Open-label, Uncontrolled Phase II Trial of Intravenous PI3K Inhibitor BAY80-6946 in Patients With Relapsed, Indolent or Aggressive Non-Hodgkin's Lymphomas (CHRONOS-1)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Bayer
ClinicalTrials.gov Identifier:
NCT01660451
First received: August 6, 2012
Last updated: June 20, 2016
Last verified: June 2016
  Purpose

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 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 3 years after last patient first treatment. In Part B, patients will enter the Active Assessment Followup 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.


Condition Intervention Phase
Lymphoma, Non-Hodgkin
Drug: Copanlisib (BAY80-6946)
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Open-label, Uncontrolled Phase II Trial of Intravenous PI3K Inhibitor BAY80-6946 in Patients With Relapsed, Indolent or Aggressive Non-Hodgkin's Lymphomas

Resource links provided by NLM:


Further study details as provided by Bayer:

Primary Outcome Measures:
  • Tumor response [ Time Frame: Up to 10 months ] [ Designated as safety issue: No ]
    Objective tumor response (OR) is defined as best response rating of complete response (CR or unconfirmed CR) or partial response (PR) according to the criteria defined in the Report of an International Workshop to Standardize Response Criteria for NHL. In patients with Chronic lymphocytic leukemia (CLL), OR is defined as best response rating of complete response (CR) or partial response (PR) according to the guidelines for the diagnosis and treatment of chronic lymphocytic leukemia of the International Workshop on Chronic Lymphocytic Leukemia.


Secondary Outcome Measures:
  • Duration of response after 12 months [ Time Frame: After 12 months ] [ Designated as safety issue: No ]
    Defined as the time (in days) from first observed tumor response (Complete response, Complete response unconfirmed or Partial Response) until progressive disease or until death caused by progressive disease.

  • Duration of response after 3 years [ Time Frame: After 3 years ] [ Designated as safety issue: No ]
    Defined as the time (in days) from first observed tumor response (Complete response, Complete response unconfirmed or Partial Response) until progressive disease or until death caused by progressive disease.

  • Progression free survival after 12 months [ Time Frame: After 12 months ] [ Designated as safety issue: No ]
    Defined as the time (in days) from treatment assignment to disease progression or death (if death occurs before a documented progression).

  • Progression free survival after 3 years [ Time Frame: After 3 years ] [ Designated as safety issue: No ]
    Defined as the time (in days) from treatment assignment to disease progression or death (if death occurs before a documented progression).

  • Overall survival after 12 months [ Time Frame: After 12 months ] [ Designated as safety issue: No ]
    Defined as the time (in days) from treatment assignment until death from any cause or until the last date the patient is known to be alive.

  • Overall survival after 3 years [ Time Frame: After 3 years ] [ Designated as safety issue: No ]
    Defined as the time (in days) from treatment assignment until death from any cause or until the last date the patient is known to be alive.

  • Number of participants with adverse events as a measure of safety and tolerability [ Time Frame: Up to 4 years ] [ Designated as safety issue: Yes ]
  • Duration of response after study withdrawal [ Time Frame: After 12 months ] [ Designated as safety issue: No ]
    Defined as the time (in days) from first observed tumor response (Complete response, complete response unconfirmed or Partial response) until progressive disease or until death caused by progressive disease .


Enrollment: 223
Study Start Date: November 2012
Estimated Study Completion Date: July 2018
Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Copanlisib (indolent NHL)
Part A: Participants in this arm will be patients with indolent NHL.
Drug: Copanlisib (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.

Experimental: Copanlisib (aggressive NHL)
Part A: Participants in this arm will be patients with aggressive NHL.
Drug: Copanlisib (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.

Experimental: Copanlisib (indolent B-cell NHL)
Part B: Participants in this arm will be patients with indolent B-cell NHL.
Drug: Copanlisib (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.


  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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)].
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01660451

  Show 205 Study Locations
Sponsors and Collaborators
Bayer
Investigators
Study Director: Bayer Study Director Bayer
  More Information

Additional Information:
Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT01660451     History of Changes
Other Study ID Numbers: 16349  2012-002602-52 
Study First Received: August 6, 2012
Last Updated: June 20, 2016
Health Authority: Belgium: Federal Agency for Medicines and Health Products, FAMHP
Finland: Finnish Medicines Agency
Germany: Federal Institutte for Drugs and Medical devices
France: French National Authority for Health
Italy: Italian Pharmaceutical Agency
Spain: Medicines and Health Products
United Kingdom: The medicines and Healthcare products regulatory Agency
United States: Food and Drug Administration
Canada: Health Canada
Sweden: Medical Products Agency
Australia: Therapeutics Goods Administration
China: State Food and Drug Adminstration
Israel: State of Israel Ministry of Health
South Korea: Korea Food and Drug administration
New Zealand: Medicines and Medical Devices Safety Authority
Poland: The Office for Registrationof Medicinal Products, Medical Devices and Biocidal Products
Russia: Ministry of Health of Russian Federation
Turkey: Republic of Turkey Ministry of Health
Austria: Austrian Agency for Health and Food Safety
Bulgaria: Bulgarian Drug Agency
Denmark: Danish Health and Medicines Authority
Hungary: National Institute of Pharmacy
Hong Kong: Department of Health
Portugal: National Authority of Medicines and Health Products
Singapore: Health Sciences Authority
Luxembourg: Ministère de la Santé
Greece: EOF
Ireland: Health Products Regulatory Authority
Mexico: Secretaria de Salud

Keywords provided by Bayer:
Clinical trial, phase II
Phosphatidylinositol 3-Kinase
Class I, Non-Hodgkin's lymphoma

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Non-Hodgkin
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases

ClinicalTrials.gov processed this record on August 24, 2016