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 follicular 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 follicular 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 | 21.1 |
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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10029621 |
E.1.2 | Term | Non-Hodgkin's lymphomas unspecified histology indolent |
E.1.2 | System Organ Class | 100000004851 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10029608 |
E.1.2 | Term | Non-Hodgkin's lymphomas unspecified histology aggressive |
E.1.2 | System Organ Class | 100000004851 |
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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 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, 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.
For all patients: • Ability to understand and willingness to sign written informed consent (IC). Signed informed consent must be obtained before any study specific procedure. • Male or female patients > 18 years of age. • Patients must have at least one measurable lesion (that has not been previously irradiated) according to the recommendations of the Revised Reponse Criteria for Malignant Lymphoma. • Availability of archival and/or fresh tumor tissue • ECOG performance status ≤ 2. • Life expectancy of at least 3 months. • Women of childbearing potential and men must agree to use adequate contraception since signing of the informed consent form until at least 3 months after the last test drug administration. 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 recommended method (or combination of methods) as per standard of care. An adequate contraception includes a hormonal contraception with implants or combined oral, transdermal or injectable contraceptives, certain intrauterine devices, bilateral tubal ligation, hysterectomy, or vasectomy of the partner. In addition the use of condoms for patients or their partners is required unless the woman has had a hysterectomy. • Adequate bone marrow, liver and renal function as assessed by laboratory requirements conducted within 7 days before starting study treatment. • Left ventricular ejection fraction (LVEF) ≥ lower limit of normal (LLN) for the Institution
Applicable to all patients in 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 extra-nodal) • Patients must have at least one bi-dimensionally measurable lesion (that has not been previously irradiated) according to the recommendations of the Revised Response Criteria for Malignant Lymphoma • In addition to the measurable lesion criterion above, patients affected by Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM) must have also measurable disease, defined as presence of immunoglobulin M paraprotein with a minimum IgM level of equal to or greater than 2 times the ULN OR over 10% of lymphoplasmacytic cells in bone marrow • Availability of archival tumor tissue or fresh tumor tissue for central pathology review and biomarkers analysis |
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E.4 | Principal exclusion criteria |
Patients who meet any of the following criteria at the time of screening will be excluded: Excluded medical conditions: • Previous or concurrent cancer that is distinct in primary site or histology from non-Hodkin's lymphoma within 5 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)]. • 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 hypertension. • Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months before start of study medication. • Non-healing wound, ulcer, or bone fracture. • Active clinically serious infections (> CTCAE grade 2). • 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. • Patients with seizure disorder requiring medication. • Patients with evidence or history of bleeding diathesis. • Renal failure requiring hemo-or peritoneal dialysis. • Proteinuria of CTCAE grade 3 or higher: urine protein: creatinine ratio >3.5 on a random urine sample. • Known hypersensitivity to any of the test drugs, test drug classes, or excipients in the formulation. • 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. • Current diagnosis of Type 1 or 2 diabetes mellitus, fasting blood glucose > 125 mg/dL (> 6.9 mmol/L) or HbA1c ≥ 7.0 % • Concurrent diagnosis of phaeochromocytoma. • Pregnant or breast-feeding patients. Women of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of treatment, and a negative result must be documented before start of treatment.
Excluded previous therapies and medications: • Prior treatment with PI3K inhibitors. • Treatment with investigational drugs other than PI3K inhibitors within 28 days prior to treatment start. • Ongoing immunosuppressive therapy. • Radiotherapy within 4 weeks prior to treatment start. • Myeloid growth factors within 14 days prior to treatment start. • Blood or platelet transfusion within 14 days prior to treatment start. • Systemic corticosteroid therapy (ongoing). Previous corticosteroids therapy must be stopped within 7 days prior to first study drug administration. Patients may be using topical or inhaled corticosteroids. • History of having received an allogeneic bone marrow or organ transplant • Major surgical procedure, or significant traumatic injury within 28 days before start of study medication; open biopsy within 7 days before start of study medication. • Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted). • Use of strong inhibitors of CYP3A4 is prohibited from Day -14 and for the duration of the study • Use of inducers of CYP3A4 is prohibited from Day -14 of Cycle 1 and for the duration of the study.
For study Part B: Excluded medical conditions: • Known lymphomatous involvement of the central nervous system • Histologically confirmed diagnosis of follicular lymphoma grade 3b or transformed disease or chronic lymphocytic leukemia (CLL) • History or concurrent condition of interstitial lung disease or severely impaired pulmonary function (as judged by the investigator) • Previous or concurrent cancer that is distinct in primary site or histology from indolent B-cell NHL within 5 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, nonmelanoma skin cancer and superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)]. • Type I or II diabetes mellitus with HbA1c > 8.5% or fasting plasma glucose > 160 mg/dL at screening. • Proteinuria of CTCAE grade 3 or higher (urine protein:creatinine ratio >3.5 on a random urine sample).
Excluded previous therapies and medications: • Systemic corticosteroid therapy (ongoing). Previous corticosteroids therapy must be stopped at least 7 days prior to first study drug administration. 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 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 due to any cause. • 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 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 |