E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
patients with relapsed or refractory diffuse large B cell lymphoma |
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E.1.1.1 | Medical condition in easily understood language |
patients with relapsed or refractory diffuse large B cell lymphoma |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to assess the potential efficacy (in terms of objective response) of single agent copanlisib in patients with relapsed or refractory DLBCL and assess the relationship between efficacy and a potentially predictive biomarker. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives of this study are to assess:
- Other radiological and survival indicators of treatment efficacy.
- Safety and tolerability of copanlisib
- Long-term effects of the treatment
Further objectives of this study are to assess:
-Pharmacokinetics of copanlisib
- To explore additional biomarkers in predicting efficacy
- Patient-reported outcomes |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Ability to understand and willingness to sign written informed consent. Signed informed consent (including consent to genetic analysis) must be obtained before any study specific procedure .
2.Male or female patients age ≥ 18 years old
3.Diagnosis of DLBCL (de novo or DLBCL transformed from follicular lymphoma on the basis of a tissue biopsy). Pathology and immunohistochemistry reports documenting the current histological diagnosis of DLBCL or DLBCL transformed from follicular lymphoma according to WHO classification must be reviewed by the sponsor or designee prior to enrollment. Patients whose NHL has transformed from follicular lymphoma must have had a complete or partial response to first-line therapy for NHL lasting at least 12 weeks.
• DLBCL not otherwise specified (NOS)
• T-cell/histiocyte-rich large B-cell lymphoma
• Epstein-Barr virus (EBV) positive DLBCL of the elderly
4.Received at least one prior therapy for aggressive NHL (DLBCL)
Note: High dose myeloablative therapy with SCT used to consolidate a response and local consolidative radiation, corticosteroids as single agents, and maintenance therapy with rituximab or other agents are not considered independent regimens.
5.Received CHOP + rituximab or equivalent regimen (addition of etoposide or substitution of idarubicin, epirubicin, or mitoxantrone for doxorubicin is allowed) for NHL
6.At least 28 days from completion of last NHL therapy to first dose of study treatment.
7.Patients must have measurable disease (at least one bidimensionally measurable site of disease that has not been previously irradiated: nodal disease >1.5 cm or an extranodal lesion > 1.0 cm in longest perpendicular diameter). Lesion must be PET-positive if a PET scan is obtained.
8.Not eligible or not willing to receive the high-dose (myeloablative) chemotherapy (HDC) and SCT.
9.A fresh tumor biopsy collected during screening and /or archival tumor tissue collected after the last relapse/disease progression (material which has been collected before the last line of treatment is not accepted). In addition, a sufficient amount of the material is required for acceptance of the archival material. If neither condition occurs a fresh tumor biopsy needs to be performed as stated above.
10.ECOG performance status (PS) ≤ 2
11.Life expectancy ≥ 12 weeks in investigator’s judgment
12.Left ventricular ejection fraction (LVEF) ≥ the lower limit of normal (LLN) for the Institution (as per local standard of care) as measured by ECHO (echocardiogram) or Multiple gated acquisition (MUGA) scan
13.Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements conducted within 7 days before start of study treatment:
- Hemoglobin ≥ 8 g/dL
- Platelet count ≥ 100 x 109L/; platelet count ≥ 75 x 109/L permitted if documented bone marrow involvement
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L; ANC ≥ 1.0 x 109/L permitted if documented bone marrow involvement
- Total bilirubin ≤ 1.5 x upper limit of normal (ULN); patients with proven Gilbert’s syndrome and total bilirubin ≤ 5 x ULN may be enrolled.
- Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2 x ULN, or ≤ 5 x ULN if elevation is due to hepatic involvement by lymphoma
- Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 according to the Modification of Diet in Renal Disease (MDRD) abbreviated formula (See Appendix 16.4) .
- International normalized ratio (INR) and partial thromboplastin time (PTT) ≤ 1.5 x ULN. Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists. Close monitoring is recommended according to the local standard of care.
- Lipase < 1.5 x the ULN
14.Willingness and ability to comply with the visit schedule and assessments required by the study protocol
15.Women and men of reproductive potential must agree to use adequate contraception when sexually active. This applies for the time period between signing of the ICF and 3 months after the last administration of study drug. The investigator or a designated associate is requested to advise the patient how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommend method (or combination of methods) as per standard of care.
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E.4 | Principal exclusion criteria |
1. Previous assignment to treatment during this study. Patients permanently withdrawn from study participation will not be allowed to re-enter the study.
