Lymphoma, Non-Hodgkin
Conditions
Keywords
Clinical trial, phase II, Phosphatidylinositol 3-Kinase, Class I, Non-Hodgkin's lymphoma
Brief summary
The objective of the study (part A) is to evaluate the efficacy and safety of BAY80-6946 in patients with indolent or aggressive Non-Hodgkin's Lymphoma, who have progressed after standard therapy. 30 patients will be enrolled to both indolent and aggressive disease group. The objective of the study part B (CHRONOS-1) is to evaluate the efficacy and safety of BAY80-6946 in patients with relapsed/refractory follicular lymphoma. 120 patients will be enrolled in the part B of the study. Further objectives are to evaluate the pharmacokinetics and biomarkers. Quality of life will be a further objective of part B of the study. In a cohort of 20 patients (enrolled both in part A and B) an ECG substudy will be performed to assess the potential for cardiac toxicity and QT/QTc interval prolongation of BAY80-6946. After an up to 28-day screening period, eligible patients will start treatment with BAY80-6946 at a dose of 0.8 mg/kg (Part A) and at a dose of 60 mg (Part B). Treatment will be continued until disease has progressed or until another criterion is met for withdrawal from study. An end-of-treatment visit will be performed within 7 days after discontinuation of study treatment. Thirty to 35 days after last study drug administration, a safety followup 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 4 years after last patient completed treatment. Patients who discontinue study drug for reasons other than disease progression 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. The efficacy is measured by the decrease in tumor size. Tumor assessments will be done at Screening, every 8 weeks during Year 1, every 12 weeks during Year 2, and every 6 months during Year 3. Blood samples will be collected for pharmacokinetic analysis. Archival tumor tissue and blood samples will be collected for biomarker analysis (mandatory) and for central pathology review (part B), fresh biopsy tissue will also be collected if available.
Interventions
BAY 80-6946 is administered in a normal saline solution, 100 mL, intravenously over 1h. No intravenous glucose preparations should be administered on the days of infusion. Dosing is weekly for the first 3 weeks (on Days 1, 8, and 15) of a 28-day cycle, followed by a 1-week break (i.e., no infusion on Day 22). Part A: The individual dose will be 0.8 mg/kg (max. 65 mg) per infusion from Cycle 1 on. The maximum dose of 65 mg should never be exceeded. Part B: The individual dose will be 60 mg per infusion from Cycle 1 on.
Sponsors
Bayer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 (DLBCL), 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 * Consent to provide fresh tumor tissue during screening * Indolent B-cell NHL lymphoma (study part B): * Histologically confirmed diagnosis of indolent B-cell NHL, with histological subtype limited to the following: * Follicular lymphoma (FL) grade 1-2-3a * Small lymphocytic lymphoma (SLL) with absolute lymphocyte count \< 5 x 109/L at the time of diagnosis and at study entry * Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM) * Marginal zone lymphoma (MZL) (splenic, nodal, or extranodal) * Relapsed or refractory after ≥ 2 prior lines of therapy (refractory defined as not responding to a standard regimen or progressing within 6 months of the last course of a standard regimen). Patients must have received Rituximab and alkylating agents. * For all patients: * Male or female patients \> 18 years of age * ECOG performance status ≤ 2 (ECOG: Eastern Cooperative Oncology Group) * Life expectancy of at least 3 months * Adequate bone marrow, liver and renal function as assessed within 7 days before starting study treatment * Left ventricular ejection fraction (LVEF) ≥ lower limit of normal (LLN) for the Institution * Availability of archival tumor tissue
Exclusion criteria
* Uncontrolled hypertension (blood pressure ≥ 150/90 mmHg despite optimal medical management) * Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks of start of study medication (CTCAE: Common Terminology Criteria for Adverse Events). * History or concurrent condition of interstitial lung disease * Unresolved toxicity higher than CTCAE grade 1 (NCI-CTC version 4.0) attributed to any prior therapy/procedure excluding alopecia. (NCI: National Cancer Institute) * Prior treatment with PI3K inhibitors * Systemic corticosteroid therapy (ongoing) * 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. * For Part B: * Histologically confirmed diagnosis of follicular lymphoma grade 3b or transformed disease and chronic lymphocytic leukemia (CLL) * History or concurrent condition of interstitial lung disease or severely impaired pulmonary function * Excluded medical conditions: * 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 \[Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)\]. * 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. * Type I or II diabetes mellitus with HbA1c \> 8.5% or fasting plasma glucose \> 160 mg/dL at screening. * 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 \[Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)\].
