoimmunotherapy regimen (R2-ICE) would lead to clinically meaningful improvement in the overall response rates (ORR) for patients with first-relapse/refractory diffuse large B-cell lymphoma (DLBCL). (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the effect of the addition of lenalidomide to RICE on the number (percentage) of patients proceeding to stem cell transplant (SCT).

II. To evaluate the effect of the addition of lenalidomide to RICE on other surrogate outcome measures including complete metabolic response (CMR) rate and overall survival.

III. To describe the toxicities associated with the addition of lenalidomide to the R-ICE chemoimmunotherapy regimen (R2ICE).

TERTIARY OBJECTIVES:

I. To evaluate ORR based on germinal center B-cell-like (GCB) versus non-GCB subtypes.

II. To evaluate ORR based on percent standardized uptake value (SUV) reduction and percent anatomic size reduction on interim positron emission tomography (PET)/computed tomography (CT) scans.

III. To evaluate ORR based on minimal residual disease (MRD) detection (positive versus [vs.] negative) and quantification after 2 cycles of treatment.

IV. Future tissue and blood based studies.

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

Patients receive lenalidomide orally (PO) daily on days 1-14, rituximab intravenously (IV) on day 1, ifosfamide IV over 24 hours on day 2, carboplatin IV over 1-2 hours on day 2, and etoposide IV over 1 hour on days 1-3. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CMR, partial metabolic response (PMR), or no metabolic response (NMR) may receive 2 more courses per physician discretion. After completion of 2 cycles of R2ICE treatment, patients achieving objective status of CMR, PMR or NMR may proceed to SCT during the event monitoring phase.

After completion of study treatment, patients are followed up every 3 months for 3 years and then every 6 months for 2 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 63 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II, Open-Label Study of R-ICE (Rituximab-Ifosfamide-Carboplatin-Etoposide) With Lenalidomide (R2-ICE) in Patients With First-Relapse/Primary Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
Actual Study Start Date : May 20, 2016
Estimated Primary Completion Date : May 20, 2020
Estimated Study Completion Date : January 20, 2023


Arm Intervention/treatment
Experimental: Treatment (R2-ICE)
Patients receive lenalidomide PO daily on days 1-14, rituximab IV on day 1, ifosfamide IV over 24 hours on day 2, carboplatin IV over 1-2 hours on day 2, and etoposide IV over 1 hour on days 1-3. Treatment repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CMR, PMR, or NMR may receive 2 more courses per physician discretion. After completion of 2 cycles of R2ICE treatment, patients achieving objective status of CMR, PMR or NMR may proceed to SCT during the event monitoring phase.
Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo

Drug: Etoposide
Given IV
Other Names:
  • Demethyl Epipodophyllotoxin Ethylidine Glucoside
  • EPEG
  • Lastet
  • Toposar
  • Vepesid
  • VP 16-213
  • VP-16
  • VP-16-213

Drug: Ifosfamide
Given IV
Other Names:
  • Asta Z 4942
  • Asta Z-4942
  • Cyfos
  • Holoxan
  • Holoxane
  • Ifex
  • IFO
  • IFO-Cell
  • Ifolem
  • Ifomida
  • Ifomide
  • Ifosfamidum
  • Ifoxan
  • IFX
  • Iphosphamid
  • Iphosphamide
  • Iso-Endoxan
  • Isoendoxan
  • Isophosphamide
  • Mitoxana
  • MJF 9325
  • MJF-9325
  • Naxamide
  • Seromida
  • Tronoxal
  • Z 4942
  • Z-4942

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Lenalidomide
Given PO
Other Names:
  • CC-5013
  • CC5013
  • CDC 501
  • Revlimid

Biological: Rituximab
Given IV
Other Names:
  • ABP 798
  • BI 695500
  • C2B8 Monoclonal Antibody
  • Chimeric Anti-CD20 Antibody
  • CT-P10
  • IDEC-102
  • IDEC-C2B8
  • IDEC-C2B8 Monoclonal Antibody
  • MabThera
  • Monoclonal Antibody IDEC-C2B8
  • PF-05280586
  • Rituxan
  • Rituximab Biosimilar ABP 798
  • Rituximab Biosimilar BI 695500
  • Rituximab Biosimilar CT-P10
  • Rituximab Biosimilar GB241
  • Rituximab Biosimilar IBI301
  • Rituximab Biosimilar PF-05280586
  • Rituximab Biosimilar RTXM83
  • Rituximab Biosimilar SAIT101
  • RTXM83




Primary Outcome Measures :
  1. Maximum tolerated dose defined as the dose level below the lowest dose that induces dose-limiting toxicity in at least one-third of patients of the addition of lenalidomide to rituximab-ifosfamide-carboplatin-etoposide (Phase I) [ Time Frame: 21 days ]
    The number and severity of all adverse events (overall and by dose-level) will be tabulated and summarized in this patient population. The grade 3+ adverse events will also be described and summarized in a similar fashion. This will provide an indication of the level of tolerance for this treatment combination in this patient group.

  2. Toxicity profile defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment as measured by Common Terminology Criteria for Adverse Events version 4.0 (Phase I) [ Time Frame: Up to 30 days after completion of study treatment ]
    Overall toxicity incidence as well as toxicity profiles by dose level and patient will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses.

  3. Overall response rate defined as a complete metabolic response or partial metabolic response (Phase II) [ Time Frame: At 42 days (after 2 courses) of treatment ]
    The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.


Secondary Outcome Measures :
  1. Percentage of patients proceeding to stem cell transplant [ Time Frame: At 42 days of treatment ]
    Estimated by the number of patients who proceed to transplant divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success proportion will be calculated.

  2. Complete metabolic response rate [ Time Frame: Up to 5 years ]
    Estimated by the number of patients with an objective status of complete metabolic response divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true complete metabolic response rate will be calculated.

  3. Overall survival [ Time Frame: From registration to death due to any cause, assessed up to 5 years ]
    Will be estimated using the method of Kaplan-Meier.

  4. Incidence of adverse events [ Time Frame: Up to 30 days after completion of study treatment ]
    The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.


Other Outcome Measures:
  1. Histologic subtype (germinal center B-cell-like versus activated B-cell-like versus unclassified subtype) [ Time Frame: Up to 5 years ]
    Evaluated by 2 methods: Hans algorithm by immunohistochemistry and gene expression profiling using nanostring technology. For each method, the relationship between overall response (responder versus non-responder) complete response rate and subtype will be evaluated using Chi-square tests (or Fisher?s exact test if the data in the contingency table is sparse).

  2. Standardized uptake value [ Time Frame: Up to 5 years ]
    Evaluated by calculating the percentage (%) standardized uptake value noted on interim positron emission tomography/computed tomography scan and correlated with the overall response (responder versus non-responder) by using a two sample t-test.

  3. Anatomic size reduction [ Time Frame: Up to 5 years ]
    Evaluated by calculating the percentage (%) anatomic size reduction noted on interim positron emission tomography/computed tomography scan and correlated with the overall response (responder versus non-responder) by using a two sample t-test.

  4. Minimum residual disease detection in blood [ Time Frame: Up to 5 years ]
    The correlation of minimal residual disease detection (positive versus negative) with overall response will be evaluated using Chi-square tests (or Fisher?s exact test if the data in the contingency table is sparse).

  5. Minimum residual disease blood level [ Time Frame: Up to 5 years ]
    The correlation of minimal residual disease quantification (responder versus non-responder) with overall response will be evaluated using two sample t-tests.

  6. Serum sample collected and stored for future and ongoing research [ Time Frame: Up to 5 years ]
    Some of the initial work for which this would be utilized would include but not limited to studying the serum free light chains, serum free deoxyribonucleic acid and the minimal residual disease. These measures will be summarized descriptively using medians and ranges (continuous measures) or frequencies (categorical measures).



Information from the National Library of Medicine

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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:

  • Histological confirmation of expressing CD20 antigen as determined by pathology at the respective institution and central pathology review at Mayo Clinic Rochester; Notes: for phase I, all types of B-cell lymphomas are allowed to participate; for phase II, only DLBCL patients are allowed to participate; for phase I only, patients with primary mediastinal large B-cell (PMLBCL) or transformed lymphoma are allowed to participate; additional notes regarding slide submission: central pathology review is mandatory, but is retrospective in nature; slides must be submitted =< 30 days after registration to allow for confirmation of DLBCL diagnosis and to have sufficient material for GCB/ABC assessment by a gene-expression profiling method; patients can be enrolled prior to submission of slides; for phase II, if central review of pathology shows that the patient does not have DLBCL or the amount of formalin-fixed paraffin-embedded (FFPE) material is not considered sufficient for cell-of-origin (COO) analysis, the patient may remain on the study but the patient should be replaced
  • Measurable disease (at least 1 lesion >= 1.5 cm in diameter) as detected by PET/CT
  • Only 1 line of previous anti-lymphoma therapy is allowed and not currently receiving any other agent that would be considered as a treatment for the lymphoma; patients must be >= 2 weeks from prior anti-lymphoma therapy; the use of steroids and/or rituximab up to 1 week prior to registration for management of symptoms is allowed
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2
  • Absolute neutrophil count (ANC) >= 1500/mm^3, obtained =< 7 days prior to registration
  • Platelet count >= 75,000/mm^3, obtained =< 7 days prior to registration
  • Total bilirubin =< 2 x upper limit of normal (ULN) (unless related to lymphoma or Gilbert?s disease) OR =< 5 x ULN for subjects with documented or suspected Gilbert?s disease, or related to involvement of the liver by the lymphoma, obtained =< 7 days prior to registration
  • Aspartate transaminase (AST) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN unless evidence of the direct liver and/or bone involvement by lymphoma, then =< 5 x ULN, obtained =< 7 days prior to registration
  • PHASE I: Subjects must have calculated creatinine clearance >= 60 ml/min by Cockcroft-Gault formula, obtained =< 7 days prior to registration
  • PHASE II: Subjects must have calculated creatinine clearance >= 30 ml/min by Cockcroft-Gault formula, obtained =< 7 days prior to registration
  • For women of childbearing potential only: Negative pregnancy test =< 10-14 days prior to registration; NOTE: the patient must have an additional negative pregnancy test =< 24 hours prior to receiving the initial prescription of lenalidomide, per requirements of the REVLIMID Risk Evaluation and Mitigation Strategies (REMS) program
  • Provide informed written consent
  • Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study [i.e. active treatment and observation])
  • Willing to provide blood samples for correlative research purposes
  • Considered transplant-eligible, as determined by the opinion of the investigator at the participating institution; the participating institution does not need to be a transplant center but patients can be referred to a transplant center if needed
  • Willing and able to register into and comply with the mandatory requirements of Celgene?s REVLIMID REMS program
  • Females of reproductive potential are willing and able to adhere to the scheduled pregnancy testing as required by Celgene?s REVLIMID REMS program
  • Willing and able to take aspirin (81 mg) daily as prophylactic anticoagulation (patients intolerant to acetylsalicylic acid [ASA] may use warfarin or low molecular weight heparin)

Exclusion Criteria:

  • Pregnant women
  • Nursing women
  • Men or women of childbearing potential who are unwilling to employ adequate contraception

    • NOTE: patients unwilling or unable to do any of the following are also excluded:

      • Men must agree to use a latex condom during sexual contact with a female of child-bearing potential even if they have had a successful vasectomy
      • Women of child bearing potential must agree to use 2 methods of reliable contraception simultaneously
      • All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure
  • 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
  • Immunocompromised patients and patients known to be human immunodeficiency virus (HIV) positive and currently receiving antiretroviral therapy; NOTE: patients known to be HIV positive, but without clinical evidence of an immunocompromised state, are eligible for this trial; patients with HIV on antiretroviral therapy other than zidovudine (AZT) and/or stavudine and without prior acquired immunodeficiency syndrome (AIDS) defining conditions and adequate CD4 count (> 400) are eligible
  • History of myocardial infarction =< 180 days prior to registration or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
  • Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm; patients must be >= 2 weeks from prior anti-lymphoma therapy; the use of steroids and/or rituximab up to 1 week prior to registration for management of symptoms is allowed
  • Other active malignancy =< 3 years prior to registration; EXCEPTIONS: non-melanotic skin cancer, carcinoma-in-situ of the cervix, or 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; NOTE: if there is a history of prior malignancy, they must not be receiving other specific treatment such as radiation, chemotherapy, or immunotherapy for their cancer
  • Unable or unwilling to take any prophylaxis; patients with history of or new/active deep vein thrombosis/embolism/thrombophilia are allowed to participate if they are on appropriate therapeutic anticoagulation during the treatment on the trial; these patients would not need the aspirin with the lenalidomide unless clinically indicated; therefore, patients must be able and willing to receive anticoagulation (prophylaxis versus therapeutic as clinically indicated)
  • History of radiation therapy to >= 25% of the bone marrow for other diseases
  • Receiving erythroid stimulating agents (epoetin alfa [EPO]: Procrit, Aranesp)
  • Patients with active or prior central nervous system (CNS) lymphoma or cerebrospinal fluid involvement with malignant lymphoma cells; NOTE: these patients are usually treated with CNS directed therapy; screening for cerebrospinal fluid (CSF)/CNS involvement is NOT required but can be performed per treating medical doctor (MD) discretion
  • Active hepatitis B as defined by seropositivity for hepatitis B surface antigen (HBsAg); subjects with positive hepatitis B core antibody titers and normal liver transaminases are allowed provided that antiviral prophylaxis is administered per institutional guidelines; NOTE: subjects with hepatitis C antibody will be eligible provided that they do not have elevated liver transaminases or other evidence of active hepatitis

