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

  • STATUS
    Recruiting
  • End date
    Jul 23, 2023
  • participants needed
    45
  • sponsor
    Memorial Sloan Kettering Cancer Center
Updated on 23 June 2021

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.

Details
Condition Refractory/Recurrent Primary Central Nervous System Lymphoma (PCNSL)
Treatment Ibrutinib, Copanlisib
Clinical Study IdentifierNCT03581942
SponsorMemorial Sloan Kettering Cancer Center
Last Modified on23 June 2021

Eligibility

Yes No Not Sure

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
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
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Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

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If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

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Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

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