E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with relapsed indolent non-Hodgkin's lymphoma |
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E.1.1.1 | Medical condition in easily understood language |
Relapsed indolent non-Hodgkin's lymphoma |
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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 | 20.0 |
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) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Safety run-in part
Primary objective is to determine:
The recommended phase III dose (RP3D) of copanlisib in combination with standard immunochemotherapy (rituximab and bendamustine [RB] or rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone [R-CHOP]) to be used in the subsequent phase III part of the study
Phase III part (randomized, controlled trial)
Primary objective is:
To evaluate whether copanlisib in combination with standard immunochemotherapy, is superior to standard immunochemotherapy in prolonging progression-free survival (PFS), in patients with relapsed indolent non-Hodgkin’s lymphoma, who have received at least one, but at most three lines of treatment, including rituximab-based immunochemotherapy and alkylating agents, and for whom the combination of rituximab with either bendamustine or CHOP represents a valid therapeutic option |
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E.2.2 | Secondary objectives of the trial |
Safety run-in part
The secondary objectives are to evaluate (for patients that stay on treatment after Cycle 1):
Radiological and clinical indicators of treatment efficacy
Safety and tolerability of copanlisib in combination with R-B/R-CHOP
Phase III part (randomized, controlled trial)
Secondary objectives are to evaluate:
Other radiological and clinical indicators of treatment efficacy (objective response rate (ORR), duration of response (DOR), complete response rate (CRR), time to progression (TTP), time to next antilymphoma treatment (TTNT), overall survival (OS, 5 year survival rate), time to improvement and the time to deterioration in diseaserelated symptoms - physical)
Safety and tolerability of copanlisib in combination with R-B/R-CHOP |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Main criteria for inclusion:
- Histologically confirmed diagnosis of CD20 positive iNHL with histological subtype limited to:
o Follicular lymphoma (FL) G1, G2, or G3a
o Small lymphocytic lymphoma (SLL) with absolute lymphocyte count <5x109/L at study entry
o Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM)
o Marginal zone lymphoma (MZL) (splenic, nodal, or extra-nodal)
-- Patients must have relapsed (recurrence after complete response or presented progression after partial response) or progressed after at least one but at most three prior lines of therapy, including rituximab-based immunochemotherapy and alkylating agents (if given concomitantly is considered one line of therapy). A previous regimen is defined as one of the following: at least 2 months of single-agent therapy (less than 2 months of therapy with single agent rituximab can be considered a previous regimen in the case the patient responded to it); at least 2 consecutive cycles of polychemotherapy; autologous transplant; radioimmunotherapy. Previous exposure to other PI3K inhibitors (except copanlisib) is acceptable provided there is no resistance (resistance defined as no response (response defined as partial response [PR] or complete response [CR]) at any time during therapy, or PD after any response (PR/CR) or after stable disease within 6 months from the end of the therapy with a PI3K inhibitor.
- Non-WM patients must have at least one bi-dimensionally measurable lesion (that has not been previously irradiated) according to the Lugano Classification. For patients with splenic MZL this requirement may be restricted to splenomegaly alone since that is usually the only manifestation of measurable disease.
- 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 and positive immunofixation test.
- Male or female patients ≥ 18 years of age.
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
- Life expectancy of at least 3 months.
- Availability of fresh tumor tissue and/or archival tumor tissue at Screening.
- Women of childbearing potential (WOCBP) and men must agree to use effective contraception when sexually active. This applies for the time period between signing of the informed consent form and 12 months (for WOCBP) and 6 months (for men) after the last administration of study treatment. The use of condoms by male patients is required unless the female partner is permanently sterile.
- Adequate baseline laboratory values as assessed within 7 days before starting study treatment.
- Left ventricular ejection fraction ≥ 50%. |
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E.4 | Principal exclusion criteria |
Main criteria for exclusion:
- Histologically confirmed diagnosis of follicular lymphoma (FL) grade 3b
or transformed disease, or chronic lymphocytic leukemia. In patients
with clinical suspicion of transformed disease, a fresh biopsy is
recommended.
- Rituximab resistance at any line of therapy (resistance defined as lack
of response, or progression within 6 months of the last date of rituximab administration, including rituximab maintenance).
