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

NCT01660451 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 163492012-002602-52
• Study Type: interventional
• Target: 227
• Locations: 24 countries
• Sites: 101

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

Keywords

Clinical trial, phase II; Phosphatidylinositol 3-Kinase; Class I, Non-Hodgkin's lymphoma

Outcome Measures

Primary Outcomes (4)

• 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

• 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 Outcomes (12)

• Duration of Response (DOR) Based on Independent Review-Part A

  Baseline up to approximately 6 years

• DOR Based on Independent Review-Part B

  Baseline up to approximately 9 years 7 months

• DOR Based on Investigator Assessment-Part A

  Baseline up to approximately 6 years

• DOR Based on Investigator Assessment-Part B

  Baseline up to approximately 9 years 7 months

• Progression Free Survival (PFS) Based on Independent Review-Part A

  Baseline up to approximately 6 years

Study Arms (3)

Copanlisib (indolent NHL)

EXPERIMENTAL

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

Drug: Copanlisib (Aliqopa, BAY80-6946)

Copanlisib (aggressive NHL)

EXPERIMENTAL

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

Drug: Copanlisib (Aliqopa, BAY80-6946)

Copanlisib (indolent B-cell NHL)

EXPERIMENTAL

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

Drug: Copanlisib (Aliqopa, BAY80-6946)

Interventions

Copanlisib (Aliqopa, BAY80-6946) 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); Copanlisib (indolent B-cell NHL); Copanlisib (indolent NHL)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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 \[Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)\].

Sponsors & Collaborators

• Bayer: lead

Study Sites (102)

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Birmingham, Alabama, 35213, United States

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Gilbert, Arizona, 85234, United States

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Anaheim, California, 90801, United States

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Aurora, Colorado, 80012, United States

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Englewood, Colorado, 80113, United States

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Fort Collins, Colorado, 80528, United States

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Seattle, Florida, 98101, United States

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Louisville, Kentucky, 40207, United States

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Detroit, Michigan, 48202, United States

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Saint Louis Park, Minnesota, 55426, United States

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Westbury, New York, 11590, United States

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Clinton, North Carolina, 2753, United States

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Canton, Ohio, 44718, United States

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San Antonio, Texas, 78229, United States

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Spokane, Washington, 99208-1129, United States

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Garran, Australian Capital Territory, 2605, Australia

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Linz, 4020, Austria

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Brussels, 1070, Belgium

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Bruxelles - Brussel, 1200, Belgium

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Ghent, 9000, Belgium

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Leuven, 3000, Belgium

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Turnhout, 2300, Belgium

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Wilrijk, 2610, Belgium

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Sofia, 1431, Bulgaria

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Saint John, New Brunswick, E2L 4L2, Canada

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Montreal, Quebec, H1T 2M4, Canada

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Montreal, Quebec, H3T 1E2, Canada

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Helsinki, 00290, Finland

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Oulu, 90020, Finland

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Tampere, 33521, Finland

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Turku, FIN-20521, Finland

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Brest, 29285, France

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Créteil, 94010, France

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La Roche-sur-Yon, 85925, France

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Lille, 59037, France

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Paris, 75475, France

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Pessac, 33600, France

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Pierre-Bénite, 69495, France

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Poitiers, 86021, France

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Rouen, 76038, France

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Vandœuvre-lès-Nancy, 54500, France

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München, Bavaria, 81377, Germany

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Münster, North Rhine-Westphalia, 48149, Germany

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Recklinghausen, North Rhine-Westphalia, 45659, Germany

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Mainz, Rhineland-Palatinate, 55131, Germany

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Dresden, Saxony, 01307, Germany

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Potsdam, State of Berlin, 14467, Germany

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Berlin, 10967, Germany

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Berlin, 13353, Germany

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Athens, 11526, Greece

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Hong Kong, Hong Kong

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Shatin, MISSING, Hong Kong

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Budapest, 1083, Hungary

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Budapest, 1097, Hungary

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Kaposvár, 7400, Hungary

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Galway, H91 YR71, Ireland

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Petah Tikva, 4941492, Israel

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Ramat Gan, 5262000, Israel

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Ẕerifin, 7030000, Israel

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Napoli, Campania, 80131, Italy

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Bologna, Emilia-Romagna, 40138, Italy

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Rome, Lazio, 00161, Italy

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Brescia, Lombardy, 25123, Italy

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Milan, Lombardy, 20089, Italy

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Turin, Piedmont, 10126, Italy

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Christchurch, New Zealand

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Gdynia, 81-519, Poland

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Krakow, 30-510, Poland

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Lisbon, 1093 CODEX, Portugal

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Lisbon, 1099-023, Portugal

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Kemerovo, 650066, Russia

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Moscow, 129128, Russia

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Nizhny Novgorod, 603126, Russia

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Omsk, 644013, Russia

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Saint Petersburg, 197101, Russia

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Saratov, 410053, Russia

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Singapore, 169608, Singapore

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Singapore, 169610, Singapore

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Busan, Busan Gwang''yeogsi, 49201, South Korea

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Seoul, Seoul Teugbyeolsi, 3080, South Korea

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Seoul, 6351, South Korea

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Majadahonda, Madrid, 28222, Spain

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Marbella, Málaga, 29603, Spain

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Barcelona, 08036, Spain

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Madrid, 28050, Spain

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Seville, 41071, Spain

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Valencia, 46026, Spain

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Uddevalla, 451 80, Sweden

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Ankara, 06100, Turkey (Türkiye)

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Istanbul, 34093, Turkey (Türkiye)

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Izmir, 35100, Turkey (Türkiye)

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Izmir, 35340, Turkey (Türkiye)

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Cambridge, Cambridgeshire, CB2 0QQ, United Kingdom

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Plymouth, Devon, PL6 8DH, United Kingdom

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Southampton, Hampshire, SO16 6YD, United Kingdom

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Harrow, London, HA1 3UJ, United Kingdom

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Liverpool, Merseyside, L7 8XP, United Kingdom

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Sutton, Surrey, SM2 5PT, United Kingdom

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Birmingham, West Midlands, B9 5SS, United Kingdom

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Leeds, LS9 7TF, United Kingdom

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Manchester, M20 4BX, United Kingdom

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Romford, RM7 0AG, United Kingdom

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Related Publications (3)

• 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.

  PMID: 28633365 RESULT

• 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.

  PMID: 38226495 DERIVED

• 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.

  PMID: 33560394 DERIVED

Related Links

• Click here to find further information and, after study completion, the study results according to Bayer's transparency standards.
• Click here to find information about studies related to Bayer Healthcare products conducted in Europe

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin

Interventions

copanlisib

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Results Point of Contact

• Title: Therapeutic Area Head
• Organization: Bayer

clinical-trials-contact@bayer.com

+1-888-8422937

Study Officials

• Bayer Study Director

  Bayer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 6, 2012
• First Posted: August 8, 2012
• Study Start: November 19, 2012
• Primary Completion: June 22, 2016
• Study Completion: May 18, 2023
• Last Updated: July 17, 2024
• Results First Posted: January 8, 2018

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

CA (3); AU (1); PT (2); TU (4); BE (6); US (15); IL (3); IT (6); BU (1); FI (4); GR (1); DE (8); NZ (1); RU (6); SG (2); KR (3); PL (2); FR (10); HK (2); IE (1); ES (6); SE (1); GB (10); HU (3)