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): NCT02628405


Locations
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United States, Florida
Mayo Clinic in Florida Recruiting
Jacksonville, Florida, United States, 32224-9980
Contact: Kathleen M. Burke    904-953-2000    Burke.Kathleen@mayo.edu   
Principal Investigator: Han W. Tun         
United States, Illinois
Illinois CancerCare-Peoria Withdrawn
Peoria, Illinois, United States, 61615
Carle Cancer Center NCI Community Oncology Research Program Recruiting
Urbana, Illinois, United States, 61801
Contact: Pauline Mbuvi    217-383-4085    Pauline.Mbuvi@Carle.com   
Principal Investigator: Priyank P. Patel         
United States, Iowa
University of Iowa/Holden Comprehensive Cancer Center Recruiting
Iowa City, Iowa, United States, 52242
Contact: Susan B. Butcher    319-467-5827    susan-butcher@uiowa.edu   
Principal Investigator: Umar Farooq         
Siouxland Regional Cancer Center Recruiting
Sioux City, Iowa, United States, 51101
Contact: Thomas S. Hoopingarner    712-252-9326    HoopingarnerT@jencc.com   
Principal Investigator: Donald B. Wender         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Mayo Clinic Clinical Trials Office    855-776-0015      
Principal Investigator: Grzegorz S. Nowakowski         
Coborn Cancer Center at Saint Cloud Hospital Recruiting
Saint Cloud, Minnesota, United States, 56303
Contact: Stacy St. Onge    320-229-4907    stacy.stonge@centracare.com   
Principal Investigator: Donald J. Jurgens         
Metro Minnesota Community Oncology Research Consortium Recruiting
Saint Louis Park, Minnesota, United States, 55416
Contact: Elizabeth J. Wagner    952-992-1555    Elizabeth.wagner@parknicollet.com   
Principal Investigator: Daniel M. Anderson         
United States, Nebraska
University of Nebraska Medical Center Withdrawn
Omaha, Nebraska, United States, 68198
United States, New Hampshire
Dartmouth Hitchcock Medical Center Recruiting
Lebanon, New Hampshire, United States, 03756
Contact: Julie Gurnsey    603-653-3640    Julie.d.gurnsey@hitchcock.org   
Principal Investigator: Frederick Lansigan         
United States, New Jersey
Hackensack University Medical Center Recruiting
Hackensack, New Jersey, United States, 07601
Contact: Kara M. Yannotti    551-996-5900    Kara.Yannotti@HackensackMeridian.org   
Principal Investigator: Tatyana A. Feldman         
United States, New York
State University of New York Upstate Medical University Recruiting
Syracuse, New York, United States, 13210
Contact: Joanne M. Chilton    315-464-8240    chiltonj@upstate.edu   
Principal Investigator: Teresa C. Gentile         
United States, Pennsylvania
Geisinger Medical Center Withdrawn
Danville, Pennsylvania, United States, 17822
United States, South Dakota
Rapid City Regional Hospital Completed
Rapid City, South Dakota, United States, 57701
United States, Wisconsin
Marshfield Clinic Recruiting
Marshfield, Wisconsin, United States, 54449
Contact: Sheryl L. Mandel    715-389-4457    Mandel.Sheryl@mcrf.mfldclin.edu   
Principal Investigator: Ali W. Bseiso         
Sponsors and Collaborators
Academic and Community Cancer Research United
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Grzegorz Nowakowski Academic and Community Cancer Research United

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Responsible Party: Academic and Community Cancer Research United
ClinicalTrials.gov Identifier: NCT02628405     History of Changes
Other Study ID Numbers: RU051417I
NCI-2015-01990 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
RU051417I ( Other Identifier: Academic and Community Cancer Research United )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: December 11, 2015    Key Record Dates
Last Update Posted: July 2, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Carboplatin
Rituximab
Lenalidomide
Etoposide
Etoposide phosphate
Ifosfamide
Isophosphamide mustard
Antineoplastic Agents, Immunological
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Antirheumatic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antineoplastic Agents, Phytogenic