- History or concurrent condition of interstitial lung disease and/or
severely impaired lung function (as judged by the investigator).
- Known lymphomatous involvement of the central nervous system.
- HbA1c > 8.5% at Screening.
- Known history of human immunodeficiency virus (HIV) infection.
- Hepatitis B (HBV) or C (HCV) infection. Patients positive for hepatitis B
surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) will be
eligible if they are negative for HBV-DNA, these patients should receive
prophylactic antiviral therapy as per rituximab label. Patients positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA.
- Previous or concurrent history of malignancies other than indolent non-
Hodgkin's lymphoma within 5 years prior to study treatment except for
curatively treated: Cervical carcinoma in situ, Non-melanoma skin
cancer, Superficial bladder cancer (Ta [non-invasive tumor], Tis
[carcinoma in situ] and T1 [tumor invades lamina propria]), Localized
prostate cancer
- 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 despite optimal medical management (per
investigator's assessment).
- Arterial or venous thrombotic or embolic events such as
cerebrovascular accident (including transient ischemic attacks), deep
vein thrombosis or pulmonary embolism within 3 months before the
start of study medication.
- Non-healing wound, ulcer, or bone fracture.
- Active, clinically serious infections (> CTCAE grade 2).
- Patients with seizure disorder requiring medication
- Patients with evidence or history of bleeding diathesis. Any
hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks of start
of study medication.
- Known hypersensitivity to any of the study drugs, study drug classes,
or excipients in the formulation.
- Proteinuria of CTCAE Grade 3 or estimated by urine protein : creatinine
ratio > 3.5 (> 396 mg/mmol)on a random urine sample
- Unresolved toxicity higher than NCI-CTCAE grade 1 attributed to any
prior therapy/procedure excluding alopecia.
- Concurrent diagnosis of pheochromocytoma.
- 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.
- Substance abuse, medical, psychological or social conditions that may
interfere with the patient's participation in the study or evaluation of the
study results.
- Any illness or medical conditions that are unstable or could jeopardize
the safety of the patients and their compliance in the study.
- Prior treatment with copanlisib
- Cytomegalovirus (CMV) infection. Patients who are CMV PCR positive at
baseline will not be eligible.
CMV PCR test is considered positive if the result can be interpreted as a CMV viremia according to local SOC
- Live vaccination, including virus vaccination and yellow fever
vaccination, within 6 months before start of study treatment. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary completion event for this study is PFS (progression assessed by central review or death from any cause if death occurs before progression). The analysis will be performed when approximately 256 PFS events in the FAS are observed. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The analysis will be performed when approximately 256 PFS events in the FAS are observed. |
|
E.5.2 | Secondary end point(s) |
Secondary efficacy variables are objective response rate (ORR), duration of response (DOR), complete response rate (CRR), time to progression (TTP), time to next anti-lymphoma treatment (TTNT), overall survival (OS, 5 year survival rate), time to improvement and the time to deterioration in disease-related symptoms - physical (disease-related symptoms - physical (DRS-P)) of at least 3 points of lymphoma as measured by the FLymSI-18 questionnaire (FLymSI = NCCN-FACT Lymphoma Symptom Index). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
All secondary efficacy endpoints will be analyzed in the FAS at the time of the analysis of the primary efficacy endpoint. Depending on study success in the primary efficacy variable in the FAS, the secondary efficacy variables ORR, time to deterioration and time to improvement in DRS-P subscale of FLymSI-18 of at least 3 points will be tested hierarchically in the FAS.
ORR will be tested first and, if successful, will be followed by time to deterioration in DRS-P, and finally, if all previous tests are successful, will be followed by time to improvement of DRS-P. |
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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 | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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) | No |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 105 |
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 |
Brazil |
Bulgaria |
Canada |
Chile |
China |
Czech Republic |
Denmark |
Finland |
France |
Germany |
Greece |
Hong Kong |
Hungary |
Ireland |
Israel |
Italy |
Japan |
Korea, Republic of |
Mexico |
Poland |
Portugal |
Romania |
Russian Federation |
Singapore |
Slovakia |
South Africa |
Spain |
Sweden |
Switzerland |
Taiwan |
Thailand |
Turkey |
Ukraine |
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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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 | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |