E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with relapsed, indolent or aggressive Non- Hodgkin’s lymphomas or patients with indolent B-cell Non-Hodgkin's lymphoma relapsed after or refractory to standard therapy. |
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E.1.1.1 | Medical condition in easily understood language |
Patients with relapsed, indolent or aggressive Non-Hodgkin’s lymphomas or patients with indolent B-cell Non-Hodgkin's lymphoma relapsed after or refractory to standard therapy. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029600 |
E.1.2 | Term | Non-Hodgkin's lymphoma recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 objective of this study is to evaluate the efficacy and safety of copanlisib in patients with indolent or aggressive Non-Hodgkin’s Lymphoma (NHL) who have progressed after standard therapy.
The objective of study part B is to evaluate the efficacy and safety of
copanlisib in patients with indolent B-cell NHL relapsed after, or refractory to
widely used approved therapies in standard practice. |
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E.2.2 | Secondary objectives of the trial |
Further objectives are to evaluate the pharmacokinetics of copanlisib and
biomarkers.
Part B, further objectives are to evaluate the pharmacokinetics of copanlisib, biomarkers and quality of life. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Indolent NHL:
- Histologically confirmed diagnosis of follicular lymphoma (FL) grades 1, 2 or 3a, marginal zone lymphoma (including nodal or splenic marginal zone B-cell
lymphoma and mucosa-associated lymphoid tissue [MALT]
lymphoma), lymphoplasmacytic lymphoma/Waldenström
macroglobulinemia, chronic lymphocytic leukemia (CLL).
- Relapsed after ≥ 2 prior chemotherapy- or immunotherapy-based regimens for indolent NHL, or refractory to 2 prior chemotherapy and/ or immunotherapy-based regimens.
Aggressive NHL:
- Histologically confirmed diagnosis of grade 3b follicular lymphoma (FL), transformed indolent lymphoma, diffuse large B-cell lymphoma (DLBCL), mediastinal large B-cell lymphoma, mantle cell lymphoma (MCL), peripheral T-cell lymphoma unspecified, or anaplastic large cell lymphoma primary systemic type, or angioimmunoblastic T cell lymphoma.
- Relapsed after ≥ 2 prior chemotherapy regimens, including the following: First-line treatment with standard anthracycline-containing regimen (e.g., cyclophosphamide, doxorubicin, vincristine, and prednisone or equivalent). At least 1 additional combination
chemotherapy regimen. Patients relapsed after or refractory to first prior chemotherapy- and/or immunotherapy-based regimen for aggressive NHL and not eligible for high-dose regimen followed by transplant. High-dose chemotherapy, or chemoradiotherapy with autologous stem cell transplantation is considered 1 regimen. Patients with CD20
expressing neoplastic cells must have received prior rituximab, if available.
- Patients with transformed indolent lymphoma must have received at least 2 prior chemotherapy- and/or immunotherapy-based regimens
- Availability of fresh tumor tissue
Indolent B-cell NHL lymphoma (study part B):
- Histologically confirmed diagnosis of indolent B-cell NHL, with histological subtype limited to the following:
o Follicular lymphoma (FL) grade 1-2-3a
o Small lymphocytic lymphoma (SLL) with absolute lymphocyte count < 5 x 109/L at the time of diagnosis and at study entry
o Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM)
o Marginal zone lymphoma (MZL) (splenic, nodal, or extranodal)
- Relapsed or refractory after ≥ 2 prior lines of therapy (refractory defined as not responding to a standard regimen or progressing within 6 months of the last course of a standard regimen). Patients must have received Rituximab and alkylating agents.
For all patients:
- Male or female patients > 18 years of age
- ECOG performance status ≤ 2 (ECOG: Eastern Cooperative
Oncology Group)
- Life expectancy of at least 3 months
- Adequate bone marrow, liver and renal function as assessed within 7 days before starting study treatment
- Left ventricular ejection fraction (LVEF) ≥ lower limit of normal (LLN) for the Institution
- Availability of archival and/or fresh tumor tissue |
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E.4 | Principal exclusion criteria |
For Part A:
-Uncontrolled hypertension (blood pressure ≥ 150/90 mmHg despite optimal medical management)
-Current diagnosis of Type 1 or 2 diabetes mellitus, fasting blood glucose > 125 mg/dL (> 6.9 mmol/L) or HbA1c ≥ 7.0 % (HbA1c: glycated hemoglobin)
- Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks of start of study medication (CTCAE: Common Terminology Criteria for Adverse Events).
- History or concurrent condition of interstitial lung disease or severely impaired pulmonary function (as judged by the investigator).
- Unresolved toxicity higher than CTCAE grade 1 (NCI-CTC version 4.0) attributed to any prior therapy/procedure excluding alopecia. (NCI: National Cancer Institute)
- Prior treatment with PI3K inhibitors
- Systemic corticosteroid therapy (ongoing)
- Hepatitis B or C. All subjects must be screened for hepatitis B and C up to 28 days prior to study drug start using the hepatitis virus panel laboratorial routine. Subjects positive for HBsAg or HBcAb will be eligible if they are negative for HBV-DNA; subjects positive for HCV IgG will be eligible if they are negative for HCV-RNA.
For Part B
- Uncontrolled hypertension (blood pressure ≥ 150/90 mmHg despite optimal medical management)
- Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks of start of study medication (CTCAE: Common Terminology Criteria for Adverse Events).
- History or concurrent condition of interstitial lung disease or severely impaired pulmonary function (as judged by the investigator)
- Unresolved toxicity higher than CTCAE grade 1 (NCI-CTC version 4.0) attributed to any prior therapy/procedure excluding alopecia. (NCI: National Cancer Institute)
- Prior treatment with PI3K inhibitors
- Systemic corticosteroid therapy (ongoing)
- Type I or II diabetes mellitus with HbA1c > 8.5% or fasting plasma glucose > 160 mg/dL at Screening
- Known history of human immunodeficiency virus (HIV) infection.
- Hepatitis B or C. All subjects must be screened for hepatitis B and C up to 28 days prior to study drug start using the hepatitis virus panel laboratorial routine. Subjects positive for HBsAg or HBcAb will be eligible if they are negative for
HBV-DNA; subjects positive for HCV IgG will be eligible if they are negative for HCV-RNA.
- Known lymphomatous involvement of the central nervous system
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable will be the objective tumor response (OR).
OR will be assessed in all patients up to 16 weeks after the last patient fully evaluable for the primary endpoint will have started treatment.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis of the primary efficacy variable will be performed 16 weeks after the last patient fully evaluable for the primary endpoint will have started treatment. At that timepoint, an exploratory analysis of all other variables will be performed, if possible. |
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E.5.2 | Secondary end point(s) |
Secondary efficacy variables in this study will be:
- Duration of response (DOR), defined as the time (in days) from first observed tumor response (CR, CRu [applicable only in patients with NHL] or PR) until PD or until death caused by PD.
- Progression free survival (PFS), defined as the time (in days) from treatment assignment to disease progression or death (if death occurs before a documented progression).
- Overall survival (OS), defined as the time (in days) from treatment assignment until death from any cause or until the last date the patient is known to be alive.
Secondary efficacy variables in the Part B will be:
- Progression free survival (PFS), defined as the time (in days) from treatment assignment to disease progression or death (if death occurs before a documented progression)
- Duration of response (DOR), defined as the time (in days) from first observed tumor response (CR or PR) until PD or until death due to any cause.
- Overall survival (OS), defined as the time (in days) from treatment assignment until death
from any cause or until the last date the patient is known to be alive.
- Quality of Life questionnaire (FACT-Lym total score) at week 16 |
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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 3 years after the last patient’s first treatment or when all patients got PD, whatever comes 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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 73 |
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 |
Austria |
Belgium |
Bulgaria |
Canada |
Chile |
China |
Colombia |
Denmark |
Finland |
France |
Germany |
Greece |
Hong Kong |
Hungary |
Ireland |
Israel |
Italy |
Korea, Republic of |
Luxembourg |
Mexico |
New Zealand |
Peru |
Poland |
Portugal |
Russian Federation |
Singapore |
Spain |
Sweden |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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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Thirty to 35 days after last study drug administration, a safety follow-up visit will be performed for the collection of adverse events (AEs) and concomitant medication data. Patients will be contacted quarterly to determine overall survival status up to 3 years after last patient first treatment. In Part B, patients will enter the Active Assessment Follow-up Period. The end of study notification to Health Authorities will be based on the completion of the collection of survival data.
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 9 |