What is the mechanism of action of this treatment?

The most common treatments for Central Nervous System Lymphoma (CNSL) include targeted therapies such as PI3K inhibitors (e.g., Copanlisib) and BTK inhibitors (e.g., Ibrutinib). PI3K inhibitors block the phosphoinositide 3-kinase pathway, which is essential for cell growth and survival, thereby reducing lymphoma cell proliferation. BTK inhibitors target Bruton's tyrosine kinase, disrupting critical B-cell receptor signaling necessary for lymphoma cell survival. These targeted mechanisms are crucial for CNSL patients as they offer potentially more effective and less toxic treatment options in the challenging central nervous system environment.

What side effects are associated with this type of intervention?

Common side effects of treatments for Central Nervous System Lymphoma, particularly with PI3K inhibitors like copanlisib and BTK inhibitors like ibrutinib, include headache, fatigue, hypocalcemia, hypokalemia, hypophosphatemia, increased liver enzymes, and an increased risk of bleeding. These treatments are generally aimed at managing recurrent or refractory cases and are being studied for their safety and efficacy in combination.

What prior FDA approvals exist?

The FDA has approved several treatments for Central Nervous System Lymphoma (CNSL), though specific approvals for PI3K inhibitors like copanlisib and BTK inhibitors like ibrutinib in CNSL are not detailed in the provided context. Generally, treatments for CNSL have included high-dose methotrexate-based chemotherapy, often combined with other agents such as cytarabine. The investigational use of targeted therapies, including PI3K inhibitors and BTK inhibitors, is being explored in clinical trials to improve outcomes for patients with recurrent or refractory CNSL.

What other types of research exist?

Promising novel alternatives for Central Nervous System Lymphoma patients include chimeric antigen receptor (CAR) T-cell therapies, bispecific T cell engagers (BiTEs), and immune checkpoint inhibitors. Specific agents to consider are idecabtagene vicleucel, teclistamab, and nivolumab. These therapies are being evaluated for their efficacy in various lymphomas and may offer new treatment avenues for PCNSL.

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PI3K inhibitor

Copanlisib + Ibrutinib for Central Nervous System Lymphoma

Phase 1 & 2

Waitlist Available

Led By Christian Grommes, MD

Research Sponsored by Memorial Sloan Kettering Cancer Center

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

- Serum creatinine ≤ 2 times the upper limit of normal

- Creatinine clearance ≥ 30 mL/min

Must not have

Newly diagnosed PCNSL who qualify for standard methotrexate-based chemotherapy

- Prior treatment with a PI3K inhibitor, AKT inhibitor, or mTOR inhibitor (prior ibrutinib exposure is allowed)

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 2 years

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing the safety of using two drugs, copanlisib and ibrutinib, together. The study focuses on patients with a type of brain and spinal cord cancer called PCNSL. These drugs work by blocking proteins that cancer cells need to grow.

Who is the study for?

Adults with primary central nervous system lymphoma (PCNSL) that's come back or hasn't responded to treatment, or those newly diagnosed but can't have standard chemo. They must be able to handle MRI/CT scans and lumbar punctures, have a life expectancy over 3 months, and good organ function. Contraception is required during the study.

What is being tested?

The trial tests the safety of combining two drugs, copanlisib and ibrutinib, for treating PCNSL. Participants will receive both medications in an effort to determine how well they work together against this type of lymphoma.

What are the potential side effects?

Possible side effects include high blood sugar levels especially in diabetics; bleeding issues; digestive problems affecting absorption; potential interactions with other drugs like warfarin or certain antiepileptics; risk of infection including HIV/HBV/HCV; heart complications.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My kidney function, measured by creatinine, is within normal limits.

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My kidneys are functioning well enough (creatinine clearance ≥ 30 mL/min).

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My blood tests show my organs and bone marrow are working well.

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I can take care of myself but might not be able to do heavy physical work.

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My hemoglobin is at least 8 g/dL and I haven't had a blood transfusion in the last 2 weeks.

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My bilirubin levels are within the normal range or slightly above.

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I agree to use birth control during and after the study as required.

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I am using contraception or am not of childbearing potential.

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I can undergo spinal taps or Ommaya reservoir procedures.

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My diagnosis of primary central nervous system lymphoma is confirmed by tissue analysis.

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My platelet count is above 75 x 10^9/L without transfusions in the last 2 weeks.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have been newly diagnosed with primary CNS lymphoma and can receive methotrexate chemotherapy.

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I have previously been treated with a PI3K, AKT, or mTOR inhibitor, but ibrutinib is allowed.

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My diabetes is not well-managed, with a HbA1c level over 8%.

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I haven't had a stroke, deep vein thrombosis, or lung clot in the last 3 months.

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I do not have HIV, hepatitis B or C, or any uncontrolled infections.

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I have not had major surgery within the last 2 weeks and have no plans for surgery in the next 2 weeks.

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I haven't had chemotherapy, radiation, or cancer antibodies in the last 21 days.

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I haven't taken any targeted cancer drugs in the last 4 weeks or less.