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Based on Independent Review-Part A | Baseline up to the last patient has completed the 16 weeks of treatment | Objective response rate was defined as the proportion of participants with a best response rating of complete response (CR), unconfirmed complete response (CRu) or partial response (PR), based on the Report of an International Workshop to Standardize Response Criteria for non-Hodgkins Lymphomas, Cheson, 1999, as evaluated by the Independent Response Adjudication Committee (IRAC). For chronic lymphocytic leukemia (CLL) patients Hallek criteria (2008) were used and assessed by investigator. |
| ORR Based on Independent Review-Part B | Baseline up to the last patient has completed the 16 weeks of treatment | Objective response rate was defined as the proportion of participants with a best response rating of CR or PR, based on the International Working Group Revised response Criteria for Malignant Lymphoma, Cheson 2007. |
| ORR Based on Investigator Assessment-Part A | Baseline up to the last patient has completed the 16 weeks of treatment | Objective response rate was defined as the proportion of participants with a best response rating of CR, CRu or PR, based on the Report of an International Workshop to Standardize Response Criteria for non-Hodgkins Lymphomas, Cheson, 1999. For CLL patients Hallek criteria (2008) were used and assessed by investigator. |
| ORR Based on Investigator Assessment-Part B | Baseline up to the last patient has completed the 16 weeks of treatment | Objective response rate was defined as the proportion of participants with a best response rating of CR or PR, based on the International Working Group Revised response Criteria for Malignant Lymphoma, Cheson 2007. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| DOR Based on Investigator Assessment-Part B | Baseline up to approximately 9 years 7 months | DOR was defined as the time from the date of the first observed tumor response of CR or PR (whichever was noted earlier) to first subsequent disease progression (either first progressive disease \[PD\], first clinical progression or first AE associated with clinical disease progression) or death caused by disease progression, if this death occurred before progression was documented. All deaths were considered as 'caused by disease progression' except deaths with the reason other or AE not related to disease progression. DOR was evaluated only for patients with at least one tumor response of CR, CRu, or PR. Some patients may have had no report of disease progression nor death caused by disease progression until the date of the LPLV. With regards to DOR, these patients were considered as right censored at the date of their last tumor assessment after first observed tumor response. |
| Progression Free Survival (PFS) Based on Independent Review-Part A | Baseline up to approximately 6 years | PFS was defined as the time (in days) from the date of the first treatment to the date of first observed PD (radiological or clinical, or first AE associated with clinical PD, whichever was earlier) or death due to any cause (if death occurred before progression was documented). |
| PFS Based on Independent Review-Part B | Baseline up to approximately 9 years 7 months | PFS was defined as the time (in days) from the date of the first treatment to the date of first observed PD (radiological or clinical, or first AE associated with clinical PD, whichever was earlier) or death due to any cause (if death occurred before progression was documented). |
| PFS Based on Investigator Assessment-Part B | Baseline up to approximately 9 years 7 months | PFS was defined as the time (in days) from the date of the first treatment to the date of first observed PD (radiological or clinical, or first AE associated with clinical PD, whichever was earlier) or death due to any cause (if death occurred before progression was documented). |
| Duration of Response (DOR) Based on Independent Review-Part A | Baseline up to approximately 6 years | DOR was defined as the time from the date of the first observed tumor response of CR or PR (whichever was noted earlier) to first subsequent disease progression (either first progressive disease \[PD\], first clinical progression or first AE associated with clinical disease progression) or death caused by disease progression, if this death occurred before progression was documented. All deaths were considered as 'caused by disease progression' except deaths with the reason other or AE not related to disease progression. DOR was evaluated only for patients with at least one tumor response of CR, CRu, or PR. Some patients may have had no report of disease progression nor death caused by disease progression until the date of the LPLV. With regards to DOR, these patients were considered as right censored at the date of their last tumor assessment after first observed tumor response. |
| OS-Part B | Baseline up to approximately 9 years 7 months | OS was defined as the time (in days) from the date of first administration of study treatment to death due to any cause. OS was defined as the time (in days) from the date of first administration of study treatment to death due to any cause. Patients who were alive at the date of the LPLV were censored at the minimum of the date of LPLV and the last available date of evidence that the patient was still alive. |
