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Ibrutinib and Combination Chemotherapy in Treating Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Information source: National Cancer Institute (NCI)
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Recurrent Adult Diffuse Large Cell Lymphoma; Refractory Diffuse Large B-Cell Lymphoma

Intervention: Carboplatin (Drug); Etoposide (Drug); Ibrutinib (Drug); Ifosfamide (Drug); Pharmacological Study (Other); Rituximab (Biological)

Phase: Phase 1

Status: Recruiting

Sponsored by: National Cancer Institute (NCI)

Official(s) and/or principal investigator(s):
Craig Sauter, Principal Investigator, Affiliation: Memorial Sloan Kettering Cancer Center


This phase I trial studies the side effects and best dose of ibrutinib when given together with rituximab, ifosfamide, carboplatin, and etoposide (combination chemotherapy) in treating patients with diffuse large B-cell lymphoma (DLBCL) that has returned after a period of improvement or has not responded to treatment. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as, rituximab, ifosfamide, carboplatin, and etoposide, 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 ibrutinib together with combination chemotherapy may be a better treatment for patients with relapsed or refractory DLBCL.

Clinical Details

Official title: A Phase I Study Combining Ibrutinib With Rituximab, Ifosfamide, Carboplatin, and Etoposide (R-ICE) in Patients With Relapsed or Primary Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Study design: Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome:

Maximum tolerated dose (MTD) of the combination of ibrutinib with standard dosing R-ICE, graded using the Common Terminology Criteria for Adverse Events (CTCAE) 4.0

Toxicity of the combination of ibrutinib with standard dosing R-ICE, graded using the CTCAE 4.0

Secondary outcome:

Overall response rate, defined as the sum of partial and complete responses as determined by revised International Working Group (IWG) Criteria for Malignant Lymphoma

PK parameters of ibrutinib in the presence of R-ICE as a measure of potential drug-drug interaction

Detailed description: PRIMARY OBJECTIVES: I. Safety of ibrutinib in combination with rituximab-ifosfamide, carboplatin, and etoposide (R-ICE). II. Establishment of maximum tolerated dose of ibrutinib with R-ICE. SECONDARY OBJECTIVES: I. Pharmacokinetic (PK) studies of ibrutinib in combination with R-ICE. II. Clinical response rate of ibrutinib+R-ICE. OUTLINE: This is a dose-escalation study of ibrutinib. Patients receive ibrutinib orally (PO) once daily (QD) on days 1-21 (days 3-21 of course 1), rituximab intravenously (IV) on day 1, ifosfamide IV continuously over 24 hours on day 3, carboplatin IV on day 3, and etoposide IV on days 2-4. Treatment repeats every 21 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 52 weeks.


Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.


Inclusion Criteria:

- Autologous transplant eligible patients must have histologically or cytologically

confirmed cluster of differentiation (CD)20 positive relapsed or refractory DLBCL by biopsy within 45 days prior to subject enrollment and must have been previously treated with an anthracycline and rituximab-containing regimen

- Baseline fludeoxyglucose F 18 (FDG)-positron emission tomography (PET) scans must

demonstrate positive lesions compatible with computed tomography (CT) defined anatomical tumor sites

- CT scan showing at least:

- 2 or more clearly demarcated lesions/nodes with a long axis > 1. 5 cm and

short axis >= 1. 0 cm OR

- 1 clearly demarcated lesion/node with a long axis > 2. 0 cm and short axis

>= 1. 0 cm

- Patient must have been previously treated for B cell non-Hodgkin lymphoma with any of

the allowable below:

- First-line treatment with rituximab and an anthracycline-based chemotherapy

- Monotherapy rituximab, dosed prior to first-line rituximab combined with

chemotherapy, or as maintenance therapy

- Radiotherapy as part of the first-line treatment plan

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Life expectancy of greater than 6 weeks

- Absolute neutrophil count >= 1,000/mcL (unless due to lymphoma involvement of the

bone marrow)

- Platelets >= 75,000/mcL (unless due to lymphoma involvement of the bone marrow)

