| 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 | 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) |
|
| 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 alkylating agents, 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 after at least 1 prior line of therapy, including rituximab and alkylating agents. A previous regimen is defined as one of the following: at least 2 months of single-agent therapy; at least 2 consecutive cycles of polychemotherapy; autologous transplant; radioimmunotherapy. Patients must be not refractory to rituximab at any prior line of therapy (response shorter than 6 months from the end of any prior rituximab- containing treatment) but can be refractory to any non-rituximab containing regimen. Previous exposure to PI3K is acceptable provided there is no resistance (see also exclusion criterion 40).
4. Non-WM patients must have at least one bi-dimensionally measurable lesion (which has not been previously irradiated) according to the Lugano Classification.
5. Patients affected by WM who do not have at least one bi-dimensionally measurable lesion in the 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).
6. Male or 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 and men must agree to use adequate contraception when sexually active. This applies since signing of the informed consent form until at least 3 months after the last study 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.
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 (≤ 5 x ULN for patients with liver involvement by lymphoma)
- Lipase ≤ 1.5 x ULN
- Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 according to the Modification of Diet in Renal Disease (MDRD) abbreviated formula
- International normalized ratio (INR) and partial thromboplastin time (PTT) ≤ 1.5 x ULN
- Platelet count ≥ 75,000 /mm3
- Hemoglobin (Hb) ≥ 8 g/dL
- Absolute neutrophil count (ANC) ≥ 1,000/mm3
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. Patients in whom chemotherapy is contraindicated are defined by one of the following features:
o Age ≥ 80 years
o Age < 80 years and at least 1 of the following conditions:
• at least 3 grade 3 CIRS-G comorbidities (see Appendix 14.7)
OR
• at least 1 grade 4 CIRS-G comorbidity (if compatible to participation in the study - see exclusion criterion no. 26). |
|
| E.4 | Principal exclusion criteria |
1. Previous assignment to treatment during this study.
2. Close affiliation with the site.
3. Histologically confirmed diagnosis of FL grade 3b or transformed disease, or chronic lymphocytic leukemia
4. Last rituximab infusion within 12 mths of the start of the next treatment.
5. Previous/concurrent cancer that is distinct in primary site or histology from indolent B-cell NHL within 5 yrs prior to treatment start except for curatively treated cervical carcinoma in situ, non-melanoma skin cancer, superficial bladder cancer (Ta, Tis and 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 the central nervous system
7. Congestive heart failure > New York Heart Association class 2
8. Unstable angina, new-onset angina. Myocardial infarction less than 6 mths before start of test drug
9. Uncontrolled arterial hypertension
10. Type I or II diabetes mellitus with HbA1c >8.5% or fasting plasma glucose >160mg/dL at Screening
11. Arterial or venous thrombotic or embolic events such as cerebrovascular accident, deep vein thrombosis or pulmonary embolism within 3 mths before start of study treatment
12. Non-healing wound, ulcer, or bone fracture
13. Active, clinically serious infections > CTCAE Grade 2
14. Known history of human immunodeficiency virus 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 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 antibody will be eligible if they are negative for HCV-RNA
16. Patients with seizure disorder requiring medication
17. Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 wks prior to the start of study treatment
19. Proteinuria of CTCAE Grade 3 or higher
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 treatment, and a negative result must be documented before start of treatment
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 the test drugs, test drug classes, or excipients in the formulation
25. Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results
26. Any illness or medical conditions that are unstable or could jeopardize the safety of patients and their compliance in the study
28. Treatment with investigational drugs other than PI3K inhibitors less than 28 days before start of treatment, unless evidence of progression since last treatment
29. Ongoing immunosuppressive therapy
30. Radiotherapy or immuno-/chemotherapy less than 4 wks before start of treatment, unless evidence of progression since last treatment
31. Radioimmunotherapy or autologous transplant less than 3 mths before start of treatment, unless evidence of progression since last treatment
32. Myeloid growth factors less than 7 days before start of treatment
33. Blood or platelet transfusion less than 7 days before start of treatment
34. Ongoing systemic corticosteroid therapy at daily dose higher than 15mg prednisone/equivalent. Previous corticosteroid therapy must be stopped/reduced to the allowed dose 7 days before performing the screening CT/MRI and again prior to the first study drug administration. If a patient is on chronic corticosteroid therapy, corticosteroids should be de-escalated to the max. allowed dose before the screening. Patients may be using topical or inhaled corticosteroids.
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 treatment
37. Anti-arrhythmic therapy
38. Use of strong inhibitors of CYP3A4 is prohibited from Day -14 of Cycle 1 until Safety follow up 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 |
|
| 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 |
| Australia |
| Austria |
| Belgium |
| Brazil |
| Bulgaria |
| Chile |
| China |
| Colombia |
| Denmark |
| France |
| Germany |
| Greece |
| Hong Kong |
| Hungary |
| Ireland |
| Italy |
| Korea, Republic of |
| Lithuania |
| Luxembourg |
| Mexico |
| Philippines |
| Poland |
| Portugal |
| Russian Federation |
| Singapore |
| South Africa |
| Spain |
| Sweden |
| 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 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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