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Diffuse Large B-cell LymphomaPhase 2NCT04433182

Copanlisib With Rituximab-Bendamustine in Patients With Relapsed-Refractory Diffuse Large B-cell Lymphoma

A Phase 2 study testing Copanlisib in people with Diffuse Large B-cell Lymphoma, run by Fondazione Italiana Linfomi - ETS at 17 sites in Italy.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

This is a multicentric single arm phase II trial, to investigate the efficacy (in terms of PFS) of the combination regimen rituximab-bendamustine in association with copanlisib in patients affected by relapsed/refractory DLBCL, not eligible to HDC and ASCT or relapsed after intensified regimens. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Diffuse Large B-cell Lymphoma
What is being tested?
Copanlisib
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
37 participants
Where
17 sitesItaly
Study dates
18 Aug 2020to 19 Dec 2024
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Histologically confirmed diagnosis of DLBCL (de-novo DLBCL or DLBCL transformed by indolent lymphoma) including:
  • DLBCL, NOS including GCB type, ABC type;
  • T-cell rich large B-cell Lymphoma;
  • Epstein-Barr virus-positive DLBCL, NOS;
  • High-grade B-cell Lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double- hit or triple-hit lymphoma);
  • High-grade B-cell lymphoma NOS;
Show all 31Show fewer
  • Intravascular B-cell Lymphoma;
  • Extranodal DLBCL;
  • DLBCL coexistent with either follicular lymphoma of any grade or marginal-zone lymphoma;
  • FL grade 3b. Patients must be CD20 positive. New biopsy at relapse time is recommended, but not mandatory.
  • Patients must have relapsed (recurrence after complete response or presented progression after partial response) or refractory after at least ≥ 1 (but < 4) prior lines of therapy, including rituximab-based immunochemotherapy.
  • A previous regimen is defined as one of the following: at least 2 months of single-agent therapy; at least 2 consecutive cycles of polychemotherapy; autologous transplant; radioimmunotherapy.
  • Patients must not be eligible to high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) or relapsed after that.
  • Patients must not be eligible to CAR T-cell therapy or relapsed after that.
  • Patients must have at least one bi-dimensionally measurable lesion (that has not been previously irradiated) according to the 2014 Lugano criteria.
  • Male or female patient ≥ 18 years of age.
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 if not related to lymphoma disease.
  • Ann Arbor stage II-IV disease.
  • Life expectancy of at least 3 months.
  • 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 6 months after last administration of bendamustine or copanlisib or 12 months after last rituximab dose. 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 method (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.
  • Adequate liver, renal and bone marrow function, assessed by baseline laboratory values as assessed within 7 days before starting study treatment; as assessed by the following (ULN= upper level of normality):
  • Total bilirubin ≤ 1.5 x ULN (< 3 x ULN for patients with Gilbert-Meulengracht syndrome, patients with cholestasis due to compressive adenopathies of the hepatic hilum or documented liver involvement by lymphoma).
  • Alanine transaminase (ALT or GPT) and aspartate aminotransferase (AST or GOT) < 2.5 x ULN (< 5x ULN for patients with documented liver involvement or with biliary obstruction due to lymphoma).
  • Lipase ≤ 1.5 x ULN.
  • Glomerular filtration rate (GFR) ≥ 30mL/min/1.73 m2 according to the Modification of Diet in Renal Disease (MDRD) abbreviated formula. If not on target, this evaluation may be repeated once after at least 24 hours either according to the MDRD abbreviated formula or by 24-hour sampling. If the latter result is within acceptable range, it may be used to fulfil the inclusion criteria instead.
  • International normalized ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) ≤ 1.5 x ULN. PTT can be used instead of INR if PTT ≤ 1.5 x ULN.
  • Platelet count ≥ 75,000/mm3. For patients with lymphomatous bone marrow infiltration (local assessment) or splenomegaly, platelet count ≥ 50,000/mm3. Platelet transfusion should not be given less than 7 days before the exam collection.
  • Absolute neutrophil count (ANC) ≥ 1,000/mm3 (unless neutropenia related to lymphomatous bone marrow infiltration).
  • Hemoglobin (Hb) ≥ 8 g/dL (unless anemia related to active lymphoma).
  • Left ventricular ejection fraction ≥ 45%.
  • Ability to understand and willingness to sign written informed consent. Signed informed consent must be obtained before any study specific procedure.

