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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Pharmacyclics
Information provided by (Responsible Party):
Janssen Research & Development, LLC
ClinicalTrials.gov Identifier:
NCT01569750
First received: March 30, 2012
Last updated: June 16, 2014
Last verified: June 2014
  Purpose

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).


Condition Intervention Phase
CD20-positive B-cell Non-Hodgkin Lymphoma
Drug: Part 1, Cohort 1
Drug: Part 1, Cohort 2
Drug: Part 1, Cohort 3
Drug: Part 2, Cohort 1
Drug: Part 2, Cohort 2
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by Janssen Research & Development, LLC:

Primary Outcome Measures:
  • Part 1 maximum tolerated dose of ibrutinib [ Time Frame: Up to Cycle 1, Day 21 in Part 1 ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Up to Cycle 6, Day 21 in Part 1 ] [ Designated as safety issue: Yes ]
  • Number of participants with potential drug-drug interactions between ibrutinib and vincristine [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: Yes ]
  • Overall response rate [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  • Duration of response [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  • Progression-free survival [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  • Mean plasma concentrations of ibrutinib [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  • Maximum observed plasma concentration of ibrutinib [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  • Time to reach the maximum plasma concentration of ibrutinib [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  • Area under the plasma concentration-time curve from time 0 to 24 hours of ibrutinib [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  • Elimination half-life associated with the terminal slope of the semilogarithmic drug concentration-time curve of ibrutinib [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  • Elimination half-life associated with the terminal slope of the semilogarithmic drug concentration-time curve of vincristine [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  • Partial area under the plasma concentration versus time curve of vincristine [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  • The number of participants with pharmacodynamic markers of ibrutinib in peripheral blood mononuclear cells [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  • The number of participants with biomarkers predictive of clinical response [ Time Frame: Up to Cycle 6, Day 21 in Part 2 ] [ Designated as safety issue: No ]
  • The number of participants affected by an adverse event [ Time Frame: Up to 30 days after the last dose of study medication ] [ Designated as safety issue: Yes ]

Enrollment: 33
Study Start Date: June 2012
Estimated Study Completion Date: July 2014
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Ibrutinib

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.

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.
Drug: 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.
Drug: 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.
Drug: 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.
Drug: 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.

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01569750

Locations
United States, New York
New York, New York, United States
Rochester, New York, United States
United States, Tennessee
Nashville, Tennessee, United States
United States, Texas
Houston, Texas, United States
France
Lille Cedex, France
Paris, France
Vandoeuvre Les Nancy, France
Sponsors and Collaborators
Janssen Research & Development, LLC
Pharmacyclics
Investigators
Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC
  More Information

No publications provided by Janssen Research & Development, LLC

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT01569750     History of Changes
Other Study ID Numbers: CR100844, PCI-32765DBL1002, 2012-000546-35
Study First Received: March 30, 2012
Last Updated: June 16, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Janssen Research & Development, LLC:
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

Additional relevant MeSH terms:
Lymphoma, Non-Hodgkin
Lymphoma
Lymphoma, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Rituximab
Liposomal doxorubicin
Doxorubicin
Prednisone
Vincristine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on September 18, 2014