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A Study Combining Ibrutinib With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With CD20-Positive B-Cell Non Hodgkin Lymphoma

Primary Purpose

CD20-positive B-cell Non-Hodgkin Lymphoma

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

Part 1, Cohort 1

Part 1, Cohort 2

Part 1, Cohort 3

Part 2, Cohort 1

Part 2, Cohort 2

About this trial

This is an interventional treatment trial for CD20-positive B-cell Non-Hodgkin Lymphoma focused on measuring CD20-positive B-cell non-Hodgkin lymphoma, Diffuse large B-cell lymphoma, Mantle cell lymphoma, Follicular lymphoma, Ibrutinib, R-CHOP, Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Histopathologically-confirmed CD20-positive B-cell non Hodgkin lymphoma disease for whom R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is an appropriate therapy (diffuse large B-cell lymphoma, mantle cell lymphoma, or follicular lymphoma); for the expansion cohort, at least 1 cohort will only include patients with newly diagnosed diffuse large B-cell lymphoma
Stage I AX (bulk defined as single lymph node mass >=10 cm in diameter) to Stage IV disease
At least 1 measurable site of disease based on the Revised Response Criteria for Malignant Lymphoma
Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
Adequate bone marrow, liver, and renal function

Exclusion Criteria:

History of protocol-defined disallowed therapies
Prior multidrug chemotherapy treatment for lymphoma
History of stroke or intracranial hemorrhage within 6 months prior to the first dose of study drug
Major surgery within 3 weeks before enrollment
Known bleeding diatheses, platelet dysfunction disorders, or requires therapeutic anticoagulation
Known lymphoma of the central nervous system
Uncontrolled or severe cardiovascular disease including myocardial infarction within 6 months of enrollment, New York Heart Association Class III or IV heart failure, uncontrolled angina, pericardial disease, cardiac amyloidosis, clinically significant cardiac arrhythmia, or left ventricular ejection fraction outside of institutional limits
Active systemic infection requiring treatment including hepatitis B and hepatitis C infection
Documented or suspected human immunodeficiency virus infection
Diagnosed or treated for a malignancy other than non-Hodgkin lymphoma except; adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ of the breast, or other solid tumors curatively treated with no evidence of disease for >5 years
Has any condition that, in the opinion of the investigator, would make study participation not be in the best interest (eg, compromise the well-being) of the patient or that could prevent, limit, or confound the protocol-specified assessments

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Ibrutinib

Arm Description

Part 1 (Dose Escalation): Escalating doses of ibrutinib (starting on Day 3 for Cycle 1 and on Day 1 for subsequent cycles) administered once daily in with standard-of-care doses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) until maximum tolerated dose is achieved. Part 2: Ibrutinib at the recommended Part 1 dose administered once daily with standard-of-care doses of R-CHOP.

Outcomes

Primary Outcome Measures

Part 1 maximum tolerated dose of ibrutinib

The Part 1 maximum tolerated dose (MTD) is the Part 2 recommended ibrutinib dose.

Secondary Outcome Measures

The number of participants affected by a dose-limiting toxicity

Number of participants with potential drug-drug interactions between ibrutinib and vincristine

Overall response rate

Duration of response

Progression-free survival

Mean plasma concentrations of ibrutinib

Maximum observed plasma concentration of ibrutinib

Time to reach the maximum plasma concentration of ibrutinib

Area under the plasma concentration-time curve from time 0 to 24 hours of ibrutinib

Elimination half-life associated with the terminal slope of the semilogarithmic drug concentration-time curve of ibrutinib

Elimination half-life associated with the terminal slope of the semilogarithmic drug concentration-time curve of vincristine

Partial area under the plasma concentration versus time curve of vincristine

The number of participants with pharmacodynamic markers of ibrutinib in peripheral blood mononuclear cells

The number of participants with biomarkers predictive of clinical response

The number of participants affected by an adverse event

Full Information

NCT ID

NCT01569750

First Posted

March 30, 2012

Last Updated

August 18, 2017

Sponsor

Janssen Research & Development, LLC

Collaborators

Pharmacyclics LLC.

1. Study Identification

Unique Protocol Identification Number

NCT01569750

Brief Title

A Study Combining Ibrutinib With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients With CD20-Positive B-Cell Non Hodgkin Lymphoma

Official Title

A Phase 1b Study Combining Ibrutinib With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Subjects With CD20-Positive B-Cell Non Hodgkin Lymphoma (NHL)

Study Type

Interventional

2. Study Status

Record Verification Date

August 2017

Overall Recruitment Status

Completed

Study Start Date

June 14, 2012 (Actual)

Primary Completion Date

September 4, 2014 (Actual)

Study Completion Date

September 4, 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Janssen Research & Development, LLC

Collaborators

Pharmacyclics LLC.

