Safety and Efficacy Study of a BTK Inhibitor in Subjects With Relapsed or Refractory Diffuse Large B-cell Lymphoma

• ClinicalTrials.gov Identifier: NCT01325701
• Recruitment Status: Completed
• First Posted: March 30, 2011
• Results First Posted: February 16, 2017
• Last Update Posted: March 31, 2017
• Sponsor: Pharmacyclics LLC.
• Information provided by (Responsible Party): Pharmacyclics LLC.

Tracking Information

• First Submitted Date: February 2, 2011
• First Posted Date: March 30, 2011
• Results First Submitted Date: June 30, 2016
• Results First Posted Date: February 16, 2017
• Last Update Posted Date: March 31, 2017
• Study Start Date: May 2011
• Actual Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 22, 2016)

Percentage of Patients With an Overall Response to Study Drug [ Time Frame: The median follow up time on the study for all treated participants is 1.7 months (range 0.1- 32.3 months) ]

The primary endpoint of the study was overall response rate (ORR), defined as the proportion of participants who achieved a best overall response of complete response (CR) or partial response (PR), according to the revised International Working Group Criteria for non-Hodgkin's lymphoma (Cheson et al, 2007), as assessed by the investigator.

Original Primary Outcome Measures (submitted: March 29, 2011)

To measure the number of patients with a response to study drug [ Time Frame: 24 weeks from first dose ]

Participants will be followed until progression of disease or start of another anti-cancer treatment.

Current Secondary Outcome Measures (submitted: March 2, 2017)

• Number of Patients With Adverse Events as a Measure of Safety and Tolerability [ Time Frame: Adverse events determined to be related to study drug are collected from first dose until study exit (approximately 3 years). ]
  Participants will be followed until progression of the disease or start of another anticancer treatment. The clinical database captured all AEs from baseline through end of treatment. Treatment Emergent AEs were collected pre-dose, at the beginning of each cycle and 30 days post last dose of study drug, unless related to study drug.
• Ibrutinib and Its Metabolite (PCI-45227) AUC0-24h After Repeat Dosing of PCI-32765 [ Time Frame: Performed during the first month of receiving study drug. ]
  Treatment Group 1 PK collection schedule: Cycle 1 Day 1: Pre-dose, 1, 2, 4, 7, and 24 hours post-dose Cycle 1 Day 8: Pre-dose, 1, 2, 4, 7, and 24 hours post-dose Cycle 1 Day 15: Pre-dose and 2 hours post-dose Cycle 1 Day 22: Pre-dose and 2 hours post-dose Treatment Group 2 PK collection schedule: Cycle 1 Day 8: Pre-dose, 1, 2, 4 and 7 hours post-dose Cycle 1 Day 15: Pre-dose and 2 hours post-dose Cycle 1 Day 22: Pre-dose and 2 hours post-dose Cycle 3 Day 1: Pre-dose, 1, 2, and 4 hours post-dose

Original Secondary Outcome Measures (submitted: March 29, 2011)

• To measure the number of patients with adverse events as a measure of safety and tolerability. [ Time Frame: For 30 days after the last dose of PCI-32765 ]
  Participants will be followed until progression of the disease or start of another anticancer treatment.
• To measure the number of participants pharmacokinetics to assist in determining how the body responses to the study drug. [ Time Frame: Procedure will be performed during the first month of receiving study drug. ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety and Efficacy Study of a BTK Inhibitor in Subjects With Relapsed or Refractory Diffuse Large B-cell Lymphoma
• Official Title: A Multicenter, Open-label, Phase 2, Safety and Efficacy Study of the Bruton's Tyrosine Kinase (Btk) Inhibitor, PCI-32765, in Subjects With Relapsed or Refractory or de Novo Diffuse Large B-cell Lymphoma (DLBCL)
• Brief Summary: The purpose of this study is to evaluate the efficacy of ibrutinib (PCI-32765) in relapsed/refractory de novo activated B-cell (ABC) and germinal-cell B-Cell (GCB) Diffuse Large B-cell Lymphoma (DLBCL).

Detailed Description

The primary objectives of this study were to evaluate the efficacy of ibrutinib administered at 560 mg once per day in relapsed or refractory de novo ABC and GCB DLBCL, and to evaluate the efficacy of ibrutinib administered at 840 mg once per day in relapsed or refractory de novo ABC DLBCL.

