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

NCT03204188 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 17011817-H-0118
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief 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, Lymphocytic, Chronic; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytic Leukemia, Chronic, B Cell; Lymphocytic Leukemia, Chronic, B-Cell; Leukemia, Chronic Lymphocytic, B-Cell

Keywords

Deletion 17p; TP53 Mutation; NOTCH1 mutation; Complex Cytogenetics; Bruton's Tyrosine Kinase (BTK) Inhibitor

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Complete Response of the Combination of Ibrutinib, Fludarabine, and Pembrolizumab in Patients With High-risk and/or Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Leukemia

  Rate of complete response with combination ibrutinib, fludarabine, and pembrolizumab in patients with high-risk and/or relapsed/refractory chronic lymphocytic leukemia and small lymphocytic leukemia. Response assessments defined by IWCLL 2008 guidelines incorporating the 2012 and 2013 clarifications for patients treated with kinase inhibitors. Complete response defined as: Lymphadenopathy is none \> 1.5 cm; No Splenomegaly or Hepatomegaly; Blood Lymphocytes \<4000/uL; Bone Marrow is normocellular, \<30% lymphocytes, no B-lymphoid nodules; Platelet count \>100,000/uL; Hemoglobin \> 11.0 g/dL and Neutrophils \>1500/uL. Partial response is defined by meeting 2 criteria: Lymphadenopathy decrease \> or = 50%; Splenomegaly or Hepatomegaly decrease \> or = 50%; Blood Lymphocytes decrease \> or = 50% from baseline; Platelet is \> 100,000/uL or increase \> or = 50% over baseline; Hemoglobin is \> 11.0 g/dL or increase \> or = 50% over baseline; Neutrophils is \> 1500/uL or increase \> or = 50% over baseline.

  1 year

Secondary Outcomes (1)

• Tolerability, Response and Best Response, Survival

  2 years

Study Arms (1)

Ibrutinib, Fludarabine, and Pembrolizumab in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

EXPERIMENTAL

Ibrutinib, Fludarabine, and Pembrolizumab combination therapy will be administered in participants with High-Risk or Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL). Ibrutinib will be administered daily by mouth starting cycle -3 at 420 mg until end study or disease progression or intolerable side effects occur. Fludarabine will be administered intravenously only on cycle -2 at 25mg/m\^2 x5 days. Pembrolizumab will be administered intravenously every 3 weeks at 200 mg starting from cycle 1 through cycle 17 or 1 year of immunotherapy phase.

Drug: Ibrutinib; Drug: Fludarabine; Drug: Pembrolizumab

Interventions

Ibrutinib DRUG

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

Also known as: Imbruvica

Ibrutinib, Fludarabine, and Pembrolizumab in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Fludarabine DRUG

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

Also known as: Fludara

Ibrutinib, Fludarabine, and Pembrolizumab in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Pembrolizumab DRUG

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

Also known as: Keytruda

Ibrutinib, Fludarabine, and Pembrolizumab in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and women with histologically confirmed CLL or SLL
• Active disease as defined by at least one of the following IWCLL consensus criteria:
• Weight loss greater than or equal to 10% within the previous 6 months.
• Extreme fatigue.
• Fevers of greater than 100.5 degrees F for greater than or equal to 2 weeks without evidence of infection.
• Night sweats for more than one month without evidence of infection.
• Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia.
• Massive or progressive splenomegaly.
• Massive nodes or clusters or progressive lymphadenopathy.
• Progressive lymphocytosis with an increase of \>50% over a 2-month period, or an anticipated doubling time of less than 6 months.
• High-risk disease defined by meeting at least one of the following three criteria:
• Relapsed and/or refractory CLL/SLL.
• Presence of high-risk mutations detected by FISH or targeted sequencing, regardless of prior treatments status.
• FISH: deletion 17p (or TP53), complex cytogenetics (3 or more abnormalities)
• Targeted sequencing: TP53 mutations, SF3B1 mutations, or NOTCH1 mutation. Pathologic mutations occurring at the coding regions are accepted as relevant mutations.

You may not qualify if:

• Transformation of CLL into lymphomas other than those with Hodgkin-like cells.
• Currently receiving or previously participated to receive an investigational agent within 4 weeks prior to study treatment.
• Currently receiving or previously received monoclonal antibodies, immunomodulatory therapy, chemotherapy, radiation, or radioimmunotherapy within 4 weeks prior to study treatment, or has not recovered from non-hematologic adverse events due to a previously administered agent.
• Major surgery within 4 weeks of first dose of study drug
• Currently receiving systemic steroid therapy (i.e. prednisone) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
• Prior therapy with BTK inhibitor, anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
• Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g.., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Known additional malignancy that is progressing or requires active treatment.
• Known history of, or any evidence of active, non-infectious pneumonitis that required steroids.
• Known bleeding disorders (i.e., von Willebrand s disease or hemophilia).
• Known HIV infection
• Active hepatitis B or hepatitis C infection.
• Recent known active infection requiring systemic therapy that was completed less than or equal to 14 days before the first dose of study drug.
• Known history of active tuberculosis.
• Any uncontrolled active systemic infection.

Sponsors & Collaborators

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

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Chromosome 17 deletion

Interventions

ibrutinib; fludarabine; fludarabine phosphate; pembrolizumab

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Adrian Wiestner, M.D., Ph.D., Principal Investigator
• Organization: National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (NHLBI)

wiestnea@nhlbi.nih.gov

301-594-6855

Study Officials

• Adrian U Wiestner, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 28, 2017
• First Posted: June 29, 2017
• Study Start: September 22, 2017
• Primary Completion: July 18, 2022
• Study Completion: January 9, 2026
• Last Updated: January 30, 2026
• Results First Posted: April 19, 2023

Record last verified: 2026-01

Locations

US (1)