Who cannot join

  • Patients who meet any of the following criteria at the time of screening will be excluded.
  • Previous assignment to treatment during this study. Patients permanently withdrawn from study participation will not be allowed to re-enter the study.
  • Previous (within 28 days or less than 5 half-lives of the drug before start of study treatment) or concomitant participation in another clinical study with investigational medicinal product(s).
  • Excluded medical conditions:
  • Primary mediastinal B-cell Lymphoma (PMBCL)
  • DLBCL with concomitant HHV8 positivity or chronic inflammation
Show all 81Show fewer
  • ALK positive DLBCL
  • Known lymphomatous involvement of the central nervous system
  • Congestive heart failure > New York Heart Association (NYHA) class 2
  • Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months).
  • Myocardial infarction less than 6 months before start of test drug
  • Uncontrolled arterial hypertension despite optimal medical management
  • HbA1c> 8.5%
  • Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before the start of study medication. Patients with venous thrombotic events related to lymphoma vascular infiltration or compressive disease are eligible providing no signs of pulmonary embolism
  • Non-healing wound, ulcer, or bone fracture
  • Active, clinically serious infections > CTCAE Grade 2
  • History of, or current autoimmune disease
  • Known history of Human immunodeficiency virus (HIV) infection. All patients must be screened for HIV up to 28 days prior to study drug start using a blood test for HIV according to local regulations.
  • DLBCL with concomitant primitive or secondary immunodeficiency
  • Hepatitis B (HBV) or hepatitis C (HCV). All patients must be screened for HBV and HCV up to 28 days prior to study drug start using the routine hepatitis virus laboratorial panel. Patients positive for HBsAg are excluded. Patients positive for HBcAb will be eligible if they are negative for HBV-DNA, these patients should receive prophylactic antiviral therapy. Patients positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA
  • CMV PCR positive at baseline
  • Previous or concurrent history of malignancies other than DLBCL within 5 years prior to study treatment except for curatively treated:
  • Cervical carcinoma in situ
  • Non-melanoma skin cancer
  • Superficial bladder cancer (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria])
  • Localized prostate cancer
  • Patients with seizure disorder requiring medication
  • Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication
  • Proteinuria of ≥ CTCAE Grade 3 as assessed by a 24h protein quantification or estimated by urine protein: creatinine ratio > 3.5 on a random urine sample
  • History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function (as judged by the investigator)
  • Concurrent diagnosis of pheochromocytoma
  • Pregnant or breast-feeding patients. Women of childbearing potential must have a serum pregnancy test performed a maximum of 7 days before start of treatment, and a negative result must be documented before start of treatment.
  • Patients who meet any of the following criteria at the time of screening will be excluded.
  • Previous assignment to treatment during this study. Patients permanently withdrawn from study participation will not be allowed to re-enter the study.
  • Previous (within 28 days or less than 5 half-lives of the drug before start of study treatment) or concomitant participation in another clinical study with investigational medicinal product(s).
  • Excluded medical conditions:
  • Primary mediastinal B-cell Lymphoma (PMBCL)
  • DLBCL with concomitant HHV8 positivity or chronic inflammation
  • ALK positive DLBCL
  • Known lymphomatous involvement of the central nervous system
  • Congestive heart failure > New York Heart Association (NYHA) class 2
  • Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months).
  • Myocardial infarction less than 6 months before start of test drug
  • Uncontrolled arterial hypertension despite optimal medical management
  • HbA1c> 8.5%
  • Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before the start of study medication. Patients with venous thrombotic events related to lymphoma vascular infiltration or compressive disease are eligible providing no signs of pulmonary embolism
  • Non-healing wound, ulcer, or bone fracture
  • Active, clinically serious infections > CTCAE Grade 2
  • History of, or current autoimmune disease
  • Known history of Human immunodeficiency virus (HIV) infection. All patients must be screened for HIV up to 28 days prior to study drug start using a blood test for HIV according to local regulations.
  • DLBCL with concomitant primitive or secondary immunodeficiency
  • Hepatitis B (HBV) or hepatitis C (HCV). All patients must be screened for HBV and HCV up to 28 days prior to study drug start using the routine hepatitis virus laboratorial panel. Patients positive for HBsAg are excluded. Patients positive for HBcAb will be eligible if they are negative for HBV-DNA, these patients should receive prophylactic antiviral therapy. Patients positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA
  • CMV PCR positive at baseline
  • Previous or concurrent history of malignancies other than DLBCL within 5 years prior to study treatment except for curatively treated:
  • Cervical carcinoma in situ
  • Non-melanoma skin cancer
  • Superficial bladder cancer (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria])
  • Localized prostate cancer
  • Patients with seizure disorder requiring medication
  • Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication
  • Proteinuria of ≥ CTCAE Grade 3 as assessed by a 24h protein quantification or estimated by urine protein: creatinine ratio > 3.5 on a random urine sample
  • History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function (as judged by the investigator)
  • Concurrent diagnosis of pheochromocytoma
  • Pregnant or breast-feeding patients. Women of childbearing potential must have a serum pregnancy test performed a maximum of 7 days before start of treatment, and a negative result must be documented before start of treatment.
  • Unresolved toxicity higher than CTCAE Grade 1 attributed to any prior therapy/procedure, excluding alopecia
  • Known hypersensitivity to any of the test drugs, test drug classes, or excipients in the formulation
  • Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
  • Any illness or medical conditions that are unstable or could jeopardize the safety of patients and their compliance in the study e.g., uncontrolled diabetes, uncontrolled dyslipidemia, etc.)
  • Excluded previous therapies and medications:
  • Prior treatment with copanlisib.
  • Prior exposure to idelalisib or other PI3K inhibitors, less than 28 days before start of treatment, unless evidence of progression since last treatment
  • Prior treatment with bendamustine: subjects treated with bendamustine at least 24 months before, with a response > one year to bendamustine containing regimen, will be eligible
  • Ongoing immunosuppressive therapy.
  • Radiotherapy or immuno-/chemotherapy less than 2-4 weeks before start of treatment (corticosteroids are allowed) and use of myeloid growth factors within 14 days prior to treatment
  • platelet transfusion less than 7 days before start of treatment
  • Systemic continuous corticosteroid therapy at a daily dose higher than 15 mg prednisone or equivalent is not allowed. Previous corticosteroid therapy must be stopped or reduced to the allowed dose 7 days before performing the screening PET or PET/CT and/or CT/MRI, whichever is performed first, and again prior to the first study drug administration. If a patient is on chronic corticosteroid therapy, corticosteroids should be de-escalated to the maximum allowed dose after the patient has signed the IC. Patients may be using topical or inhaled corticosteroids. A pre-phase with corticosteroids is allowed to control the disease in case of systemic symptoms and/or compressive disease with a maximum of prednisone 100 mg (or equivalent) daily for a maximum of 15 days prior start of treatment.
  • Autologous transplant less than 2 months before start of treatment. Prior Autologous stem cell performed more than 2 months before start of treatment is allowed.
  • History of having received an allogeneic bone marrow or organ transplant.
  • Major surgical procedure or significant traumatic injury (as judged by the investigator) within 28 days before start of treatment or have not recovered from major side effects.
  • Anti-arrhythmic therapy (beta blockers or digoxin are permitted).
  • Use of CYP3A4 inhibitors and inducers. Copanlisib is primarily metabolized by CYP3A4. Therefore, concomitant use of strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir), and strong inducers of CYP3A4 (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St. John's Wort) are not permitted from Day -28 of Cycle 1 until restaging at the end of treatment.