| Functional Assessment of Cancer Therapy - Lymphoma Lymphoma Subscale (FACT-Lym LymS) at Week 16 - Part B | Baseline up to week 16 | HRQoL assessment was used to describe development of patients with copanlisib by using FACT-Lym questionnaire assessment tool. It contains 42 items (questions) covering HRQoL, common lymphoma symptoms and treatment side-effects. The FACT - General (FACT-G) questionnaire contains 27 items covering 4 core HRQoL subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 items) (FACT-Lym LymS), addressing issues typically experienced by lymphoma patients. Some of the issues covered include pain, itching, night sweats, trouble sleeping, fatigue and trouble concentrating. FACT-Lym also asks patients about lumps and swelling, fevers, infections, weight, appetite, emotional stability and treatment. Score range for the FACT-Lym LymS was 0 - 60, higher score represent less symptoms. Here in below table n signifies evaluable participants for the respective category. |
| Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Total Score at Week 16 - Part B | Baseline up to week 16 | HRQoL assessment was used to describe development of patients with copanlisib by using FACT-Lym questionnaire assessment tool. It contains 42 items (questions) covering HRQoL, common lymphoma symptoms and treatment side-effects. The FACT - General (FACT-G) questionnaire contains 27 items covering 4 core HRQoL subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 items) (FACT-Lym LymS), addressing issues typically experienced by lymphoma patients. Some of the issues covered include pain, itching, night sweats, trouble sleeping, fatigue and trouble concentrating. FACT-Lym also asks patients about lumps and swelling, fevers, infections, weight, appetite, emotional stability and treatment. FACT-Lym total score range was 0-168, higher score indicates better HRQoL. Here, in the below table n signifies evaluable participants for the respective category. |
| Overall Survival (OS)-Part A | Baseline up to approximately 6 years | OS was defined as the time (in days) from the date of first administration of study treatment to death due to any cause. Patients who were alive at the date of the LPLV were censored at the minimum of the date of LPLV and the last available date of evidence that the patient was still alive. |
| PFS Based on Investigator Assessment-Part A | Baseline up to approximately 6 years | PFS was defined as the time (in days) from the date of the first treatment to the date of first observed PD (radiological or clinical, or first AE associated with clinical PD, whichever was earlier) or death due to any cause (if death occurred before progression was documented). |
| DOR Based on Independent Review-Part B | Baseline up to approximately 9 years 7 months | DOR was defined as the time from the date of the first observed tumor response of CR or PR (whichever was noted earlier) to first subsequent disease progression (either first progressive disease \[PD\], first clinical progression or first AE associated with clinical disease progression) or death caused by disease progression, if this death occurred before progression was documented. All deaths were considered as 'caused by disease progression' except deaths with the reason other or AE not related to disease progression. DOR was evaluated only for patients with at least one tumor response of CR, CRu, or PR. Some patients may have had no report of disease progression nor death caused by disease progression until the date of the LPLV. With regards to DOR, these patients were considered as right censored at the date of their last tumor assessment after first observed tumor response. |
| DOR Based on Investigator Assessment-Part A | Baseline up to approximately 6 years | DOR was defined as the time from the date of the first observed tumor response of CR or PR (whichever was noted earlier) to first subsequent disease progression (either first progressive disease \[PD\], first clinical progression or first AE associated with clinical disease progression) or death caused by disease progression, if this death occurred before progression was documented. All deaths were considered as 'caused by disease progression' except deaths with the reason other or AE not related to disease progression. DOR was evaluated only for patients with at least one tumor response of CR, CRu, or PR. Some patients may have had no report of disease progression nor death caused by disease progression until the date of the LPLV. With regards to DOR, these patients were considered as right censored at the date of their last tumor assessment after first observed tumor response. |
Countries
Australia, Austria, Belgium, Bulgaria, Canada, Finland, France, Germany, Greece, Hong Kong, Hungary, Ireland, Israel, Italy, New Zealand, Poland, Portugal, Russia, Singapore, South Korea, Spain, Sweden, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Part A-Study enrolled participants from 41 study centers in 10 countries, between 19 NOV 2012 (first participant first visit \[FPFV\]) and 13 AUG 2018 (last participant last visit \[LPLV\]). Part B-Study enrolled participants from 81 study centers in 24 countries, between 04 NOV 2013 (FPFV) and 18 MAY 2023 (LPLV),
Pre-assignment details
Part A: Overall 125 participants were screened, of them 41 were screened but never assigned to treatment. Total 84 were assigned to treatment. Part B: Overall 213 participants were screened, of them 70 were screened but never assigned to treatment. Total 143 were assigned to treatment, of them 1 was suspected as fraudulent and excluded from analysis sets. Therefore 142 participants were evaluable.
