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

  • STATUS
    Recruiting
  • End date
    Aug 1, 2024
  • participants needed
    81
  • sponsor
    Fondazione Italiana Linfomi ONLUS
Updated on 16 May 2022

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.

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.

Details
Condition Diffuse Large B-cell Lymphoma
Treatment Copanlisib
Clinical Study IdentifierNCT04433182
SponsorFondazione Italiana Linfomi ONLUS
Last Modified on16 May 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Histologically confirmed diagnosis of DLBCL (de-novo DLBCL or DLBCL transformed by indolent lymphoma) including
DLBCL, NOS including GCB type, ABC type
A previous regimen is defined as one of the following: at least 2 months of
T-cell rich large B-cell Lymphoma
single-agent therapy; at least 2 consecutive cycles of polychemotherapy
Epstein-Barr virus-positive DLBCL, NOS
autologous transplant; radioimmunotherapy
High-grade B-cell Lymphoma with MYC and BCL2 and/or BCL6 rearrangements (doublehit or triple-hit lymphoma)
High-grade B-cell lymphoma NOS
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
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)
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
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)

Exclusion Criteria

DLBCL with concomitant HHV8 positivity or chronic inflammation
ALK positive DLBCL
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
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
Primary mediastinal B-cell Lymphoma (PMBCL)
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)
DLBCL with concomitant primitive or secondary immunodeficiency
Myocardial infarction less than 6 months before start of test drug
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
Uncontrolled arterial hypertension despite optimal medical management
HbA1c> 8.5%
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
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
CMV PCR positive at baseline
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
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])
Patients who meet any of the following criteria at the time of screening will
Localized prostate cancer
be excluded
Patients with seizure disorder requiring medication
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
History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function (as judged by the investigator)
Primary mediastinal B-cell Lymphoma (PMBCL)
Concurrent diagnosis of pheochromocytoma
DLBCL with concomitant HHV8 positivity or chronic inflammation
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
ALK positive DLBCL
Unresolved toxicity higher than CTCAE Grade 1 attributed to any prior therapy/procedure, excluding alopecia
Known lymphomatous involvement of the central nervous system
Known hypersensitivity to any of the test drugs, test drug classes, or excipients in the formulation
Congestive heart failure > New York Heart Association (NYHA) class 2
Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months)
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.)
Myocardial infarction less than 6 months before start of test drug
Excluded previous therapies and medications
Uncontrolled arterial hypertension despite optimal medical management
Prior treatment with copanlisib
HbA1c> 8.5%
Prior exposure to idelalisib or other PI3K inhibitors, less than 28 days before start of treatment, unless evidence of progression since last treatment
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
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
Non-healing wound, ulcer, or bone fracture
Ongoing immunosuppressive therapy
Active, clinically serious infections > CTCAE Grade 2
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
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
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
DLBCL with concomitant primitive or secondary immunodeficiency
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
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
History of having received an allogeneic bone marrow or organ transplant
CMV PCR positive at baseline
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
Previous or concurrent history of malignancies other than DLBCL within 5 years prior to study treatment except for curatively treated
Anti-arrhythmic therapy (beta blockers or digoxin are permitted)
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
platelet transfusion less than 7 days before start of treatment
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
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