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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03581942
Recruitment Status : Recruiting
First Posted : July 10, 2018
Last Update Posted : June 12, 2020
Sponsor:
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

Tracking Information
First Submitted Date  ICMJE June 26, 2018
First Posted Date  ICMJE July 10, 2018
Last Update Posted Date June 12, 2020
Actual Study Start Date  ICMJE August 23, 2018
Estimated Primary Completion Date July 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 28, 2018)
  • 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.
  • overall response rate (ORR) (phase II) [ Time Frame: 1 year ]
    This study will use the modified International Primary CNS Lymphoma Collaborative Group (IPCG)12.
Original Primary Outcome Measures  ICMJE
 (submitted: June 27, 2018)
maximum tolerated dose (MTD) [ Time Frame: 1 year ]
The "3+3" design will be applied in the phase Ib portion of the trial.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 28, 2018)
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Copanlisib With Ibrutinib for Patients With Recurrent/ Refractory Primary Central Nervous System Lymphoma (PCNSL)
Official Title  ICMJE Phase IB/II Study Combining the PI3K Inhibitor Copanlisib With the BTK Inhibitor Ibrutinib in Patients With Recurrent/Refractory Primary CNS Lymphoma
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
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).
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Refractory/Recurrent Primary Central Nervous System Lymphoma (PCNSL)
Intervention  ICMJE
  • Drug: Ibrutinib
    Dose level 1: Ibrutinib 560 mg daily, Dose level 2: Ibrutinib 840 mg daily, Dose level -1: Ibrutinib 560 mg daily
  • Drug: Copanlisib
    Copanlisib 60 mg weekly (3w on/1w off), Copanlisib 60 mg weekly (3w on/1w off), Copanlisib 45 mg weekly (3w on/1w off)
Study Arms  ICMJE Experimental: Copanlisib in combination with Ibrutinib
The "3+3" design will be applied in the phase Ib portion of the trial. 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).In the phase II portion a Simon two-stage design will be used. At the first stage, 14 patients will be enrolled at the MTD. If at least 11 patients respond then an additional 19 patients will be accrued to the second stage.Up to 15 patients with newly diagnosed PCNSL not eligible to receive standard first-line therapy(based on the treating physicians assessment) as these patients might benefit from first-line therapy without significant chemotherapy-associated adverse events). Participants will remain on treatment until tumor progression, as long as there are no unacceptable toxicities.
Interventions:
  • Drug: Ibrutinib
  • Drug: Copanlisib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 27, 2018)
45
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2021
Estimated Primary Completion Date July 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Christian Grommes, MD 212-610-0344 grommesc@mskcc.org
Contact: Ingo Mellinghoff, MD 646-888-2766
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03581942
Other Study ID Numbers  ICMJE 18-246
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Memorial Sloan Kettering Cancer Center
Study Sponsor  ICMJE Memorial Sloan Kettering Cancer Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Christian Grommes, MD Memorial Sloan Kettering Cancer Center
PRS Account Memorial Sloan Kettering Cancer Center
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP