A Study of Copanlisib and Ibrutinib in Mantle Cell Lymphoma

Study Overview
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Brief Summary
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The purpose of this study is to test the safety and any good and bad side effects of combining 2 study drugs, copanlisib and ibrutinib. This combination of drugs could shrink your Mantle Cell Lymphoma (MCL), but it could also cause side effects. Both these drugs have been given to people before, but this is the first time that they are being given together.

Official Title
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Phase I/II Clinical Trial of Copanlisib and Ibrutinib in Mantle Cell Lymphoma

Conditions
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Mantle Cell Lymphoma (MCL)

Intervention / Treatment
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* Drug: Copanlisib
* Drug: Ibrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient is ≥ 18 years of age at the time of signing Informed Consent Patient is able and willing to adhere to the study visit schedule and other protocol requirements Patient has histologically confirmed diagnosis of R/R mantle cell lymphoma who has received at least 1 line of therapy °Autologous stem cell transplant recipients must have adequate bone marrow recovery and transfusion independent Patients may have been previously treated with BTK or PI3K inhibitors: °If BTK/P13K inhibitors were part of their last treatment, patients must have had a best response of stable disease or better Patient has at least one measurable lesion (≥ 2 cm) according to RECIL criteria[37] Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Patient has adequate bone marrow and organ function by: Absolute neutrophil count (ANC) ≥ 1 x 10^9/L , independent of growth factor support for 14 days unless there is bone marrow involvement. For patients with bone marrow involvement, ANC ≥ 500/uL independent of growth factor support for 14 days Platelets ≥100 x 10^9/L, or ≥50 x 10^9/L if bone marrow involvement and independent of transfusion support for 14 days in either situation Hemoglobin (Hgb) ≥ 9.0 g/dL (no RBC transfusion within past 14 days) International Normalized Ratio (INR) ≤ 1.5 Serum Creatinine ≤ 1.5 x upper limit of normal (ULN) or creatinine clearance ≥ 25 mL/min as determined by the Cockcroft-Gault equation or a 24 hour urine collection Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ ULN (or ≤ 3 x ULN if liver involved with disease Total serum bilirubin ≤ ULN (or ≤ 1.5 x ULN if documented hepatic involvement; or total bilirubin ≤ 3 x ULN with direct bilirubin ≤ 1.5 x ULN in patients with documented Gilbert's Syndrome. Lipase ≤ 1.5x ULN LVEF ≥ 50% Hemoglobin A1c ≤ 8.5% Exclusion Criteria: Patient has a history of non-compliance to medical regimen or inability to grant consent Patient is concurrently using other approved or investigational antineoplastic agent with the exception of BTK or Pi3K inhibitors in patients who had these agents as the last line of treatment °Patient on BTK or P13K inhibitors will be continued on therapy as they transition to protocol therapy Patient has not recovered to Grade 1 or better (except alopecia) from related side effects of any prior antineoplastic therapy Patient has had major surgery or a wound that has not fully healed within 4 weeks of starting study drugs. Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier. Patients who have undergone an allogenic hematopoietic stem cell transplant Patient has active or history of central nervous system (CNS) disease or meningeal involvement. Patient has history of clinically significant interstitial lung disease and/or lung disease that severely impairs lung function (as judged by the investigator) Patient has history of stroke or intracranial hemorrhage ≤ 6 months from starting study drugs. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) Patient has clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification, Left Ventricular Ejection Fraction (LVEF) <50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO), unstable angina pectoris, symptomatic pericarditis, QTcF > 480 msec on the screening ECG (using the QTcF formula) Patient has a concurrent active malignancy. Malignancies treated with a curative intent with an expected life expectancy ≥ 5 years or a non-competing life expectancy risk are eligible (i.e. adequately treated basal or squamous cell carcinoma, non-melanomatous skin cancer, early stage breast cancer, treated prostate cancer or any other cancer from which the patient has been disease free for ≥ 3 years). Patient with known history of human immunodeficiency virus (HIV), or any uncontrolled active systemic infection. Patient has CMV viremia (peripheral blood CMV PCR positive), acute viral hepatitis (typically defined by elevated AST/ALT), or a history of chronic or active HBV or HCV infection. HBV infection is defined as having HBsAg and/or HBcAb positive test with concurrent detectable HBV DNA levels. HCV infection is defined as detectable HCV RNA levels. Patient requires treatment with a strong or moderate cytochrome P450 (CYP) 3A4 inhibitors, and inducers, and the treatment cannot be discontinued or switched to a different medication prior to starting study drug. Moderate and strong CYP modulators (inducers and inhibitors) should have a washout period of at least 5-6 half-lives before initiating ibrutinib or copanlisib. Patients with known bleeding diathesis (e.g. von Willebrand 's disease) or hemophilia Patient is currently receiving warfarin or other Vitamin K antagonist. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed. Refer to Section 9.5 for Concomitant medication Patients with Child Pugh Class B or C hepatic cirrhosis Patients with any life threatening illness, medical condition or organ system dysfunction that in the opinion of the investigator could compromise the subject's safety, interfere with absorption of metabolism of study drugs or put the study outcomes at undue risk.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: This is a two stage protocol comprised of a single institution phase I dose escalation trial using standard 3+3 design and a phase II two stage Simon mini-max clinical trial.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Copanlisib and Ibrutinib<br>Copanlisib is given intravenously on days 1, 8, and 15 of 28 day cycles. Ibrutinib is given orally every day on 28 days cycles. The maximum duration of treatment is 36 cycles not exceeding 36 months. In the phase II study, the cohort will expand and accrue patients at the recommended phase II dose of copanlisib and ibrutinib determined during phase I dose escalation. In a simon two stage mini-max design, an initial 18 patients will be enrolled, inclusive of 6 patients treated at MTD or RP2D from phase I study, in first stage. | Drug: Copanlisib<br>* Treatment will be with intravenous copanlisib on days 1, 8, 15 of 28 day cycles.<br>Drug: Ibrutinib<br>* Oral ibrutinib daily in 28 day cycles. A cycle is defined as 28 days of therapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response | using the RECIL criteria | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Copanlisib, Ibrutinib, 18-450