| Eligibility |
Inclusion Criteria:
1. 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;
- 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.
2. 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.
3. Patients must not be eligible to high-dose chemotherapy (HDC) and autologous stem cell
transplantation (ASCT) or relapsed after that.
4. Patients must not be eligible to CAR T-cell therapy or relapsed after that.
5. Patients must have at least one bi-dimensionally measurable lesion (that has not been
previously irradiated) according to the 2014 Lugano criteria.
6. Male or female patient = 18 years of age.
7. Eastern Cooperative Oncology Group (ECOG) performance status = 2 if not related to
lymphoma disease.
8. Ann Arbor stage II-IV disease.
9. Life expectancy of at least 3 months.
10. 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.
11. 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).
12. Left ventricular ejection fraction = 45%.
13. Ability to understand and willingness to sign written informed consent. Signed
informed consent must be obtained before any study specific procedure.
Exclusion Criteria:
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:
1. Primary mediastinal B-cell Lymphoma (PMBCL)
2. DLBCL with concomitant HHV8 positivity or chronic inflammation
3. ALK positive DLBCL
4. Known lymphomatous involvement of the central nervous system
5. Congestive heart failure > New York Heart Association (NYHA) class 2
6. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3
months).
7. Myocardial infarction less than 6 months before start of test drug
8. Uncontrolled arterial hypertension despite optimal medical management
9. HbA1c> 8.5%
10. 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
11. Non-healing wound, ulcer, or bone fracture
12. Active, clinically serious infections > CTCAE Grade 2
13. History of, or current autoimmune disease
14. 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.
15. DLBCL with concomitant primitive or secondary immunodeficiency
16. 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
17. CMV PCR positive at baseline
18. 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
19. Patients with seizure disorder requiring medication
20. 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
21. 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
22. History or concurrent condition of interstitial lung disease of any severity and/or
severely impaired lung function (as judged by the investigator)
23. Concurrent diagnosis of pheochromocytoma
24. 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:
1. Primary mediastinal B-cell Lymphoma (PMBCL)
2. DLBCL with concomitant HHV8 positivity or chronic inflammation
3. ALK positive DLBCL
4. Known lymphomatous involvement of the central nervous system
5. Congestive heart failure > New York Heart Association (NYHA) class 2
6. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3
months).
7. Myocardial infarction less than 6 months before start of test drug
8. Uncontrolled arterial hypertension despite optimal medical management
9. HbA1c> 8.5%
10. 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
11. Non-healing wound, ulcer, or bone fracture
12. Active, clinically serious infections > CTCAE Grade 2
13. History of, or current autoimmune disease
14. 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.
15. DLBCL with concomitant primitive or secondary immunodeficiency
16. 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
17. CMV PCR positive at baseline
18. 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
19. Patients with seizure disorder requiring medication
20. 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
21. 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
22. History or concurrent condition of interstitial lung disease of any severity and/or
severely impaired lung function (as judged by the investigator)
23. Concurrent diagnosis of pheochromocytoma
24. 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.
25. Unresolved toxicity higher than CTCAE Grade 1 attributed to any prior
therapy/procedure, excluding alopecia
26. Known hypersensitivity to any of the test drugs, test drug classes, or excipients in
the formulation
27. Substance abuse, medical, psychological or social conditions that may interfere with
the patient's participation in the study or evaluation of the study results
28. 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.
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