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

February 21, 2024 updated by: Memorial Sloan Kettering Cancer Center

Phase IB/II Study Combining the PI3K Inhibitor Copanlisib With the BTK Inhibitor Ibrutinib in Patients With Recurrent/Refractory Primary CNS Lymphoma

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

Study Overview

Study Type

Interventional

Enrollment (Actual)

18

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

  • Name: Ingo Mellinghoff, MD
  • Phone Number: 646-888-2766

Study Locations

    • New Jersey
      • Basking Ridge, New Jersey, United States, 07920
        • Memorial Sloan Kettering Basking Ridge (Limited Protocol Activities)
      • Middletown, New Jersey, United States, 07748
        • Memorial Sloan Kettering Monmouth (Limited Protocol Activities)
      • Montvale, New Jersey, United States, 07645
        • Memorial Sloan Kettering Bergen (Limited Protocol Activities)
    • New York
      • Commack, New York, United States, 11725
        • Memorial Sloan Kettering Commack (Limited Protocol Activities)
      • Harrison, New York, United States, 10604
        • Memorial Sloan Kettering Westchester (Limited Protocol Activities)
      • New York, New York, United States, 10065
        • Memorial Sloan Kettering Cancer Center
      • Uniondale, New York, United States, 11553
        • Memorial Sloan Kettering Nassau (Limited protocol activities)

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

Patients eligible for inclusion in this study must meet ALL the following criteria:

  • 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
    • Lipase ≤ 1.5 x upper limit of normal
  • Women of childbearing potential (WOCBP) and men must agree to use effective contraception when sexually active. This applies for the time period between signing of the informed consent form and 30 days (for WOCBP) and 90 days (for men) after the last administration of study treatment. A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include but are not limited to hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for continuous 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy.

    • The investigator or a designated associate is requested to advise the patient how to achieve highly effective birth control (failure rate of less than 1%), e.g. intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner and sexual abstinence
    • The use of condoms by male patients is required unless the female partner is permanently sterile. Female subjects of childbearing potential must have a negative plasma pregnancy test upon study entry
  • Must be able to tolerate MRI/CT scans
  • Must be able to tolerate lumbar puncture and/or Ommaya taps
  • Must have recovered to grade 1 toxicity from prior therapy
  • Able to submit up to 20 unstained formalin-fixed, paraffin-embedded (FFPE) slides from the initial or most recent tissue diagnosis for correlative studies

NOTE: Prior autologous stem cell transplant as well as prior radiation to the CNS does NOT prevent patients from enrollment into the trial.

Exclusion Criteria:

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
  • Any life-threatening illness, medical condition including uncontrolled diabetes mellitus (DM), uncontrolled hypertension or organ system dysfunction that, in the opinion of the investigator, could compromise the subject"s safety or put the study outcomes at undue risk
  • Lactating or pregnant

Excluded previous Therapies and medications:

  • Any chemotherapy, external beam radiation therapy, or anticancer antibodies within 21 days of the first dose of study drug
  • Prior treatment with a PI3K inhibitor, AKT inhibitor, or mTOR inhibitor (prior ibrutinib exposure is allowed)
  • Any targeted anticancer therapy ≤ 4 weeks or 5 half-lives, whichever is shorter
  • Use of radio- or toxin-immunoconjugates within 70 days of the first dose of study drug
  • Concurrent use of warfarin or other vitamin K antagonists (need to be stopped 7 days prior to starting on trial drug)
  • Concurrent use of a strong cytochrome P450 (CYP) 3A4/5 inhibitor and inducers (see Appendix 1) (need to be stopped 2 weeks prior to starting on trial drug)
  • Enzyme-inducing antiepileptic drugs (EIAED) need to be discontinued and switched to a nonnon-EIAED 2 weeks prior to starting on trial drug)
  • Patient requires more than 4 mg of dexamethasone daily or the equivalent
  • Patient is using systemic immunosuppressant therapy, including cyclosporine A, tacrolimus, sirolimus, and other such medications, or chronic administration of > 5 mg/day or prednisone or the equivalent. Participants must be off of immunosuppressant therapy for at least 28 days prior to the first dose of the study drug
  • Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc., or chronic administration of > 5 mg/day of prednisone) within 28 days of the first dose of study drug
  • Prior allogeneic stem cell transplant

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Copanlisib in combination with Ibrutinib
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.
(MTD) Dose Escalation level 2: Ibrutinib 840 mg daily
(MTD) Copanlisib 60 mg weekly (3w on/1w off)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
maximum tolerated dose (MTD) (phase Ib)
Time Frame: 1 year
The "3+3" design will be applied in the phase Ib portion of the trial.
1 year
overall response rate (ORR) (phase II)
Time Frame: 1 year
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
adverse events in terms of incidence and severity (phase Ib and II)
Time Frame: 2 years
adverse events at each visit with the NCI CTCAE v4.03 used as a guide for the grading of severity.
2 years
progression free survival (PFS) (phase II)
Time Frame: 2 years
Progression-free survival (PFS) is defined as the time from the date of treatment start to the date of the first documented PD or death due to any cause.
2 years
duration of response (DOR) (phase II)
Time Frame: 2 years
Duration of response is defined as the time from the date of first occurrence of CR or PR to the date of the first documented PD or death due to any cause.
2 years
overall survival (OS) (phase II)
Time Frame: 2 years
Overall survival time (OS) is defined as the time from treatment start to the date of death due to any cause.
2 years
To evaluate cerebral spinal fluid (CSF) pharmacokinetics of Copanlisib and Ibrutinib and correlate with plasma pharmacokinetics (phase Ib)
Time Frame: 2 years
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Christian Grommes, MD, Memorial Sloan Kettering Cancer Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 23, 2018

Primary Completion (Estimated)

July 1, 2025

Study Completion (Estimated)

July 1, 2025

Study Registration Dates

First Submitted

June 26, 2018

First Submitted That Met QC Criteria

June 27, 2018

First Posted (Actual)

July 10, 2018

Study Record Updates

Last Update Posted (Estimated)

February 22, 2024

Last Update Submitted That Met QC Criteria

February 21, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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