Ibrutinib, Fludarabine, and Pembrolizumab in High-Risk or Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Summary

Background:

Chronic lymphocytic leukemia and small lymphocytic lymphoma (hereby referred as CLL) are tumors of B cells. A subset of patients categorized as high-risk CLL has a poor clinical outcome when treated with conventional chemotherapy. This single-arm, phase II study investigates the combination of ibrutinib, fludarabine and pembrolizumab for treatment of CLL. Ibrutinib is an orally administered therapy for CLL. Fludarabine is a well-tolerated drug that has been widely used to treat CLL. Also, fludarabine can modulate CLL cells as well as immune cells that support the growth of CLL cells. Pembrolizumab recruits immune cells to attack CLL cells. With this approach we hope to achieve a greater reduction in CLL cells than with single agent ibrutinib and to restore healthier immune system that could contribute to durable responses.

Objective:

To investigate the rate of complete response to ibrutinib, short course fludarabine and pembrolizumab.

Eligibility:

Patients with active CLL meeting treatment indications defined by 2008 International Workshop on CLL (IWCLL) consensus guideline.

High-risk CLL defined by one of the following:

* Relapsed/refractory disease status, or
* Presence of high-risk mutations regardless of prior treatment status: deletion 17p, TP53 mutation, NOTCH1 mutation, SF3B1 mutation, MYC aberration, or complex cytogenetics.

Design:

This is a single-arm, open-label phase II study.

Timeline: Treatment on this study is given in cycles from cycle -3 to 17, then in months beyond cycle 17. Cycles -3 to -1 are 28-day cycles. Cycles 1 to 17 are 21-day cycles. After completion of 1 year of pembrolizumab, the time on study is by chronological months on study from starting pembrolizumab.

Treatment plan:

* Ibrutinib is given starting from cycle -3 and continuously until disease progression or intolerable side effects occur.
* Fludarabine is given on D1-D5 on cycle -2 only
* Pembrolizumab is given every 3 weeks starting from cycle 1 for 1 year.
* Minimal residual disease will be measured at 2 years from cycle 1 to determine the need for long- term treatment with ibrutinib.

* Previously-untreated patients who achieve minimal residual disease negativity will stop ibrutinib.
* Patients who do not achieve minimal residual disease negativity or who has Relapsed/refractory CLL will continue ibrutinib.

Conditions

• B-Cell Chronic Lymphocytic Leukemia
• B-Lymphocytic Leukemia, Chronic
• Chronic Lymphocytic Leukemia
• Leukemia, Chronic Lymphatic
• Leukemia, Chronic Lymphocytic, B-Cell
• Leukemia, Lymphocytic, Chronic
• Leukemia, Lymphocytic, Chronic, B-Cell
• Lymphocytic Leukemia, Chronic, B Cell
• Lymphocytic Leukemia, Chronic, B-Cell

Interventions

DRUG

Ibrutinib

Ibrutinib will be administered daily by mouth starting cycle -3 at 420 mg until end study or disease progression or intolerable side effects occur.

DRUG

Fludarabine

Fludarabine will be administered intravenously only on cycle -2 at 25mg/m\^2 x5 days.

DRUG

Pembrolizumab

Pembrolizumab will be administered intravenously every 3 weeks at 200 mg starting from cycle 1 through cycle 17 or 1 year of immunotherapy phase.

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI)

  lead NIH

Principal Investigators

• Adrian U Wiestner, M.D. · National Heart, Lung, and Blood Institute (NHLBI)

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2017-09-22

Primary Completion

2022-07-18

Completion

2026-01-09

FDA Drug

Yes

Countries

• United States

Study Locations