Trial locations and contacts

17 sites in 1 country.

17 sites in 1 country

Italy17 sites

  • AOU Ospedali Riuniti - Clinica di Ematologia

    Ancona

  • Centro Riferimento Oncologico - S.O.C. Oncologia Medica A

    Aviano, Pordenone

  • Ospedale Monsignor Raffaele Dimiccoli - Ematologia

    Barletta, Barletta-Andria-Trani

  • ASST Spedali Civili - Ematologia

    Brescia

  • Ematologia, Candiolo Cancer Institute. FPO-IRCCS

    Candiolo, Torino, 10060

  • Arnas Nuovo Ospedale Garibaldi Nesima - U.O.C. Ematologia

    Catania

  • A.O. S. Croce e Carle - S.C. di Ematologia e Trapianto di Midollo Osseo

    Cuneo

  • Ospedale Vito Fazzi - Ematologia

    Lecce

  • Azienda Ospedali Riuniti Papardo-Piemonte - S.C. Ematologia

    Messina

  • I.R.C.C.S. Istituto Oncologico Veneto - Oncologia 1

    Padova

  • AOU Policlinico Giaccone - Ematologia

    Palermo

  • Ospedale Guglielmo da Saliceto - U.O.Ematologia

    Piacenza

  • Azienda Ospedaliera Sant'Andrea - Ematologia

    Roma

  • Policlinico Umberto I - Università "La Sapienza" Istituto Ematologia -Dipartimento di Medicina Traslazionale e di Precisione

    Roma

  • Azienda Ospedaliera S. Maria di Terni - S.C. Oncoematologia

    Terni

  • Azienda Ospedaliero Universitaria Città della Salute e della Scienza - S.C.Ematologia

    Torino

  • Ospedale Ca' Foncello - S.C di Ematologia

    Treviso

Other trials in Italy

About this study

Official title: Copanlisib in Combination With Rituximab-Bendamustine in Patients With Relapsed-Refractory Diffuse Large B-cell Lymphoma: a Multicentric Phase II Trial

This is a multicentric single arm phase II trial, to investigate the efficacy (in terms of PFS) of the combination regimen rituximab-bendamustine in association with copanlisib in patients affected by relapsed/refractory DLBCL, not eligible to HDC and ASCT or relapsed after intensified regimens.