2. Concurrent participation in other clinical studies. Patients must complete their participation in another clinical study with an investigational medicinal product 28 days before the start of treatment or 5 half-lives of the investigational treatment, whichever is longer.
3. Patients who previously received therapy with copanlisib or other PI3K inhibitors are not eligible for enrollment.
4. Close affiliation with the investigational site; e.g. a close relative of the investigator, dependent person (e.g. employee or student of the investigational site)
Excluded medical conditions
5. Any of the following as the only site(s) of disease: palpable lymph nodes not visible on imaging studies, skin lesions, or bone marrow involvement only.
6. Active CTCAE Grade 3/4 infection
7. 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 or HBcAb will be eligible if they are negative for HBV-DNA; patients positive for anti-HCV will be eligible if they are negative for HCV-RNA
8. Known history of human immunodeficiency virus (HIV) infection
9. Current central nervous system (CNS) involvement by lymphoma
- Any past history or evidence of current leptomeningeal involvement by lymphoma is prohibited.
- Patients with prior localized CNS involvement who have been without recurrence for ≥ 12 months and currently have a negative head MRI and negative cerebrospinal fluid (CSF) may be eligible.
10. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months). Myocardial infarction within the past 6 months before start of study treatment
11. Uncontrolled arterial hypertension (systolic blood pressure > 150 mmHg or diastolic blood pressure > 90 mmHg despite optimal medical management).
12. Type I or II diabetes mellitus with HbA1c > 8.5% or
fasting plasma glucose > 160 mg/dL at Screening.
13. New York Heart Association (NYHA) class III or IV heart disease.
14. Any other malignancy within last 3 years except for the following, which are permitted:
a. curatively treated non-melanoma skin cancer
b. carcinoma in situ of the cervix
c. in situ ductal carcinoma of the breast after complete resection
d. superficial bladder tumors (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria])
15. Any illness or conditions (substance abuse, medical, psychological or social) that may interfere with the patient’s participation in the study, evaluation of the study results, or could jeopardize the safety of the patient and his/her compliance in the study.
16. Non-healing wound ulcer or bone fracture.
17. Major surgical procedure or significant traumatic injury (as judged by the investigator) less than 28 days before start of study treatment.
18. Patients with seizure disorder requiring medication.
19. Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event with CTCAE Grade ≥ 3 within 4 weeks prior to screening.
20. Proteinuria of CTCAE Grade 3 or higher (> 3.5 measured by urine protein to creatinine ratio on a random urine sample)
21. History or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function (as judged by the investigator).
22. Pregnant or breast-feeding patients. Women of childbearing potential must have a serum pregnancy test performed a maximum of 7 days before start of study treatment and a negative result must be documented before start of study treatment.
23. Unresolved toxicity higher than CTCAE Grade 1 attributed to any prior therapy/procedure, excluding alopecia and ≤ CTCAE Grade 2 peripheral neuropathy. Patients with B symptoms are eligible for enrollment.
Excluded previous therapies and medications:
24. Radiotherapy or immuno-/chemotherapy less than 4 weeks before start of study treatment
25. Radioimmunotherapy or autologous transplant less than 3 months before start of study treatment
26. Myeloid growth factors less than 7 days before start of study treatment
27. Blood or platelet transfusion less than 7 days before start of study treatment
28. Ongoing systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone or equivalent. Previous corticosteroid therapy must be stopped or reduced to the allowed dose (≤ 15 mg of prednisone or equivalent) at least 7 days before performing the screening CT/MRI or PET-CT 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 before the Screening. Patients may be using topical or inhaled corticosteroids.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary variableis the objective Response Rate (ORR), defined as the proportion of patients who have at least once a post baseline overall response of CR (complete response) or PR (partial response) during study conduct; according to the criteria defined in The Lugano Classification. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
It will be assessed 24 weeks after the last patient fully evaluable for the primary endpoint started treatment. |
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E.5.2 | Secondary end point(s) |
Duration of response (DOR);
Progression-free survival (PFS);
Overall survival (OS);
Disease control rate (DCR);
Duration of stable disease (DOSD). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The final analyses of all secondary efficacy and safety variables and an
additional exploratory analysis of the primary efficacy variable will be
performed 2 years after the last patient's first treatment or the last
patient dies, whichever occurs first. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Belgium |
Canada |
Denmark |
France |
Germany |
Italy |
Korea, Republic of |
Netherlands |
Poland |
Singapore |
Spain |
Sweden |
Switzerland |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of study as a whole will be reached as soon as the last survival contact of the last patient has occurred in all centers in all participating countries (EU and non-EU) |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 3 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 3 |