Participants by arm
| Arm | Count |
|---|---|
| Part A: Indolent NHL/CLL Participants with indolent Non-Hodgkin's lymphoma/Chronic lymphocytic leukemia \[iNHL/CLL\] received copanlisib 0.8 milligram per kilogram (mg/kg), maximum 65 mg, intravenous (IV) infusion dosing over 1 hour in 100 milliliter (mL) normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study. | 33 |
| Part A: Aggressive NHL Participants with aggressive NHL (aNHL) received copanlisib 0.8 mg/kg, maximum 65 mg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas by Cheson et al. 1999, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study. | 51 |
| Part B: Indolent NHL Participants with indolent B-cell NHL received copanlisib 60 mg or 0.8 mg/kg, IV infusion dosing over 1 hour in 100 mL normal saline solution on Days 1, 8, and 15 of a 28-day treatment cycle until occurrence of progressive disease, as defined in the Revised Response Criteria for Malignant Lymphoma by Cheson et al., 2007, clinical progression, unacceptable toxicity, or any other criteria meeting withdrawal from study. | 142 |
| Total | 226 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | AE associated with clinical disease progression | 1 | 3 | 11 |
| Overall Study | AE not associated with clinical disease progression | 13 | 10 | 40 |
| Overall Study | Death | 1 | 0 | 1 |
| Overall Study | Other | 0 | 0 | 1 |
| Overall Study | Physician Decision | 1 | 2 | 5 |
| Overall Study | Progressive disease - clinical progression | 4 | 10 | 9 |
| Overall Study | Progressive disease - radiological progression | 12 | 23 | 50 |
| Overall Study | Protocol Deviation | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 | 1 |
| Overall Study | Sponsor Decision | 0 | 0 | 1 |
| Overall Study | Switching to other therapy | 0 | 1 | 1 |
| Overall Study | Trial closure. | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 20 |
Baseline characteristics
| Characteristic | Part A: Indolent NHL/CLL | Part A: Aggressive NHL | Part B: Indolent NHL | Total |
|---|---|---|---|---|
| Age, Customized 18 to 90 years | 33 Participants | 51 Participants | 142 Participants | 226 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 6 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 21 Participants | 36 Participants | 124 Participants | 181 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 10 Participants | 13 Participants | 12 Participants | 35 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 15 Participants | 15 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants | 11 Participants | 7 Participants | 26 Participants |
| Race (NIH/OMB) White | 25 Participants | 40 Participants | 120 Participants | 185 Participants |
| Sex: Female, Male Female | 18 Participants | 22 Participants | 71 Participants | 111 Participants |
| Sex: Female, Male Male | 15 Participants | 29 Participants | 71 Participants | 115 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 21 / 33 | 39 / 51 | 75 / 142 |
| other Total, other adverse events | 33 / 33 | 50 / 51 | 138 / 142 |
| serious Total, serious adverse events | 16 / 33 | 31 / 51 | 81 / 142 |
Outcome results
Primary
Objective Response Rate (ORR) Based on Independent Review-Part A
Objective response rate was defined as the proportion of participants with a best response rating of complete response (CR), unconfirmed complete response (CRu) or partial response (PR), based on the Report of an International Workshop to Standardize Response Criteria for non-Hodgkins Lymphomas, Cheson, 1999, as evaluated by the Independent Response Adjudication Committee (IRAC). For chronic lymphocytic leukemia (CLL) patients Hallek criteria (2008) were used and assessed by investigator.
Time frame: Baseline up to the last patient has completed the 16 weeks of treatment
Population: Per protocol set included all patients treated with study drug and evaluated for ORR and had no major protocol deviation. (In Part A, for CLL patients, there was no independent assessment. Instead, the investigator assessment had been used.)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Indolent NHL/CLL | Objective Response Rate (ORR) Based on Independent Review-Part A | 43.75 percentage of participants |
| Part A: Aggressive NHL | Objective Response Rate (ORR) Based on Independent Review-Part A | 27.08 percentage of participants |
Comparison: Response rate was statistically compared by exact binomial test if higher than 5%.p-value: 0.000190% CI: [30.49, 61.06]Exact binomial test
Comparison: Response rate was statistically compared by exact binomial test if higher than 5%.p-value: 0.000190% CI: [16.83, 39.57]Exact binominal test
Primary
ORR Based on Independent Review-Part B
Objective response rate was defined as the proportion of participants with a best response rating of CR or PR, based on the International Working Group Revised response Criteria for Malignant Lymphoma, Cheson 2007.
Time frame: Baseline up to the last patient has completed the 16 weeks of treatment
Population: FAS included all patients assigned to study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Indolent NHL/CLL | ORR Based on Independent Review-Part B | 59.15 percentage of participants |
Comparison: Response rate was statistically compared by exact binomial test if higher than 40%.p-value: <0.000195% CI: [50.6, 67.32]Exact binominal test
Primary
ORR Based on Investigator Assessment-Part A
Objective response rate was defined as the proportion of participants with a best response rating of CR, CRu or PR, based on the Report of an International Workshop to Standardize Response Criteria for non-Hodgkins Lymphomas, Cheson, 1999. For CLL patients Hallek criteria (2008) were used and assessed by investigator.
Time frame: Baseline up to the last patient has completed the 16 weeks of treatment
Population: Per protocol set included all patients treated with study drug and evaluated for ORR and had no major protocol deviation. Patients who were not evaluable for ORR and discontinued due to a drug-related toxicity, death / progression by clinical judgment before disease was re-evaluated and included.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Indolent NHL/CLL | ORR Based on Investigator Assessment-Part A | 46.88 percentage of participants |
| Part A: Aggressive NHL | ORR Based on Investigator Assessment-Part A | 31.25 percentage of participants |
Comparison: Response rate was statistically compared by exact binomial test if higher than 5%.p-value: 0.000190% CI: [31.54, 62.66]Exact binominal test
Comparison: Response rate was statistically compared by exact binomial test if higher than 5%.p-value: 0.000190% CI: [20.35, 43.97]Exact binominal test
Primary
ORR Based on Investigator Assessment-Part B
Objective response rate was defined as the proportion of participants with a best response rating of CR or PR, based on the International Working Group Revised response Criteria for Malignant Lymphoma, Cheson 2007.
Time frame: Baseline up to the last patient has completed the 16 weeks of treatment
Population: FAS included all patients assigned to study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Indolent NHL/CLL | ORR Based on Investigator Assessment-Part B | 51.41 percentage of participants |
Comparison: Response rate was statistically compared by exact binomial test if higher than 40%.p-value: 0.003995% CI: [42.88, 59.87]Exact binominal test
Secondary
DOR Based on Independent Review-Part B
DOR was defined as the time from the date of the first observed tumor response of CR or PR (whichever was noted earlier) to first subsequent disease progression (either first progressive disease \[PD\], first clinical progression or first AE associated with clinical disease progression) or death caused by disease progression, if this death occurred before progression was documented. All deaths were considered as 'caused by disease progression' except deaths with the reason other or AE not related to disease progression. DOR was evaluated only for patients with at least one tumor response of CR, CRu, or PR. Some patients may have had no report of disease progression nor death caused by disease progression until the date of the LPLV. With regards to DOR, these patients were considered as right censored at the date of their last tumor assessment after first observed tumor response.
Time frame: Baseline up to approximately 9 years 7 months
Population: FAS included all patients assigned to study treatment. DOR was only evaluated for patients with at least one tumor response of CR, Cru (only for Part A) or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Indolent NHL/CLL | DOR Based on Independent Review-Part B | 14.9 Months |
Secondary
DOR Based on Investigator Assessment-Part A
DOR was defined as the time from the date of the first observed tumor response of CR or PR (whichever was noted earlier) to first subsequent disease progression (either first progressive disease \[PD\], first clinical progression or first AE associated with clinical disease progression) or death caused by disease progression, if this death occurred before progression was documented. All deaths were considered as 'caused by disease progression' except deaths with the reason other or AE not related to disease progression. DOR was evaluated only for patients with at least one tumor response of CR, CRu, or PR. Some patients may have had no report of disease progression nor death caused by disease progression until the date of the LPLV. With regards to DOR, these patients were considered as right censored at the date of their last tumor assessment after first observed tumor response.
