Copanlisib Plus Ibrutinib or Acalabrutinib in R/R CLL

Sponsor

Inhye Ahn, MD (Other)

Overall Status

Recruiting

CT.gov ID

NCT04685915

Collaborator

Bayer (Industry)

Enrollment

Location

Arm

84.4

Anticipated Duration (Months)

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia (CLL)	Drug: Ibrutinib Drug: Copanlisib Drug: Acalabrutinib	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase II Study of Copanlisib to Deepen Response in CLL Patients on Ibrutinib or Acalabrutinib in the Relapsed/Refractory Setting

Actual Study Start Date :

Feb 18, 2021

Anticipated Primary Completion Date :

Mar 1, 2023

Anticipated Study Completion Date :

Mar 1, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ibrutinib + Copanlisib/Acalabrutinib During 28 day study treatment cycle, participants will: Take Ibrutinib (daily) or Acalabrutinib (twice a day) at predetermined dose for as long as there are no serious side effects and disease progression Receive intravenous infusion of Copanlisib at a predetermined dose days 1, 8 and 15 for cycles 1-6.	Drug: Ibrutinib Capsule, taken by mouth once daily Other Names: Imbruvica Drug: Copanlisib Intravenous Infusion Other Names: Aliqopa Drug: Acalabrutinib Capsule, taken by mouth twice daily Other Names: Calquence

Arm

Intervention/Treatment

Experimental: Ibrutinib + Copanlisib/Acalabrutinib

During 28 day study treatment cycle, participants will: Take Ibrutinib (daily) or Acalabrutinib (twice a day) at predetermined dose for as long as there are no serious side effects and disease progression Receive intravenous infusion of Copanlisib at a predetermined dose days 1, 8 and 15 for cycles 1-6.

Drug: Ibrutinib

Capsule, taken by mouth once daily

Other Names:

Imbruvica

Drug: Copanlisib

Intravenous Infusion

Other Names:

Aliqopa

Drug: Acalabrutinib

Capsule, taken by mouth twice daily

Other Names:

Calquence

Outcome Measures

Primary Outcome Measures

Complete response (CR) Rate [6 months]
Rate of complete response (CR) by 2018 IWCLL criteria following the addition of six months of copanlisib to the therapy of patients with SD or PR or PR-L on ibrutinib or acalabrutinib in the relapsed/refractory setting.

Secondary Outcome Measures

Number of Participants with Treatment Related Adverse Events as Assessed by CTCAE ver. 5.0. [6 months]
Adverse events will be collected and reported as percentages
Duration of Response (DOR) [3 years]
Legnth of time the patients respond to therapy
Progression-free Survival (PFS) [3 years]
The time from registration to progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation.
Overall Survival (OS) [3 years]
The time from registration to death due to any cause or censored at date last known alive.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)
Adequate renal function defined by serum creatinine ≤1.5 x ULN or creatinine clearance (by Cockroft-Gauldt ≥ 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
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
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 partial response with lymphocytosis (PR-L) on ibrutinib or acalabrutinib
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)
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
Type 1 or type 2 diabetes mellitus with a HgbA1c > 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 CNS involvement
Concurrent administration of medications or foods that are strong inhibitors or inducers of CYP3A
Known hypersensitivity to copanlisib, ibrutinib, or acalabrutinib