The secondary objective was to evaluate the safety and tolerability of a fixed daily oral dosing regimen of ibrutinib in relapsed/refractory de novo DLBCL.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Diffuse Large Cell B-lymphoma

Intervention

Drug: ibrutinib

ibrutinib is an inhibitor of BTK

Other Name: PCI-32765, Imbruvica

Study Arms

• Experimental: PCI-32765: 560 mg
  Treatment Group 1: Subjects received 560 mg of ibrutinib once daily, on a continuous basis.
  Intervention: Drug: ibrutinib
• Experimental: PCI-32765: 840 mg
  Treatment Group 2: Subjects received 840 mg of ibrutinib once daily, on a continuous basis.
  Intervention: Drug: ibrutinib

• Publications *: Wilson WH, Young RM, Schmitz R, Yang Y, Pittaluga S, Wright G, Lih CJ, Williams PM, Shaffer AL, Gerecitano J, de Vos S, Goy A, Kenkre VP, Barr PM, Blum KA, Shustov A, Advani R, Fowler NH, Vose JM, Elstrom RL, Habermann TM, Barrientos JC, McGreivy J, Fardis M, Chang BY, Clow F, Munneke B, Moussa D, Beaupre DM, Staudt LM. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015 Aug;21(8):922-6. doi: 10.1038/nm.3884. Epub 2015 Jul 20.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 30, 2016): 78
• Original Estimated Enrollment (submitted: March 29, 2011): 60
• Actual Study Completion Date: October 2014
• Actual Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Men and women ≥ 18 years of age.
2. ECOG performance status ≤ 2.
3. Pathologically confirmed de novo DLBCL
4. Subjects must have available tissue for central pathology review to be eligible. Treatment Group 2: Subjects will be eligible if they have the non-GCB phenotype, as confirmed by Central IHC testing by the Hans method.
5. Relapsed or refractory disease, defined as either: 1) recurrence of disease after a CR, or 2) PR, SD, or progressive disease (PD) at completion of the treatment regimen preceding entry to the study (residual disease): Subjects must have previously received an appropriate first-line treatment regimen. Subjects who have not received HDT/ASCT must be ineligible for HDT/ASCT
6. Treatment Group 1: Subjects must have ≥ 1 measurable (> 2 cm in longest dimension) disease sites on CT scan. Treatment Group 2: Subjects must have ≥ 1 measurable (> 1.5 cm in longest dimension) disease sites on CT scan.

Exclusion Criteria:

1. Transformed DLBCL or DLBCL with coexistent histologies (eg, FL or MALT).
2. Primary mediastinal (thymic) large B-cell lymphoma.
3. Known central nervous system lymphoma. In addition, for subjects in Treatment Group 2, known leptomeningeal involvement is exclusionary.
4. Certain exclusions on prior therapy
5. Major surgery within 2 weeks of first dose of study drug.

6. Any of the following laboratory abnormalities:

   1. ANC < 0.75 x 10^9/L. Treatment Group 2: Eligible subjects must be independent of growth factor support for 7 days prior to the screening lab tests.
   2. Platelet count < 50 x 10^9/L independent of transfusion support. Treatment Group 2 only: Eligible subjects must be independent of transfusion support for 7 days prior to the screening lab tests.
   3. AST or ALT ≥ 3.0 x upper limit of normal (ULN)
   4. Creatinine > 2.0 x ULN
   5. Treatment Group 2 only: Hemoglobin < 8.0 g/dL
   6. Treatment Group 2 only: Total Bilirubin > 1.5 x ULN
7. Requires or has received anticoagulation treatment with warfarin or equivalent Vitamin K antagonists (eg, phenprocoumon)
8. Treatment Group 2: Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor
9. Treatment Group 2: Known bleeding diathesis, eg, von Willebrand's disease, hemophilia.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01325701
• Other Study ID Numbers: PCYC-1106-CA; PCI-32765 ( Other Identifier: Pharmacyclics )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Pharmacyclics LLC.
• Original Responsible Party: Ahmed Hamdy, MD, Pharmacyclics
• Current Study Sponsor: Pharmacyclics LLC.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Darrin Beaupre, MD; Pharmacyclics LLC.

• PRS Account: Pharmacyclics LLC.
• Verification Date: March 2017