Time frame: Baseline up to approximately 6 years
Population: PPS included all patients with study drug administration that were evaluable for objective tumor response and had no major protocol deviation.~DOR was only evaluated for patients with at least one tumor response of CR, Cru (only for Part A) or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Indolent NHL/CLL | DOR Based on Investigator Assessment-Part A | 189 Days |
| Part A: Aggressive NHL | DOR Based on Investigator Assessment-Part A | 190 Days |
Secondary
DOR Based on Investigator Assessment-Part B
DOR was defined as the time from the date of the first observed tumor response of CR or PR (whichever was noted earlier) to first subsequent disease progression (either first progressive disease \[PD\], first clinical progression or first AE associated with clinical disease progression) or death caused by disease progression, if this death occurred before progression was documented. All deaths were considered as 'caused by disease progression' except deaths with the reason other or AE not related to disease progression. DOR was evaluated only for patients with at least one tumor response of CR, CRu, or PR. Some patients may have had no report of disease progression nor death caused by disease progression until the date of the LPLV. With regards to DOR, these patients were considered as right censored at the date of their last tumor assessment after first observed tumor response.
Time frame: Baseline up to approximately 9 years 7 months
Population: FAS included all patients assigned to study treatment. DOR was only evaluated for patients with at least one tumor response of CR, Cru (only for Part A) or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Indolent NHL/CLL | DOR Based on Investigator Assessment-Part B | 11.5 Months |
Secondary
Duration of Response (DOR) Based on Independent Review-Part A
DOR was defined as the time from the date of the first observed tumor response of CR or PR (whichever was noted earlier) to first subsequent disease progression (either first progressive disease \[PD\], first clinical progression or first AE associated with clinical disease progression) or death caused by disease progression, if this death occurred before progression was documented. All deaths were considered as 'caused by disease progression' except deaths with the reason other or AE not related to disease progression. DOR was evaluated only for patients with at least one tumor response of CR, CRu, or PR. Some patients may have had no report of disease progression nor death caused by disease progression until the date of the LPLV. With regards to DOR, these patients were considered as right censored at the date of their last tumor assessment after first observed tumor response.
Time frame: Baseline up to approximately 6 years
Population: PPS included all patients with study drug administration that were evaluable for objective tumor response and had no major protocol deviation.~DOR was only evaluated for patients with at least one tumor response of CR, Cru (only for Part A) or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Indolent NHL/CLL | Duration of Response (DOR) Based on Independent Review-Part A | 322 Days |
| Part A: Aggressive NHL | Duration of Response (DOR) Based on Independent Review-Part A | NA Days |
Secondary
Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Total Score at Week 16 - Part B
HRQoL assessment was used to describe development of patients with copanlisib by using FACT-Lym questionnaire assessment tool. It contains 42 items (questions) covering HRQoL, common lymphoma symptoms and treatment side-effects. The FACT - General (FACT-G) questionnaire contains 27 items covering 4 core HRQoL subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 items) (FACT-Lym LymS), addressing issues typically experienced by lymphoma patients. Some of the issues covered include pain, itching, night sweats, trouble sleeping, fatigue and trouble concentrating. FACT-Lym also asks patients about lumps and swelling, fevers, infections, weight, appetite, emotional stability and treatment. FACT-Lym total score range was 0-168, higher score indicates better HRQoL. Here, in the below table n signifies evaluable participants for the respective category.
Time frame: Baseline up to week 16
Population: FAS included all patients assigned to study treatment. The analysis was performed by using last LOCF method.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: Indolent NHL/CLL | Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Total Score at Week 16 - Part B | Baseline | 127.50 units on a scale |
| Part A: Indolent NHL/CLL | Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Total Score at Week 16 - Part B | Value at Week 16 | 130.83 units on a scale |
Comparison: Hodges-Lehmann-estimate was used to calculate change to Week 16 and 95% confidence interval.95% CI: [-0.7, 3.2]
Secondary
Functional Assessment of Cancer Therapy - Lymphoma Lymphoma Subscale (FACT-Lym LymS) at Week 16 - Part B
HRQoL assessment was used to describe development of patients with copanlisib by using FACT-Lym questionnaire assessment tool. It contains 42 items (questions) covering HRQoL, common lymphoma symptoms and treatment side-effects. The FACT - General (FACT-G) questionnaire contains 27 items covering 4 core HRQoL subscales: Physical Wellbeing (7 items), Social/Family Wellbeing (7), Emotional Wellbeing (6), and Functional Wellbeing (7). The FACT-Lym also includes an Additional Concerns subscale (15 items) (FACT-Lym LymS), addressing issues typically experienced by lymphoma patients. Some of the issues covered include pain, itching, night sweats, trouble sleeping, fatigue and trouble concentrating. FACT-Lym also asks patients about lumps and swelling, fevers, infections, weight, appetite, emotional stability and treatment. Score range for the FACT-Lym LymS was 0 - 60, higher score represent less symptoms. Here in below table n signifies evaluable participants for the respective category.