- Total bilirubin < 1. 5 x within normal institutional limits (unless due to lymphoma

involvement of liver or a known history of Gilbert's disease)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase

[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2. 5 × institutional upper limit of normal (unless due to lymphoma involvement of liver)

- Creatinine within normal institutional limits OR creatinine clearance >= 40

mL/min/1. 73 m^2 for patients with creatinine levels above institutional normal (unless due to lymphoma)

- Women of child-bearing potential and men must agree to use adequate contraception

(hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 12 months after completion of ibrutinib R-ICE

- Ibrutinib must be discontinued 7 days before (when possible) until 7 days after major

surgery, and 3 days before (when possible) until 3 days after minor surgery; thus, patients to be enrolled on an ibrutinib trial must have completed major surgery > 7 days before initiating treatment, and/or must have completed minor surgery > 3 days before initiating treatment

- Ability to understand and the willingness to sign a written informed consent document

- Must be able to swallow whole capsules

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for

nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier

- Patients who are receiving any other investigational agents

- Patients with known brain metastases should be excluded from this clinical trial

- History of allergic reactions attributed to compounds of similar chemical or biologic

composition to ibrutinib or R-ICE

- Strong inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide

4 (CYP3A4)/cytochrome P450, family 3, subfamily A, polypeptide 5 (5) should be avoided and moderate inhibitors or inducers should be used with caution; because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list; medical reference texts such as the Physicians' Desk Reference may also provide this information; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product

- Uncontrolled intercurrent illness 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

- Pregnant women are excluded from this study; breastfeeding should be discontinued if

the mother is treated with ibrutinib R-ICE

- Patients receiving chronic treatment with systemic steroids; however, patients can

receive up to 7 days of steroid therapy prior to starting treatment with Ibrutinib and R-ICE

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral

therapy are eligible, unless the patient's CD4 count is below the institutional lower limit of normal, or the patient is taking prohibited CYP3A4/5 strong inhibitors or inducers

- Patients may not have received any anti-cancer therapy for their primary rel/ref

DLBCL with the exception of palliative radiation therapy (RT) =< 10 Gy

- Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura (ITP)

resulting in (or as evidenced by) declining platelet or hemoglobin (Hgb) levels within the 4 weeks prior to first dose of study drug

- Presence of transfusion-dependent thrombocytopenia

- Prior exposure to ibrutinib

- History of prior malignancy, with the exception of the following:

- Malignancy treated with curative intent and with no evidence of active disease

present for more than 3 years prior to Screening and felt to be at low risk for recurrence by treating physician

- Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma

without current evidence of disease

- Adequately treated cervical carcinoma in situ without current evidence of


- Currently active clinically significant cardiovascular disease such as uncontrolled

arrhythmia, congestive heart failure, any class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or history of myocardial infarction within 6 months prior to first dose with study drug

- Unable to swallow capsules, or disease significantly affecting gastrointestinal

function and/or inhibiting small intestine absorption, such as malabsorption syndrome, resection of the small bowel, or poorly controlled inflammatory bowel disease affecting the small intestine

- Serologic status reflecting active hepatitis B or C infection; patients that are

hepatitis B core antibody positive but antigen negative will need a negative polymerase chain reaction (PCR) prior to enrollment (hepatitis B antigen or PCR positive patients will be excluded); hepatitis C antibody positive patients are eligible if PCR is negative

- History of stroke or intracranial hemorrhage within 6 months prior to enrollment

- Current life-threatening illness, medical condition, or organ system dysfunction

which, in the Investigator's opinion, could compromise the patient's safety, or put the study at risk

- Received anticoagulation therapy with Coumadin or equivalent vitamin K antagonists

within the last 28 days

Locations and Contacts

Memorial Sloan-Kettering Cancer Center, New York, New York 10065, United States; Recruiting
Craig S. Sauter, Phone: 212-639-3460, Email: sauterc@mskcc.org
Craig S. Sauter, Principal Investigator
Additional Information

Starting date: September 2014
Last updated: May 25, 2015

Page last updated: August 23, 2015

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