Copanlisib Plus Ibrutinib or Acalabrutinib in R/R CLL

  • End date
    Mar 1, 2028
  • participants needed
  • sponsor
    Inhye Ahn, MD
Updated on 2 June 2022
platelet count
chronic lymphocytic leukemia
gilbert's syndrome
neutrophil count


This research study is examining the effect of adding a fixed duration of copanlisib to ibrutinib or acalabrutinib in select participants who have been on ibrutinib or acalabrutinib for at least six months for relapsed/refractory chronic lymphocytic leukemia (CLL).

The names of the study drugs involved in this study are:

  • Copanlisib
  • Ibrutinib
  • Acalabrutinib


This is an open-label, phase II study, adding copanlisib to ibrutinib or acalabrutinib in select participants who are receiving ibrutinib for relapsed/refractory CLL.

Copanlisib has not been approved by the U.S. Food and Drug Administration (FDA) for CLL, but it has been approved for use in relapsed/refractory follicular lymphoma. Ibrutinib and acalabrutinib are approved by the FDA as a treatment option for CLL.

This research study is:

  • Trying to understand what effects, good or bad, treatment with copanlisib in combination with ibrutinib or acalabrutinib has in select participants who are receiving ibrutinib for relapsed/refractory CLL
  • Determining if this approach is better or worse than the usual approach for this type of cancer
  • Determining whether genomic changes in CLL cells and changes in immune response make treatment with the study drugs more or less effective

The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.

Participants will receive combination therapy for six months before resuming ibrutinib alone. They will continue therapy for as long as they do not have serious side effects and their disease does not get worse and will be followed for up to 5 years.

It is expected that about 30 people will take part in this research study.

Bayer HealthCare Pharmaceuticals is supporting this research study by providing the study drug, copanlisib. Ibrutinib and acalabrutinib will be obtained from commercial supply.

Condition Chronic Lymphocytic Leukemia (CLL)
Treatment Ibrutinib, acalabrutinib, Copanlisib
Clinical Study IdentifierNCT04685915
SponsorInhye Ahn, MD
Last Modified on2 June 2022


Yes No Not Sure

Inclusion Criteria

Must have a confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma as per 2018 IWCLL criteria with evidence of persistent disease, defined as measurable adenopathy or splenomegaly, circulating disease, or marrow disease
On ibrutinib or acalabrutinib which was instituted due to patient previously meeting 2018 IWCLL criteria for treatment, started at least 6 months prior to study entry for any patient who have received at least one prior line of therapy prior to ibrutinib or acalabrutinib. Reduced dose of ibrutinib or acalabrutinib is allowed as long as the dose has been stable for at least 4 weeks and all toxicities are ≤ grade 1
Must have achieved either SD, PR or PR-L on ibrutinib or acalabrutinib by 2018 IWCLL criteria
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/mm3 (0.5 x 109/L). Growth factor is allowed in order to achieve this
Platelet count ≥50,000 cells/mm3 independent of transfusion within 7 days of screening
Adequate hepatic function defined as: 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)
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
Adequate renal function defined by serum creatinine ≤1.5 x ULN or creatinine clearance (by Cockroft-Gauldt ≥ 50 ml/min
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 or acalabrutinib within 2 weeks of Cycle 1/Day 1 with the following exceptions
Limited palliative radiation is allowed if completed > 1 weeks of 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
Prior treatment with copanlisib
Within six months of allogeneic hematologic stem cell transplant at the time of
starting study treatment or active graft vs. host disease requiring systemic
History of other malignancies, except
treatment or prophylaxis within 6 weeks of starting study treatment
Patients in CR or partial response with lymphocytosis (PR-L) on ibrutinib or acalabrutinib
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
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
Low-risk prostate cancer on active surveillance
Vaccinated with live, attenuated vaccines <4 weeks before first dose of study drug
Adequately treated carcinoma in situ without evidence of disease
Active autoimmune disease requiring systemic treatment
Known bleeding disorders (eg, von Willebrand's disease) or hemophilia
History of stroke or intracranial hemorrhage within 6 months prior to enrollment
Recent infection requiring intravenous antibiotics that was completed ≤7 days before the first dose of study drug, or any uncontrolled active systemic infection
Human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or hepatitis B virus (HBV)
CMV 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
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
Type 1 or type 2 diabetes mellitus with a HgbA1c > 8.5%
Lactating or pregnant
Patients with known CNS involvement
Concurrent administration of medications or foods that are strong inhibitors or inducers of CYP3A
Known hypersensitivity to copanlisib, ibrutinib, or acalabrutinib
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Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

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If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

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Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

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