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.

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.

Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.

Up to 2 years