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I stopped taking seizure medications that affect enzymes 2 weeks before starting the trial drug.

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I need more than 4 mg of dexamethasone or its equivalent daily.

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I haven't taken strong immune system suppressants or more than 5 mg/day of prednisone in the last 28 days.

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I have had a stem cell transplant from a donor.

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I have a bleeding disorder such as von Willebrand's disease or hemophilia.

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I have a wound, ulcer, or bone fracture that is not healing.

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I don't have a severe infection or have finished IV treatment for one within the last 14 days.

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I am currently receiving treatment for another cancer.

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I do not have serious heart problems like recent heart attacks or uncontrolled heart failure.

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I cannot swallow pills or have serious digestive issues.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 2 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~2 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and 2 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

maximum tolerated dose (MTD) (phase Ib)

overall response rate (ORR) (phase II)

Secondary study objectives

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

duration of response (DOR) (phase II)

overall survival (OS) (phase II)

+1 more

Side effects data

From 2021 Phase 2 trial • 24 Patients • NCT02631590

75%

Platelet count decreased

75%

Lymphocyte count decreased

71%

Fatigue

71%

White blood cell decreased

67%

Anemia

67%

Neutrophil count decreased

63%

Hypertension

54%

Hyperglycemia

50%

Nausea

46%

Diarrhea

46%

Lipase increased

46%

Anorexia

42%

Alanine aminotransferase increased

42%

Abdominal Pain

33%

Fever

29%

Hyponatremia

25%

Weight loss

25%

Dehydration

25%

Hyperkalemia

25%

Hypotension

25%

Vomiting

25%

Constipation

25%

Rash maculo-papular

21%

Edema limbs

21%

Aspartate aminotransferase increased

21%

Serum amylase increased

17%

Chills

17%

Pain

17%

Alkaline phosphatase increased

17%

Creatinine increased

17%

Thromboembolic event

17%

Sinus tachycardia

17%

Dizziness

13%

Pain in extremity

13%

Generalized muscle weakness

13%

Dyspnea

13%

Blood bilirubin increased

13%

Hypoalbuminemia

13%

Infusion related reaction

13%

Non-cardiac chest pain

13%

Gastrointestinal disorders - Other

13%

Mucositis oral

13%

Sepsis

13%

Upper respiratory infection

13%

Urinary tract infection

13%

Anxiety

13%

Tinnitus

Back pain

Pleural effusion

Cough

Hypoxia

Ascites

Neck pain

Insomnia

Gallbladder obstruction

Bloating

General disorders and administration site conditions -Other

Abdominal distension

Dysphagia

Pruritus

Rash acneiform

Peripheral sensory neuropathy

Infections and infestations - Other

Dysgeusia

Depression

Neoplasms benign, malignant and unspecified - Other

Phlebitis

Colitis

Colonic obstruction

Gastrointestinal disorders -Other

Cholecystitis

Dry mouth

Pancreatitis

Stomach pain

Toothache

Gait disturbance

Infusion site extravasation

Activated partial thromboplastin time prolonged

Blood antidiuretic hormone abnormal

Investigations - Other

Urine output decreased

Hypercalcemia

Hypernatremia

Hyperuricemia

Hypokalemia

Hypomagnesemia

Aspiration

Atelectasis

Epistaxis

Hiccups

Hoarseness

Nasal congestion

Pneumonitis

Postnasal drip

Productive cough

Sore throat

Wheezing

Bone pain

Paroxysmal atrial tachycardia

Pericarditis

Confusion

Acute kidney injury

Ear pain

Cataract

Dry eye

Fracture

Injury, poisoning and procedural complications - Other

Venous injury

Allergic reaction

Hepatic infection

Infections and Infestations - Other

Urinary tract obstruction

Lung infection

Gastroesophageal reflux disease

Malaise

Musculoskeletal and connective tissue disorders - Other

Skin ulceration

Headache

Parathesia

Gallbladder infection

Dry skin

Skin and subcutaneous tissue disorders - Other

Sinus bradycardia

Cystitis noninfective

Hematuria

Renal and urinary disorders - Other

Urine discoloration

100%

80%

60%

40%

20%

Study treatment Arm

Combination Therapy

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: Copanlisib in combination with IbrutinibExperimental Treatment2 Interventions

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.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Ibrutinib

2014

Completed Phase 4

~2060

Copanlisib

2016

Completed Phase 2

~130

0 / 29Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Central Nervous System Lymphoma (CNSL) include targeted therapies such as PI3K inhibitors (e.g., Copanlisib) and BTK inhibitors (e.g., Ibrutinib). PI3K inhibitors block the phosphoinositide 3-kinase pathway, which is essential for cell growth and survival, thereby reducing lymphoma cell proliferation. BTK inhibitors target Bruton's tyrosine kinase, disrupting critical B-cell receptor signaling necessary for lymphoma cell survival. These targeted mechanisms are crucial for CNSL patients as they offer potentially more effective and less toxic treatment options in the challenging central nervous system environment.