| 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
|
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsed indolent B-cell non-Hodgkin's lymphoma |
|
| 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 who are unwilling to receive chemotherapy/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 ICF. Signed ICF must be obtained before any study specific proced. 2. Histologically confirmed diagnosis of iNHL in CD20 positive patients, with histological subtype limited to: Follicular lymphoma (FL) grade 1-2-3a, Small lymphocytic lymphoma (SLL) with absolute monoclonal lymphocyte count<5x109/L at study entry, Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM), Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal). 3. Patients must have relapsed (recurr. after complete resp. or presented progression after partial resp.) after the last rituximab, rituximab biosimilars- or anti-CD20 monoclonal antibody (eg. obinutuzumab) cont. therapy (other previous treat.lines after rituximab are allowed). Previous regimen is defined as one of follow: at least 2 mths of single-agent therapy (<2 mths of therapy is allowed for patients who responded to single-agent rituximab, rituximab biosimilars, or anti-CD20 monoclonal antibody); ≥ 2 consecutive cycles of polychemotherapy; accept. provided there is no resistance. Patients prior intolerance to PI3K Inhibitors other than copanlisib are eligible. 4. Non-WM patients must have at least one bi-dimensionally measurable lesion (not been previously irradiated) accor. to Lugano. Patients with splenic MZL this requirem. may be restricted to splenomegaly alone since that is usually the only Manifestation of measurable disease. 5. Patients affect. by WM who do not have at least one bi-dimensionally measurable lesion in baseline radiologic assess. must have measurable disease, defined as presence of IgM paraprotein with a min. IgM level ≥ 2 x upper limit of normal and positive immunofixation test. 6. Male/female patients ≥18 yrs. 7. ECOG perform. status ≤2. 8. Life expectancy at least 3 mths. 9. Availability of fresh tissue and/or archival tumor tissue for central pathology (obtained within 5 yrs of the consent date) at Screening. 10. Women of childbearing potential (WOCBP) and men must agree to effective contraception when sexually active for time period betw. signing ICF and 12 mths (for WOCBP) and 5 mths (for men) after last admin. of study treatm. Childbearing potential, i.e. fertile, follow. menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include (not limited) hysterectomy, bilateral salpingectomy, bilateral oophorectomy. Postmenopausal state defined as no menses for cont. 12 mths without an altern. medical cause. A high FSH level in postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contracep. or hormonal replacement therapy. The investigator/designated associate is requested to advise the patient how to achieve highly effective birth control (failure rate less than 1%), eg. IUD, 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 lab values collected no more than 7 days before starting study treatment: Total bilirubin≤ 1.5xULN (< 3xULN patients with Gilbert-Meulengracht syndrome or patients with cholestasis due to compressive adenopathies of the hepatic hilum), ALT and AST≤ 2.5xULN (≤ 5xULN for patients with liver involvm. by lymphoma), Lipase≤ 1.5xULN, GFR≥30mL/min/1.73m2 acc. Modification of Diet in Renal Disease (MDRD) abbreviated formula, International normalized ratio (INR)≤1.5 and partial thromboplastin time (PTT)≤1.5xULN. PT can be used instead of INR if≤1.5xULN, 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, Hb≥8g/dL, packed red blood cell transfusion or erythropoietin should not be given less than 7 days before exam collection, 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. LVEF≥45%. 13. Patients must either: have had a progression free and treatment-free interval of at least 12 mths after completion of the last rituximab, rituximab biosimilars or anti-CD20 monoclonal antibody-containing treatment OR considered unfit to receive chemotherapy on reason of age, concomitant morbidities, and/or residual toxicity from previous treatments, unwillingness to receive chemoth. These patients must also have had a progression-free and treatment-free interval of at least 6 mths after completion of the last rituximab, rituximab biosimilar or anti-CD20 monoclonal antibody-containing treatment. Patients in whom chemoth. is contraindicated are defined by one of the following features: Age≥80 years, Age<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 assign. 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 treatm free interval of less than 12m since the last rituximab, rituximab biosimilars-, or anti-CD20 monoclonal antibody (eg. obinutuzumab) containing treatm (including rituximab maint with these drugs). For patients considered unwilling/unfit to receive chemo: Progression free interval or treatm free interval of less than 6mths since the last rituximab, rituximab biosimilars-, or anti-CD20 monoclonal antibody containing treatm (including rituximab maint with these drugs), as assessed by the investigator. 5. Previous/concurrent cancer distinct in primary site or histology from indolent B-cell NHL (as described in Inc. criteria 2) within 5y prior to treatm start except for curatively treated cervical carcinoma in situ, non-melanoma skin cancer, superficial bladder cancer (Ta, Tis and T1), and asympt. prostate cancer without known metastatic disease and with no requirem for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for≥1y 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 6m before start of test drug. 9. Uncontrolled arterial hypertension despite optimal medical mgt. 10. Patients with HbA1c>8.5% at Screening. 11. Arterial or venous thromb or embolic events as cerebrovascular accident, DVT or pulmonary embolism within 3m before start of study treatm. 12. Non-healing wound, ulcer, bone fracture. 13. Active, clinically serious infections >CTCAE Grade 2. 14. Known history HIV infection. 15. Hepatitis B or C (HBV, HCV). 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 4w 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 7d before start of treatm., and 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 hypersens. to any of test drugs, test drug classes, excipients in formulation. 25. Substance abuse, medical, psychological or social conditions that may interfere with the patient’s particip. 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. Treatm with invest. drugs other than PI3K inhibitors less than 28d before start of treatm, unless evidence of progression since last treatm. 29. Ongoing immunosuppressive therapy 30. Radiotherapy or immuno-/chemotherapy less than 4w before start of treatment, unless evidence of progression since last treatm. 31. Radioimmunotherapy or autologous transplant less than 3m before start of treatm, unless evidence of progression since last treatm. 32. Myeloid growth factors less than 7d before start of treatm. 33. Blood or platelet transfusion less than 7d 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 7d 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 28d before start of treatm, open biopsy less than 7d before start of treatm. 37. Anti-arrhythmic therapy. 38. Use of strong inhib. of CYP3A4 is prohibited from Day -14 of Cycle 1 until Safety follow up visit. 39. Use of strong inducers of CYP3A4 is prohibited from Day -14 of Cycle 1 until Safety follow up visit. 40. Documented evidence of resistance to prior treatm with idelalisib or other PI3K inhib. defined as: No response at any time during therapy, or progression after any resp or after stable disease within 6mths from the end of the therapy with a PI3K Inhibitor. 41. Prior treatm 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 | 3 |
| 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 |
| Australia |
| Austria |
| Belarus |
| Belgium |
| Brazil |
| Bulgaria |
| Chile |
| China |
| Colombia |
| France |
| Germany |
| Greece |
| Hong Kong |
| Hungary |
| Ireland |
| Italy |
| Japan |
| Korea, Republic of |
| Lithuania |
| Luxembourg |
| Malaysia |
| Mexico |
| New Zealand |
| Philippines |
| Poland |
| Portugal |
| Romania |
| Russian Federation |
| Singapore |
| Slovakia |
| South Africa |
| Spain |
| Taiwan |
| Thailand |
| Turkey |
| Ukraine |
| United States |
| Vietnam |
|
| 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 last visit of the last patient 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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