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

NCT ID: NCT01660451

Last Updated: 2024-07-17

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 227 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-11-19
• Study Completion Date: 2023-05-18

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.

Conditions

Lymphoma, Non-Hodgkin

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Copanlisib (indolent NHL)

Part A: Participants in this arm will be patients with indolent NHL.

Group Type: EXPERIMENTAL

Copanlisib (Aliqopa, BAY80-6946)

Intervention Type: DRUG

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.

Copanlisib (aggressive NHL)

Part A: Participants in this arm will be patients with aggressive NHL.

Group Type: EXPERIMENTAL

Copanlisib (Aliqopa, BAY80-6946)

Intervention Type: DRUG

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.

Copanlisib (indolent B-cell NHL)

Part B: Participants in this arm will be patients with indolent B-cell NHL.

Group Type: EXPERIMENTAL

Copanlisib (Aliqopa, BAY80-6946)

Intervention Type: DRUG

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.

Interventions

Copanlisib (Aliqopa, BAY80-6946)

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.

Intervention Type: DRUG

Eligibility Criteria

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)].

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bayer

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Bayer Study Director

Role: STUDY_DIRECTOR

Bayer

Locations

Birmingham, Alabama, United States

Gilbert, Arizona, United States

Anaheim, California, United States

Aurora, Colorado, United States

Englewood, Colorado, United States

Fort Collins, Colorado, United States

Seattle, Florida, United States

Louisville, Kentucky, United States

Detroit, Michigan, United States

Saint Louis Park, Minnesota, United States

Westbury, New York, United States

Clinton, North Carolina, United States

Canton, Ohio, United States

San Antonio, Texas, United States

Spokane, Washington, United States

Garran, Australian Capital Territory, Australia

Linz, , Austria

Brussels, , Belgium

Bruxelles - Brussel, , Belgium

Ghent, , Belgium

Leuven, , Belgium

Turnhout, , Belgium

Wilrijk, , Belgium

Sofia, , Bulgaria

Saint John, New Brunswick, Canada

Montreal, Quebec, Canada

Montreal, Quebec, Canada

Helsinki, , Finland

Oulu, , Finland

Tampere, , Finland

Turku, , Finland

Brest, , France

Créteil, , France

La Roche-sur-Yon, , France

Lille, , France

Paris, , France

Pessac, , France

Pierre-Bénite, , France

Poitiers, , France

Rouen, , France

Vandœuvre-lès-Nancy, , France

München, Bavaria, Germany

Münster, North Rhine-Westphalia, Germany

Recklinghausen, North Rhine-Westphalia, Germany

Mainz, Rhineland-Palatinate, Germany

Dresden, Saxony, Germany

Potsdam, State of Berlin, Germany

Berlin, , Germany

Berlin, , Germany

Athens, , Greece

Hong Kong, , Hong Kong

Shatin, , Hong Kong

Budapest, , Hungary

Budapest, , Hungary

Kaposvár, , Hungary

Galway, , Ireland

Petah Tikva, , Israel

Ramat Gan, , Israel

Ẕerifin, , Israel

Napoli, Campania, Italy

Bologna, Emilia-Romagna, Italy

Rome, Lazio, Italy

Brescia, Lombardy, Italy

Milan, Lombardy, Italy

Turin, Piedmont, Italy

Christchurch, , New Zealand

Gdynia, , Poland

Krakow, , Poland

Lisbon, , Portugal

Lisbon, , Portugal

Kemerovo, , Russia

Moscow, , Russia

Nizhny Novgorod, , Russia

Omsk, , Russia

Saint Petersburg, , Russia

Saratov, , Russia

Singapore, , Singapore

Singapore, , Singapore

Busan, Busan Gwang''yeogsi, South Korea

Seoul, Seoul Teugbyeolsi, South Korea

Seoul, , South Korea

Majadahonda, Madrid, Spain

Marbella, Málaga, Spain

Barcelona, , Spain

Madrid, , Spain

Seville, , Spain

Valencia, , Spain

Uddevalla, , Sweden

Ankara, , Turkey (Türkiye)

Istanbul, , Turkey (Türkiye)

Izmir, , Turkey (Türkiye)

Izmir, , Turkey (Türkiye)

Cambridge, Cambridgeshire, United Kingdom

Plymouth, Devon, United Kingdom

Southampton, Hampshire, United Kingdom

Harrow, London, United Kingdom

Liverpool, Merseyside, United Kingdom

Sutton, Surrey, United Kingdom

Birmingham, West Midlands, United Kingdom

Leeds, , United Kingdom

Manchester, , United Kingdom

Romford, , United Kingdom

Countries

United States; 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

References

Dreyling M, Morschhauser F, Bouabdallah K, Bron D, Cunningham D, Assouline SE, Verhoef G, Linton K, Thieblemont C, Vitolo U, Hiemeyer F, Giurescu M, Garcia-Vargas J, Gorbatchevsky I, Liu L, Koechert K, Pena C, Neves M, Childs BH, Zinzani PL. Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Ann Oncol. 2017 Sep 1;28(9):2169-2178. doi: 10.1093/annonc/mdx289.

Reference Type: RESULT

PMID: 28633365 (View on PubMed)

Morcos PN, Moss J, Veasy J, Hiemeyer F, Childs BH, Garmann D. Model-Based Benefit/Risk Analysis for the Copanlisib Intermittent Dosing Regimen. Clin Pharmacol Ther. 2024 May;115(5):1092-1104. doi: 10.1002/cpt.3173. Epub 2024 Jan 16.

Reference Type: DERIVED

PMID: 38226495 (View on PubMed)

Panayiotidis P, Follows GA, Mollica L, Nagler A, Ozcan M, Santoro A, Stevens D, Trevarthen D, Hiemeyer F, Garcia-Vargas J, Childs BH, Zinzani PL, Dreyling M. Efficacy and safety of copanlisib in patients with relapsed or refractory marginal zone lymphoma. Blood Adv. 2021 Feb 9;5(3):823-828. doi: 10.1182/bloodadvances.2020002910.

Reference Type: DERIVED

PMID: 33560394 (View on PubMed)

Related Links

https://clinicaltrials.bayer.com/study/16349

Click here to find further information and, after study completion, the study results according to Bayer's transparency standards.

http://www.clinicaltrialsregister.eu/

Click here to find information about studies related to Bayer Healthcare products conducted in Europe

Other Identifiers

2012-002602-52

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

16349

Identifier Type: -

Identifier Source: org_study_id