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Copanlisib and Ibrutinib for the Treatment of Relapsed or Refractory Chronic Lymphocytic Leukemia

Trial Status: Active

This phase II trial studies the effect of copanlisib given in combination with ibrutinib in treating patients with chronic lymphocytic leukemia that has come back (relapsed) or does not respond to treatment (refractory). Copanlisib and ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving copanlisib together with ibrutinib may kill more cancer cells.

Inclusion Criteria

  • Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma as per IW-CLL 2018 criteria with evidence of persistent disease, defined as measurable adenopathy or splenomegaly, circulating disease, or marrow disease
  • On ibrutinib which was instituted due to the patient previously meeting IWCLL 2018 criteria for treatment, started at least 6 months prior to study entry
  • Must have received at least one prior line of therapy for CLL prior to ibrutinib
  • Must have achieved either SD, PR or partial response with residual lymphocytosis (PR-L) (with residual lymphadenopathy in addition to lymphocytosis) on ibrutinib by IW-CLL 2018 criteria
  • Eastern Cooperative Oncology Group (ECOG) performance status < 2
  • Patients must meet the following hematologic criteria at screening, unless they have significant bone marrow involvement of CLL confirmed on biopsy: * Absolute neutrophil count >= 500 cells/mm^3 (0.5 x 10^9/L). Growth factor is allowed in order to achieve this * Platelet count >= 50,000 cells/mm3 independent of transfusion within 7 days of screening
  • Serum aspartate transaminase (AST) and alanine transaminase (ALT) =< 3.0 x upper limit of normal (ULN)
  • Bilirubin =< 2.0 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin including hemolysis)
  • Serum creatinine =< 1.5 x ULN or creatinine clearance (by Cockroft-Gault >= 50 ml/min)
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation
  • Age greater than or equal to 18 years
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

  • Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy, surgery and/or tumor embolization) other than ibrutinib within 2 weeks of cycle 1/day 1 with the following exceptions: * Limited palliative radiation is allowed if completed >= 1 weeks of cycle 1 day 1 (C1D1) * Hormonal therapy given in the adjuvant setting * Corticosteroid therapy (prednisone or equivalent =< 15 mg daily) is allowed as clinically warranted as long as the dose is stabilized at least for 7 days prior to initial dosing. Topical or inhaled corticosteroids are permitted
  • Within six months of allogeneic hematologic stem cell transplant at the time of starting study treatment or active graft vs. host disease requiring systemic treatment or prophylaxis within 6 weeks of starting study treatment
  • Prior treatment with copanlisib
  • Patients in CR, or in partial response with residual lymphocytosis (PR-L) as their only remaining evidence of disease, on ibrutinib
  • History of other malignancies, except: * Malignancy treated with curative intent and with no known active disease present for >= 2 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Adequately treated carcinoma in situ without evidence of disease. * Low-risk prostate cancer on active surveillance
  • Vaccinated with live, attenuated vaccines < 4 weeks before first dose of study drug
  • Active autoimmune disease requiring systemic treatment
  • Recent infection requiring intravenous antibiotics that was completed =< 7 days before the first dose of study drug, or any uncontrolled active systemic infection
  • Known bleeding disorders (eg, von Willebrand’s disease) or hemophilia
  • History of stroke or intracranial hemorrhage within 6 months prior to enrollment
  • Human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or hepatitis B virus (HBV)
  • Cytomegalovirus (CMV) polymerase chain reaction (PCR) positive at baseline
  • Major surgery within 4 weeks of first dose of study drug
  • History of or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function (as judged by the investigator)
  • Concurrent diagnosis of pheochromocytoma
  • Uncontrolled arterial hypertension despite optimal medical management
  • Type 1 or type 2 diabetes mellitus with a hemoglobin (Hb)A1c > 8.5%
  • Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety
  • Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization
  • Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
  • Lactating or pregnant
  • Patients with known central nervous system (CNS) involvement
  • Concurrent administration of medications or foods that are strong inhibitors or inducers of CYP3A
  • Known hypersensitivity to copanlisib or ibrutinib


Brigham and Women's Hospital
Status: ACTIVE
Contact: Jennifer Crombie
Phone: 617-632-4106
Dana-Farber Cancer Institute
Status: ACTIVE
Contact: Jennifer Crombie
Phone: 617-632-4106


I. To assess the rate of complete response (CR) by International Workshop on Chronic Lymphocytic Leukemia (IW-CLL) criteria following the addition of six months of copanlisib to the therapy of patients with stable disease (SD) or partial response (PR) on ibrutinib in the relapsed/refractory setting.


I. To assess the safety and tolerability of ibrutinib plus copanlisib.

II. To assess the efficacy of ibrutinib plus copanlisib in CLL patients on ibrutinib with respect to:

IIa. MRD status in the bone marrow and blood.

IIb. Duration of Response (DOR), progression free survival (PFS) at 3 years, overall survival (OS) at 3 years.

III. To evaluate the association of established CLL prognostic factors including fluorescence in situ hybridization (FISH) cytogenetics, IGHV mutation status, ZAP-70, and TP53 mutation status with clinical response.


I. To evaluate changes in T-cell subpopulations by mass cytometry time of flight (CyTOF) in response to the study drugs and how these changes correlate with response and toxicity.

II. To assess the association of genomic markers such as SF3B1, NOTCH1, and BCR/NFKB pathway somatic mutation with clinical response.

III. To characterize genomic alterations as determined by whole exome sequencing (WES) and gene expression as determined by ribonucleic acid (RNA) sequencing (RNASeq) in CLL patients on treatment with ibrutinib plus copanlisib.

IV. To evaluate for resistance mechanisms such as BTK mutations in patients who progress on treatment.


Patients receive copanlisib hydrochloride intravenously (IV) over 1 hour on days 1, 8, and 15. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive ibrutinib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 5 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Jennifer Crombie

  • Primary ID 20-281
  • Secondary IDs NCI-2021-02127
  • ID NCT04685915