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

CD20-positive B-cell Non-Hodgkin Lymphoma Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01569750
• Other study ID #: CR100844
• Secondary ID: PCI-32765DBL1002
• Status: Completed
• Phase: Phase 1
• First received: March 30, 2012
• Last updated: August 18, 2017
• Start date: June 14, 2012
• Est. completion date: September 4, 2014

Study information

• Verified date: August 2017
• Source: Janssen Research & Development, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 33
• Est. completion date: September 4, 2014
• Est. primary completion date: September 4, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• CD20-positive B-cell Non-Hodgkin Lymphoma
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Non-Hodgkin

Intervention

Drug:
• Part 1, Cohort 1
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.
• Part 1, Cohort 2
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.
• Part 1, Cohort 3
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.
• Part 2, Cohort 1
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.
• Part 2, Cohort 2
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.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Janssen Research & Development, LLC	Pharmacyclics LLC.

Countries where clinical trial is conducted

United States,  France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1 maximum tolerated dose of ibrutinib	The Part 1 maximum tolerated dose (MTD) is the Part 2 recommended ibrutinib dose.	Up to Cycle 1, Day 21 in Part 1
Secondary	The number of participants affected by a dose-limiting toxicity		Up to Cycle 6, Day 21 in Part 1
Secondary	Number of participants with potential drug-drug interactions between ibrutinib and vincristine		Up to Cycle 6, Day 21 in Part 2
Secondary	Overall response rate		Up to Cycle 6, Day 21 in Part 2
Secondary	Duration of response		Up to Cycle 6, Day 21 in Part 2
Secondary	Progression-free survival		Up to Cycle 6, Day 21 in Part 2
Secondary	Mean plasma concentrations of ibrutinib		Up to Cycle 6, Day 21 in Part 2
Secondary	Maximum observed plasma concentration of ibrutinib		Up to Cycle 6, Day 21 in Part 2
Secondary	Time to reach the maximum plasma concentration of ibrutinib		Up to Cycle 6, Day 21 in Part 2
Secondary	Area under the plasma concentration-time curve from time 0 to 24 hours of ibrutinib		Up to Cycle 6, Day 21 in Part 2
Secondary	Elimination half-life associated with the terminal slope of the semilogarithmic drug concentration-time curve of ibrutinib		Up to Cycle 6, Day 21 in Part 2
Secondary	Elimination half-life associated with the terminal slope of the semilogarithmic drug concentration-time curve of vincristine		Up to Cycle 6, Day 21 in Part 2
Secondary	Partial area under the plasma concentration versus time curve of vincristine		Up to Cycle 6, Day 21 in Part 2
Secondary	The number of participants with pharmacodynamic markers of ibrutinib in peripheral blood mononuclear cells		Up to Cycle 6, Day 21 in Part 2
Secondary	The number of participants with biomarkers predictive of clinical response		Up to Cycle 6, Day 21 in Part 2
Secondary	The number of participants affected by an adverse event		Up to 30 days after the last dose of study medication

External Links

•   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)