4. Oversight

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to identify if, and at what dose, ibrutinib may be administered with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and to document responses of this combination in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL).

Detailed Description

This is an open-label (individuals will know the identity of study treatments), dose escalation study to establish the recommended dose of ibrutinib combined with standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in approximately 33 adults with CD20-positive B-cell non-Hodgkin lymphoma (NHL) for whom R-CHOP is an appropriate therapy. There will be 3 periods of the study: a pretreatment (screening) period of up to 28 days before enrollment; an open-label treatment period (up to 6 cycles of ibrutinib and R-CHOP; ending at the end-of-treatment visit); and a posttreatment follow-up period until the end of study (maximum of up to 1 year after the last patient has completed the end-of-treatment visit). There are 2 parts to the study (dose escalation [Part 1] and expansion [Part 2]). During the dose escalation period, the "3+3" design will be applied and approximately 18 patients with CD20 positive B cell NHL (diffuse large B-cell lymphoma [DLBCL], mantle cell lymphoma [MCL], and follicular lymphoma [FL]) may be enrolled. Patients will be assigned to cohorts of increasing oral daily doses of ibrutinib (280, 420, and 560 mg) administered in combination with R-CHOP. The maximum tolerated dose (MTD), assessed in Cycle 1 (dose-limiting toxicity [DLT] period), is defined as the highest dose of the combination regimen at which <=33% of patients experience DLT. Baseline and follow-up electrocardiograms will be performed throughout the study. A Study Evaluation Team will review all available data upon completion of the first cycle for all patients at each dose cohort to determine DLTs, if dose escalation is acceptable, and subsequently will determine the recommended Phase 2 dose. Once the recommended Phase 2 dose is determined, approximately 15 patients with newly diagnosed DLBCL will be entered into the expansion cohort at the dose level selected to further assess the safety, pharmacokinetics, pharmacodynamics, pharmacogenomics, and activity of the combination. Patients whose disease has not progressed at the end of Cycle 1 will continue to receive ibrutinib and R CHOP up to a maximum of 6 cycles. During the posttreatment follow-up period, long term safety, survival status, disease progression, and subsequent antilymphoma therapy will be collected. The study will end 1 year after the last patient has completed the end of treatment visit.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

CD20-positive B-cell Non-Hodgkin Lymphoma

Keywords

CD20-positive B-cell non-Hodgkin lymphoma, Diffuse large B-cell lymphoma, Mantle cell lymphoma, Follicular lymphoma, Ibrutinib, R-CHOP, Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

33 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Ibrutinib

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Part 1, Cohort 1

Intervention Description

Type=exact number, unit=mg, number=280, form=capsule, route=oral use. Escalating doses of ibrutinib (starting on Day 3 for Cycle 1 and on Day 1 for subsequent cycles) administered once daily in with standard-of-care doses of R-CHOP until maximum tolerated dose is achieved.

Intervention Type

Drug

Intervention Name(s)

Part 1, Cohort 2

Intervention Description

Type=exact number, unit=mg, number=420, form=capsule, route=oral use. Escalating doses of ibrutinib (starting on Day 3 for Cycle 1 and on Day 1 for subsequent cycles) administered once daily in with standard-of-care doses of R-CHOP until maximum tolerated dose is achieved.

Intervention Type

Drug

Intervention Name(s)

Part 1, Cohort 3

Intervention Description

Type=exact number, unit=mg, number=560, form=capsule, route=oral use. Escalating doses of ibrutinib (starting on Day 3 for Cycle 1 and on Day 1 for subsequent cycles) administered once daily in with standard-of-care doses of R-CHOP until maximum tolerated dose is achieved.

Intervention Type

Drug

Intervention Name(s)

Part 2, Cohort 1

Intervention Description

Ibrutinib at the recommended Part 1 dose administered once daily with standard-of-care doses of R-CHOP in patients with newly diagnosed diffuse large B-cell lymphoma.

Intervention Type

Drug

Intervention Name(s)

Part 2, Cohort 2

Intervention Description

Ibrutinib at the recommended Part 1 dose administered once daily with standard-of-care doses of R-CHOP in patients with newly diagnosed with B-cell non-Hodgkin lymphoma.

Primary Outcome Measure Information:

Title

Part 1 maximum tolerated dose of ibrutinib

Description

The Part 1 maximum tolerated dose (MTD) is the Part 2 recommended ibrutinib dose.

Time Frame

Up to Cycle 1, Day 21 in Part 1

Secondary Outcome Measure Information:

Title

The number of participants affected by a dose-limiting toxicity

Time Frame

Up to Cycle 6, Day 21 in Part 1

Title

Number of participants with potential drug-drug interactions between ibrutinib and vincristine

Time Frame