Time frame: Baseline up to week 16
Population: FAS included all patients assigned to study treatment. The analysis was performed by using last observation carried forward (LOCF) method.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part A: Indolent NHL/CLL | Functional Assessment of Cancer Therapy - Lymphoma Lymphoma Subscale (FACT-Lym LymS) at Week 16 - Part B | Baseline | 46.50 units on a scale |
| Part A: Indolent NHL/CLL | Functional Assessment of Cancer Therapy - Lymphoma Lymphoma Subscale (FACT-Lym LymS) at Week 16 - Part B | Value at Week 16 | 49.00 units on a scale |
Comparison: Hodges-Lehmann-estimate was used to calculate change to Week 16 and 95% confidence interval.95% CI: [0.5, 2.5]
Secondary
OS-Part B
OS was defined as the time (in days) from the date of first administration of study treatment to death due to any cause. OS was defined as the time (in days) from the date of first administration of study treatment to death due to any cause. Patients who were alive at the date of the LPLV were censored at the minimum of the date of LPLV and the last available date of evidence that the patient was still alive.
Time frame: Baseline up to approximately 9 years 7 months
Population: FAS included all patients assigned to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Indolent NHL/CLL | OS-Part B | 59.1 Months |
Secondary
Overall Survival (OS)-Part A
OS was defined as the time (in days) from the date of first administration of study treatment to death due to any cause. Patients who were alive at the date of the LPLV were censored at the minimum of the date of LPLV and the last available date of evidence that the patient was still alive.
Time frame: Baseline up to approximately 6 years
Population: FAS included all patients assigned to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Indolent NHL/CLL | Overall Survival (OS)-Part A | 657 Days |
| Part A: Aggressive NHL | Overall Survival (OS)-Part A | 211 Days |
Secondary
PFS Based on Independent Review-Part B
PFS was defined as the time (in days) from the date of the first treatment to the date of first observed PD (radiological or clinical, or first AE associated with clinical PD, whichever was earlier) or death due to any cause (if death occurred before progression was documented).
Time frame: Baseline up to approximately 9 years 7 months
Population: FAS included all patients assigned to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Indolent NHL/CLL | PFS Based on Independent Review-Part B | 11.3 Months |
Secondary
PFS Based on Investigator Assessment-Part A
PFS was defined as the time (in days) from the date of the first treatment to the date of first observed PD (radiological or clinical, or first AE associated with clinical PD, whichever was earlier) or death due to any cause (if death occurred before progression was documented).
Time frame: Baseline up to approximately 6 years
Population: FAS included all patients assigned to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Indolent NHL/CLL | PFS Based on Investigator Assessment-Part A | 224 Days |
| Part A: Aggressive NHL | PFS Based on Investigator Assessment-Part A | 70 Days |
Secondary
PFS Based on Investigator Assessment-Part B
PFS was defined as the time (in days) from the date of the first treatment to the date of first observed PD (radiological or clinical, or first AE associated with clinical PD, whichever was earlier) or death due to any cause (if death occurred before progression was documented).
Time frame: Baseline up to approximately 9 years 7 months
Population: FAS included all patients assigned to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Indolent NHL/CLL | PFS Based on Investigator Assessment-Part B | 10.8 Months |
Secondary
Progression Free Survival (PFS) Based on Independent Review-Part A
PFS was defined as the time (in days) from the date of the first treatment to the date of first observed PD (radiological or clinical, or first AE associated with clinical PD, whichever was earlier) or death due to any cause (if death occurred before progression was documented).
Time frame: Baseline up to approximately 6 years
Population: FAS included all patients assigned to study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Indolent NHL/CLL | Progression Free Survival (PFS) Based on Independent Review-Part A | 223 Days |
| Part A: Aggressive NHL | Progression Free Survival (PFS) Based on Independent Review-Part A | 70 Days |