| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Patients with relapsed indolent B-cell non-Hodgkin's lymphoma
|
| Pacienți cu limfom cu celule B non-Hodgkin indolent recidivat (iNHL) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsed indolent B-cell non-Hodgkin's lymphoma |
| Limfom cu celule B non-Hodgkin indolent recidivat |
|
| 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 | 23.0 |
| 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) |
|
| 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 evaluate whether copanlisib in combination with rituximab is superior to placebo in combination with rituximab in prolonging progression free survival (PFS) in patients with relapsed iNHL who have received one or more lines of treatment, including rituximab, and who either had a treatment-free interval of ≥12 months after completion of the last rituximab-containing treatment, or for whom chemotherapy is contraindicated on reason of age, comorbidities, and/or residual toxicity. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to evaluate:
• The following characteristics of disease-related symptoms: “time to deterioration” and “time to improvement”
• Other radiological and clinical indicators of treatment efficacy
• Safety and tolerability of copanlisib
The other objectives of this study are to evaluate:
- Pharmacokinetics
- Biomarkers
- Quality of life |
|
| 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 must be obtained before any study specific procedure.
2. Histologically confirmed diagnosis of CD20 positive iNHL, with histological subtype limited to: -Follicular lymphoma (FL) grade 1-2-3a, -Small lymphocytic lymphoma (SLL) with absolute lymphocyte count <5x109/L at the time of diagnosis and at study entry, -Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM), -Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal)
3. Patients must have relapsed (recurrence after complete response or presented progression after partial response) after at least 1 prior line of therapy, including rituximab. Previous regimen is defined as one of following: at least 2 months of single-agent therapy; at least 2 consecutive cycles of polychemotherapy; autologous transplant; radioimmunotherapy. Previous exposure to PI3K (except to copanlisib) is acceptable provided there is no resistance. Patients with prior intolerance to PI3K inhibitors other than copanlisib are eligible.
4. Non-WM patients must have at least one bi-dimensionally measurable lesion (which has not been previously irradiated) according to Lugano Classification
5. Patients affected by WM who do not have at least one bi-dimensionally measurable lesion in baseline radiologic assessment must have measurable disease, defined as presence of immunoglobulin M (IgM) paraprotein with a minimum IgM level ≥2 x upper limit of normal (ULN) and positive immunofixation test
6. Male/female patients ≥18 years of age
7. ECOG performance status ≤2 (ECOG: Eastern Cooperative Oncology Group)
8. Life expectancy of at least 3 months
9. Availability of fresh tissue and/or archival tumor tissue at Screening
10. Women of childbearing potential (WOCBP) and men must agree to use effective contraception when sexually active. This applies for time period between signing of informed consent form and 12 months (for WOCBP) and 5 months (for men) after last administration of study treatment. A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming postmenopausal 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
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 (failure rate of less than 1%), e.g. intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner and sexual abstinence. Use of condoms by male patients is required unless female partner is permanently sterile
11. Adequate baseline laboratory values collected no more than 7 days before starting study treatment: -Total bilirubin ≤1.5 x ULN (<3 x ULN for patients with Gilbert-Meulengracht syndrome or for patients with cholestasis due to compressive adenopathies of the hepatic hilum), -Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN (≤umm5 x ULN for patients with liver involvement by lymphoma), -Lipase ≤1.5 x ULN, -Glomerular filtration rate (GFR) ≥30 mL/min/1.73m2 according to the Modification of Diet in Renal Disease (MDRD) abbreviated formula, -International normalized ratio (INR) ≤1.5 and partial thromboplastin time (PTT) ≤1.5 x ULN. PT can be used instead of INR if ≤1.5 x ULN, -Platelet count ≥75,000/mm3. For patients with confirmed lymphomatous bone marrow infiltration, platelet count ≥50,000/mm3. Platelet transfusion should not be given less than 7 days before exam collection, -Hemoglobin (Hb) ≥8g/dL, Packed red blood cell transfusion or erythropoietin should not be given less than 7 days before exam collection, -Absolute neutrophil count (ANC) ≥1,000/mm3, For patients with confirmed lymphomatous bone marrow infiltration, ANC count ≥750 /mm3. Myeloid growth factors should not be given less than 7 days before exam collection
12. Left ventricular ejection fraction (LVEF) ≥45%
13. Patients must either: •have had a treatment-free interval of at least 12 months after completion of the last rituximab-containing treatment
OR • be considered unfit to receive chemotherapy on reason of age, concomitant morbidities, and/or residual toxicity from previous treatments, or unwillingness to receive chemotherapy. Patients in whom chemotherapy is contraindicated are defined by one of the following features: oAge ≥80 years, oAge <80 years and at least 1 of the following conditions: •at least 3 grade 3 CIRS-G comorbidities, OR •at least 1 grade 4 CIRS-G comorbidity (if compatible to participation in the study) |
|
| E.4 | Principal exclusion criteria |
1. Previous assignment to treatm. during this study
2. Close affiliation with site
3. Histologically confirmed diagnosis of FL grade 3b or transformed disease, or CLL
4. Progression free interval or treatment free interval of less than 12 mths since the last rituximab containing treatment (including rituximab maintenance). For patients considered unfit to receive chemotherapy: progression free interval or treatment free interval of less than 6 mths since the last rituximab containing treatment (including rituximab maintenance), as assessed by the investigator
5. Previous/concurrent cancer that is distinct in primary site or histology from indolent B-cell NHL within 5 yrs prior to treatm start except for curatively treated cervical carcinoma in situ, non-melanoma skin cancer, superficial bladder cancer (Ta, Tis & T1), and asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for ≥1 yr prior to randomization
6. Known lymphomatous involvement of central nervous system
7. Congestive heart failure > NYHA class 2
8. Unstable angina, new-onset angina. Myocardial infarction less than 6 mths before start of test drug
9. Uncontrolled arterial Hypertension despite optimal medical management
10. Patients with HbA1c >8.5% at Screening
11. Arterial or venous thrombotic or embolic events such as cerebrovascular accident, DVT or pulmonary embolism within 3 mths before start of study treatm
12. Non-healing wound, ulcer, or bone fracture
13. Active, clinically serious infections >CTCAE Grade 2
14. Known history of HIV infection
15. 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. Patients positive for HBsAg or HBcAb will be eligible if negative for HBV-DNA, these patients should receive prophylactic antiviral therapy; patients positive for anti-HCV antibody will be eligible if negative for HCV-RNA
16. seizure disorder requiring medication
17. evidence or history of bleeding diathesis. Any hemorrhage or bleeding event ≥CTCAE Grade 3 within 4 wks prior to start of study treatm.
19. Proteinuria of CTCAE Grade 3
20. History/concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function
21. Concurrent diagnosis of pheochromocytoma
22. Pregnant or breast-feeding patients. Women of childbearing potential must have a serum pregnancy test performed a max of 7 days before start of treatm., and a negative result must be documented before start of treatm.
23. Unresolved toxicity higher than CTCAE Grade 1 attributed to any prior therapy/procedure, excluding alopecia, peripheral neuropathy, and bone marrow parameters
24. Known hypersensitivity to any of test drugs, test drug classes, or excipients in formulation
25. Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of study results
26. Any illness or medical conditions that are unstable or could jeopardize safety of patients and compliance in study
28. Treatment with investigational drugs other than PI3K inhibitors less than 28 days before start of treatment, unless evidence of progression since last treatm.
29. Ongoing immunosuppressive therapy
30. Radiotherapy or immuno-/chemotherapy less than 4 wks before start of treatment, unless evidence of progression since last treatm.
31. Radioimmunotherapy or autologous transplant less than 3 mths before start of treatm, unless evidence of progression since last treatm
32. Myeloid growth factors less than 7 days before start of treatm
33. Blood or platelet transfusion less than 7 days before start of treatm
34. Ongoing systemic corticosteroid therapy at daily dose higher than 15mg prednisone/equivalent. previous tx stopped or reduced to allowed dose at least 7 days before performing Screening CT/MRI. if chronic tx should be de-escalated to max allowed dose before Screening. topical/inhaled corticosteroids may be used.
35. History of having received an allogeneic bone marrow or organ transplant
36. Major surgical procedure/significant traumatic injury less than 28 days before start of treatment, open biopsy less than 7 days before start of treatm
37. Anti-arrhythmic therapy
38. Use of strong inhibitors of CYP3A4 is prohibited from Day -14 of Cycle 1 until Safety FU visit.
39. Use of inducers of CYP3A4 is prohibited from Day -14 of Cycle 1 until Safety follow up visit.
40. Documented evidence of resistance to prior treatment with idelalisib or other PI3K inhibitors defined as: •No response at any time during therapy, or •Progression after any response or after stable disease within 6 mths from the end of the therapy with a PI3K Inhibitor
41. Prior Treatment with copanlisib
42. Cytomegalovirus infection. Patients who are CMV PCR positive at baseline will not be eligible. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival (PFS) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Time (in days) from randomization to PD or death from any cause (if no progression is documented). The actual date of tumor assessments will be used for this calculation. PFS for patients without PD or death at the time of analysis will be censored at the date of their last tumor evaluation. PFS for patients who have neither tumor assessments nor death after baseline will be censored at Day 1. |
|
| E.5.2 | Secondary end point(s) |
- Objective tumor response rate (ORR)
- Duration of response (DOR)
- Complete response rate (CRR)
- Time to progression (TTP)
- Overall survival (OS)
- Time to deterioration in DRS-P
- Time to improvement in DRS-P |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- ORR - assessed in all patients up to the time of analysis of PFS.
- DOR: time (in days) from first observed tumor response (CR, VGPR, PR, or MR) until PD or death from any cause, whichever is earlier
- CRR: assessed in all patients up to the time of analysis of PFS.
- TTP: time from randomization to PD or death related to PD, whichever is earlier
- OS: time (in days) from randomization until death from any cause.
- Time to deterioration in DRS-P of at least 3 points, as measured by the FLymSI-18 questionnaire.
- Time to improvement in DRS-P of at least 3 points, as measured by the FLymSI-18 questionnaire, will be evaluated for patients with a baseline DRS-P score of 30 points or less. |
|
| 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 |
| Biomarkers and Quality of Life |
|
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 60 |
| 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 |
| Argentina |
| Chile |
| Colombia |
| Malaysia |
| New Zealand |
| Philippines |
| Singapore |
| Ukraine |
| Hong Kong |
| Taiwan |
| Australia |
| Belarus |
| Brazil |
| China |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| South Africa |
| Thailand |
| United States |
| Viet Nam |
| Austria |
| Belgium |
| Bulgaria |
| France |
| Germany |
| Greece |
| Hungary |
| Ireland |
| Italy |
| Lithuania |
| Luxembourg |
| Poland |
| Portugal |
| Romania |
| Slovakia |
| Spain |
| Türkiye |
|
| 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
|
For each participating EU country, the end of the study according to the EU Clinical Trial Directive will be reached when the LVLS for all centers in the respective country has occurred.
The end of study as a whole will be reached as soon as the end of the study according to the above definition has been reached in all participating countries (EU and non-EU).
The end of study notification to Health Authorities will be based on the completion of the collection of survival data. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 30 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| 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 | 30 |
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