Read the detailed description

The primary objective of this study is to evaluate the efficacy, in terms of Progression Free Survival (12m-PFS) at 12 months, of a treatment with copanlisib in combination with a standard rituximab-bendamustine regimen in patients with relapsed-refractory DLBCL, who have received at least one, but no more than three lines of treatment, including rituximab-based immunochemotherapy, not eligible for high-dose chemotherapy and ASCT or T-cell CAR-T therapy, or relapsed after these treatments.

Being tested
Copanlisib
Keywords
Diffuse Large B-cell Lymphoma, Relapsed-Refractory, DLBCL, Copanlisib
Medical subject headings
Lymphoma, Large B-Cell, Diffuse

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CopanlisibDrug

    Also called ALIQOPA

    Induction phase: 6 cycles of Copa-RB every 28 days according to the following schedule

    • Copanlisib (Copa): 60 mg/day i.v. on days 1,8,15
    • Rituximab (R): 375 mg/sqm i.v. day 1*
    • Bendamustine (B): 90 mg/sqm i.v. days 1-2* note: during cycle 1 rituximab can be administered on day 2: in this case bendamustine will be administered on days 2-3; in the case of a frail patient or a patient with high tumor burden copanlisib could be administered on day 1, rituximab on day 2 and bendamustine on days 3-4, at physician discretion.

    Maintenance phase: patients who reach at least SD after induction will receive a maintenance with copanlisib in monotherapy according to the following schedule:

    • Copanlisib: 60 mg/day i.v. on days 1 and 15 in 28-day cycles for 1 year
Study groups in NCT04433182
Study groupRoleWhat they receive
Single arm Copa-RBExperimentalInduction phase with Copanlisib, Rituximab and Bendamustina. Maintenance phase (for patients who reach at least SD after induction) with Copanlisib in monotherapy.
Receives: Drug: Copanlisib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression-free survival (PFS)

    Progression-Free Survival (PFS) will be defined as the time between the date of enrolment and the date of disease progression, relapse or death from any cause. Responding patients according to Response Criteria for NHL with PET and patients who are lost to follow-up will be censored at their last assessment date.

    Measured: 4 years

Secondary outcomes (6)

  1. Overall Survival (OS)

    Time between the date of enrolment and the date of death from any cause. Patients who have not died at the time of the final analysis will be censored at the date of the last contact.

    Measured: 4 years

  2. Overall Response Rate (ORR)

    ORR will be defined as the sum of CR + PR

    Measured: End of treament (EOT), 30 months

  3. Complete Response Rate (CRR)

    CRR will be defined as the proportion of patients achieving a CR

    Measured: End of induction (EOI), 18 months

  4. Duration of response (DOR)

    DOR is measured from the date when criteria for response are met (CR or PR) until the date of progression or relapse. Patients without relapse or progression will be censored at their last assessment date.

    Measured: 4 years

  5. Conversion rate from SD/PR to PR/CR with maintenance

    Conversion rate from SD/PR to PR/CR with maintenance

    Measured: End of treatment (after maintenance), 30 months

  6. Evaluation of adverse events according to the current version of the CTCAE criteria

    Evaluation of adverse events according to the current version of the CTCAE criteria

    Measured: 4 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 Jun 2020
  2. Study start18 Aug 2020
  3. Primary completion19 Dec 2024
  4. Study completion19 Dec 2024

Why it stopped: low enrollment rate

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
37 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04433182
Sponsor's protocol ID
FIL_Copa-RB
Status last verified
Aug 2025
First submitted
9 Jun 2020
Last updated
8 Aug 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Copanlisib in people with Diffuse Large B-cell Lymphoma, run by Fondazione Italiana Linfomi - ETS at 17 sites in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 31 inclusion and 81 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 8 Aug 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 17 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: low enrollment rate). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression-free survival (PFS) (time frame: 4 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04433182.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Aug 2025.

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