Copanlisib With Ibrutinib for Patients With Recurrent/ Refractory Primary Central Nervous System Lymphoma (PCNSL)

NCT03581942 | Completed Phase 1 FDA Drug

• 1 other identifier: 18-246
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 7

Brief Summary

The purpose of this study is to test the safety of combined use of the study drugs, copanlisib and ibrutinib, in people with PCNSL.

Conditions

Refractory/Recurrent Primary Central Nervous System Lymphoma (PCNSL)

Keywords

Copanlisib; Ibrutinib; Recurrent/ Refractory; PCNSL; Brain lymphoma; Primary Central Nervous System Lymphoma; BTK; PI3K

Outcome Measures

Primary Outcomes (2)

• maximum tolerated dose (MTD) (phase Ib)

  The "3+3" design will be applied in the phase Ib portion of the trial.

  1 year

• overall response rate (ORR) (phase II)

  To explore the therapeutic efficacy measured by overall response rate (ORR) of Copanlisib in combination with Ibrutinib in patients with refractory/relapsed PCNSL or newly diagnosed PCNSL not able to tolerate standard chemotherapy (phase II)This study will use the modified International Primary CNS Lymphoma Collaborative Group (IPCG)12.

  1 year

Secondary Outcomes (5)

• adverse events in terms of incidence and severity (phase Ib and II)

  2 years

• progression free survival (PFS) (phase II)

  2 years

• duration of response (DOR) (phase II)

  2 years

• overall survival (OS) (phase II)

  2 years

• To evaluate cerebral spinal fluid (CSF) pharmacokinetics of Copanlisib and Ibrutinib and correlate with plasma pharmacokinetics (phase Ib)

  2 years

Study Arms (1)

Copanlisib in combination with Ibrutinib

EXPERIMENTAL

Participants will be assigned to the following dose levels: Dose level 1: Ibrutinib 560 mg daily + Copanlisib 60 mg weekly (3w on/1w off) Dose level 2: Ibrutinib 840 mg daily + Copanlisib 60 mg weekly (3w on/1w off) Dose level -1: Ibrutinib 560 mg daily + Copanlisib 45 mg weekly (3w on/1w off). Phase II: (Simon two-stage design: 14 patients will be treated at the MTD (including 6 patients from the phaseIb portion) If at least 11 patients respond then an additional 19 patients will be accrued to the second stage. Patients in the phase II portion of the trial will receive sequential drug dosing. Patient will be treated in 28-day cycles. During one cycle, only one drug will be administered with a ibrutinib/copanlisib ratio of 1:2. Patients will receive Ibrutinib at 840 mg daily during cycle 1 (day 1 through day 28) (28-day cycles), then copanlisib 60mg weekly on day 1, 8, and 15 during cycle 2 and 3. Patients will then repeat the sequence.

Drug: Ibrutinib; Drug: Copanlisib

Interventions

Ibrutinib DRUG

(MTD) Dose Escalation level 2: Ibrutinib 840 mg daily

Copanlisib in combination with Ibrutinib

Copanlisib DRUG

(MTD) Copanlisib 60 mg weekly (3w on/1w off)

Copanlisib in combination with Ibrutinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and woman who are at least 18 years of age on the day of consenting to the study.
• Histologically documented PCNSL
• Relapsed/refractory PCNSL or newly diagnosed PCNSL patients who are deemed medically ineligible by the treating investigator (phase II only) to receive standard first-line chemotherapy. All recurrent/refractory patients need to have received at least one prior CNS directed therapy. There is no restriction on the number of recurrences.
• For recurrent/refractory patients, parenchymal lesions must have unequivocal evidence of disease progression on imaging (MRI of the brain or head CT) 21 days of study registration. For patients with leptomeningeal disease only, CSF cytology must document lymphoma cells and/or imaging findings consistent with CSF disease 21 days of study registration (at the discretion of the investigator).
• ECOG performance status ≤ 2.
• Life expectancy of \> 3 months (in the opinion of the investigator).
• Adequate bone marrow and organ function shown by:
• Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L
• Platelets ≥ 75 x 10\^9/L and no platelet transfusion within the past 14 days prior to study registration
• Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cell (RBC) transfusion within the past 14 days prior to study registration
• International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upper limit of normal
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the upper limit of normal
• Serum bilirubin ≤ 1.5 times the upper limit of normal; or total bilirubin ≤ 3 times the upper limit of normal with direct bilirubin within the normal range in patients with well documented Gilbert Syndrome
• Serum creatinine ≤ 2 times the upper limit of normal
• Creatinine clearance ≥ 30 mL/min

You may not qualify if:

• Patients eligible for this study must NOT MEET ANY of the following criteria:
• Active concurrent malignancy requiring active therapy
• Newly diagnosed PCNSL who qualify for standard methotrexate-based chemotherapy
• Excluded medical conditions:
• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure (New York Heart Association \> Class 2), unstable angina, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification
• Uncontrolled hypertension despite optimal medical management (per investigator"s assessment)
• Patient has poorly controlled diabetes mellitus with a glycosylated hemoglobin \>8% or poorly controlled steroid-induced diabetes mellitus with a glycosylated hemoglobin of \>8%
• Patient is known to have an uncontrolled active systemic infection (\>CTCAE grade 2) and recent infection requiring intravenous anti-infective treatment that was completed ≤14 days before the first dose of study drug
• Arterial or venous thrombotic or embolic events such as cerebrovascular accident, deep vein thrombosis or pulmonary embolism within 3 months before the start of study treatment
• Non-healing wound, ulcer or bone fracture
• Not recovered to a grade 1 from the toxic effects of prior therapy if clinically relevant in the opinion of the investigator (e.g. alopecia)
• Known bleeding diathesis (eg, von Willebrand"s disease) or hemophilia
• Known history of infection with human immunodeficiency virus (HIV) or history of active or chronic infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) as determined by serologic tests, or any uncontrolled active systemic infection
• Patient underwent major systemic surgery ≤ 2 weeks prior to starting the trial treatment or who has not recovered from the side effects of such surgery, or who plan to have surgery within 2 weeks of the first dose of the study drug
• Unable to swallow capsules or disease significantly affecting gastrointestinal function, such as malabsorption syndrome, resection of the stomach or small bowel, or complete bowel obstruction

Sponsors & Collaborators

• Memorial Sloan Kettering Cancer Center: lead

Study Sites (7)

Memorial Sloan Kettering Basking Ridge (Limited Protocol Activities)

Basking Ridge, New Jersey, 07920, United States

Location

Memorial Sloan Kettering Monmouth (Limited Protocol Activities)

Middletown, New Jersey, 07748, United States

Location

Memorial Sloan Kettering Bergen (Limited protocol Activities)

Montvale, New Jersey, 07645, United States

Location

Memorial Sloan Kettering Commack (Limited Protocol Activities)

Commack, New York, 11725, United States

Location

Memorial Sloan Kettering Westchester (Limited Protocol Activities)

Harrison, New York, 10604, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Memorial Sloan Kettering Nassau (Limited Protocol Activities)

Uniondale, New York, 11553, United States

Location

Related Links

• Memorial Sloan Kettering Cancer Center

MeSH Terms

Interventions

ibrutinib; copanlisib

Study Officials

• Christian Grommes, MD

  Memorial Sloan Kettering Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This is an open-label, phase Ib/II trial of the pan-Phosphoinositide 3-kinase (PI3K) inhibitor Copanlisib in combination with the Bruton Tyrosine Kinase (BTK) inhibitor Ibrutinib in patients with recurrent or refractory primary central nervous lymphoma (PCNSL and frail/elderly newly diagnosed PCNSL patients, not eligible to receive standard first-line chemotherapy).

Study Record Dates

• First Submitted: June 26, 2018
• First Posted: July 10, 2018
• Study Start: August 23, 2018
• Primary Completion: February 5, 2026
• Study Completion: February 5, 2026
• Last Updated: February 9, 2026

Record last verified: 2026-02

Locations

US (7)