Open-label, Uncontrolled Phase II Trial of Intravenous PI3K Inhibitor BAY80-6946 in Patients With Relapsed, Indolent or Aggressive Non-Hodgkin's Lymphomas

Study Overview
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Brief Summary
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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.

Official Title
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Open-label, Uncontrolled Phase II Trial of Intravenous PI3K Inhibitor BAY80-6946 in Patients With Relapsed, Indolent or Aggressive Non-Hodgkin's Lymphomas

Conditions
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Lymphoma, Non-Hodgkin

Intervention / Treatment
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* Drug: Copanlisib (Aliqopa, BAY80-6946)


Participation Criteria
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Eligibility Criteria
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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)].

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Copanlisib (indolent NHL)<br>Part A: Participants in this arm will be patients with indolent NHL. | Drug: Copanlisib (Aliqopa, BAY80-6946)<br>* 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.<br>|
| Experimental: Copanlisib (aggressive NHL)<br>Part A: Participants in this arm will be patients with aggressive NHL. | Drug: Copanlisib (Aliqopa, BAY80-6946)<br>* 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.<br>|
| Experimental: Copanlisib (indolent B-cell NHL)<br>Part B: Participants in this arm will be patients with indolent B-cell NHL. | Drug: Copanlisib (Aliqopa, BAY80-6946)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline up to the last patient has completed the 16 weeks of treatment | 
| Objective Response Rate (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. | Baseline up to the last patient has completed the 16 weeks of treatment | 
| 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. | Baseline up to the last patient has completed the 16 weeks of treatment | 
| 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. | Baseline up to the last patient has completed the 16 weeks of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) Based on Independent Review | Duration of response (DOR) was defined as the time (in days) 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 adverse event [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. | Baseline up to the last patient has completed the 16 weeks of treatment | 
| DOR Based on Investigator Assessment | Duration of response (DOR) was defined as the time (in days) 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 adverse event [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. | Baseline up to the last patient has completed the 16 weeks of treatment | 
| Progression Free Survival (PFS) Based on Independent Review | 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). | Baseline up to the last patient has completed the 16 weeks of treatment | 
| PFS Based on Investigator Assessment | 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). | Baseline up to the last patient has completed the 16 weeks of treatment | 
| Overall Survival (OS) | OS was defined as the time (in days) from the date of first administration of study treatment to death due to any cause. | Baseline up to the last patient has completed the 16 weeks of treatment | 
| 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. | Baseline up to the last patient has completed the 16 weeks of treatment | 
| 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. | Baseline up to the last patient has completed the 16 weeks of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Clinical trial, phase II, Phosphatidylinositol 3-Kinase, Class I, Non-Hodgkin's lymphoma