This site became the new ClinicalTrials.gov on June 19th. Learn more.
Show more
ClinicalTrials.gov Menu IMPORTANT: Listing of a study on this site does not reflect endorsement by the National Institutes of Health. Talk with a trusted healthcare professional before volunteering for a study. Read more...
ClinicalTrials.gov Menu IMPORTANT: Talk with a trusted healthcare professional before volunteering for a study. Read more...
ClinicalTrials.gov Menu
Give us feedback

Study of Copanlisib in Combination With Standard Immunochemotherapy in Relapsed Indolent Non-Hodgkin's Lymphoma (iNHL) (CHRONOS-4)

This study is currently recruiting participants.
See Contacts and Locations
Verified June 2017 by Bayer
Sponsor:
Information provided by (Responsible Party):
Bayer
ClinicalTrials.gov Identifier:
NCT02626455
First received: November 3, 2015
Last updated: June 13, 2017
Last verified: June 2017
  Purpose
The purpose of this study is to assess whether copanlisib in combination with standard immunochemotherapy (rituximab in combination with bendamustine [R-B] and rituximab in combination with a 4 drug combination of cyclophosphamide, doxorubicin, vincristine and prednisone/prednisolone [R-CHOP]) is effective and safe compared with placebo in combination with standard immunochemotherapy (R-B or R-CHOP) in patients with relapsed iNHL who have received at least one, but at most three, lines of treatment, including rituximab and alkylating agents.

Condition Intervention Phase
Lymphoma, Non-Hodgkin Drug: Copanlisib (BAY 80-6946) Drug: Placebo Drug: Rituximab Drug: Cyclophosphamide Drug: Doxorubicin Drug: Vincristine Drug: Bendamustine Drug: Prednisone Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Care Provider, Investigator, Outcomes Assessor
Primary Purpose: Treatment
Official Title: A Phase III, Randomized, Double-blind, Controlled Multicenter Study of Intravenous PI3K Inhibitor Copanlisib in Combination With Standard Immunochemotherapy Versus Standard Immunochemotherapy in Patients With Relapsed Indolent Non-Hodgkin's Lymphoma (iNHL)

Resource links provided by NLM:


Further study details as provided by Bayer:

Primary Outcome Measures:
  • Evaluation whether copanlisib in combination with standard immunochemotherapy, is superior to placebo and standard immunochemotherapy assessed by the prolongation of progression free survival (PFS) - applicable to Phase III part [ Time Frame: at 53 month ]
    Progression free survival is defined as the time (in days) from randomization to Disease Progression or death from any cause (if no progression documented).

  • Determination of the recommended Phase III dose (RP3D) of copanlisib in combination with standard immunochemotherapy assessed by the occurrence of dose-limiting toxicity s (DLTs) / adverse events (AEs) - applicable to safety run-in part [ Time Frame: at Cycle 1: 21 days or 28 days ]

Secondary Outcome Measures:
  • Objective tumor response rate (ORR) [ Time Frame: at 53 months ]
    Proportion of patients who have a best overall response over the whole duration of the study (i.e. up to time of analysis of PFS) of complete response (CR) or partial response (PR)

  • Duration of tumor response (DOR) [ Time Frame: at 53 months ]
    Time (in days) from first observed tumor response (complete response [CR], very good partial response [VGPR], partial response [PR], or minor response [MR]) until PD or death from any cause, whichever is earlier. DOR will only be analyzed for patients with at least one CR, VGPR, PR, or MR.

  • Complete tumor response rate (CRR) [ Time Frame: at 53 months ]
    Proportion of patients who have a best overall response of CR during the study (i.e., up to time of analysis of PFS)

  • Time to tumor progression (TTP) [ Time Frame: at 53 months ]
    Time from randomization to PD or death related to PD, whichever is earlier

  • Overall survival (OS) [ Time Frame: at 53 months ]
    The time (in days) from randomization until death from any cause.

  • Time to deterioration in disease-related physical symptoms (DRS-P) of at least 3 points as measured by by the FLymSI-18 (Lymphoma Symptom Index -18) questionnaire [ Time Frame: at 53 months ]
  • Time to improvement in DRS-P of at least 3 points, as measured by the FLymSI-18 questionnaire, will be evaluated for patients with a baseline DRS-P score of 30 points or less [ Time Frame: at 53 months ]
  • Time to next anti-lymphoma treatment (TTNT) [ Time Frame: at 53 months ]
    Time from stop of study medication to start of new anti-lymphoma therapy.

  • Radiological and clinical indicators of treatment efficacy: Progression free survival (PFS) [ Time Frame: After Cycle 1: day 22 or 29 up to 12 months ]
    Applicable to safety run-in phase

  • Radiological and clinical indicators of treatment efficacy:Objective tumor response rate (ORR) [ Time Frame: After Cycle 1: day 22 or 29 up to 12 months ]
    Applicable to safety run-in phase

  • Radiological and clinical indicators of treatment efficacy:Duration of tumor response (DOR) [ Time Frame: After Cycle 1: day 22 or 29 up to 12 months ]
    Applicable to safety run-in phase

  • Radiological and clinical indicators of treatment efficacy: Complete tumor response rate (CRR) [ Time Frame: After Cycle 1: day 22 or 29 up to 12 months ]
    Applicable to safety run-in phase

  • Radiological and clinical indicators of treatment efficacy: Time to tumor progression (TTP) [ Time Frame: After Cycle 1: day 22 or 29 up to 12 months ]
    Applicable to safety run-in phase

  • Radiological and clinical indicators of treatment efficacy: Time to next anti-lymphoma treatment (TTNT) [ Time Frame: After Cycle 1: day 22 or 29 up to 12 months ]
    Applicable to safety run-in phase

  • Radiological and clinical indicators of treatment efficacy: Overall survival (OS) [ Time Frame: After Cycle 1: day 22 or 29 up to 12 months ]
    Applicable to safety run-in phase

  • Number of participants with adverse events as a measure of safety and tolerability [ Time Frame: at 53 months ]
  • Radiological and clinical indicators of treatment efficacy: "time to deterioration" in disease-related symptoms - physical (DRS-P) will be assessed using the NCCN-FACT Lymphoma Symptom Index-18 (FLymSI-18) questionnaire [ Time Frame: After Cycle 1: day 22 or 29 up to 12 months ]
    Applicable to safety run-in phase

  • Radiological and clinical indicators of treatment efficacy: Time to improvement" in disease-related symptoms - physical (DRS-P) will be assessed using the FLymSI-18 questionnaire [ Time Frame: After Cycle 1: day 22 or 29 up to 12 months ]
    Applicable to safety run-in phase


Estimated Enrollment: 676
Actual Study Start Date: January 6, 2016
Estimated Study Completion Date: December 31, 2024
Estimated Primary Completion Date: September 30, 2021 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Copanlisib + R-B or R-CHOP / Arm 1
Combination of copanlisib with standard immunochemotherapy (rituximab and bendamustine) [R-B] or rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone [R-CHOP] (safety run-in and phase III)
Drug: Copanlisib (BAY 80-6946)
Copanlisib is supplied as lyophilized preparation in a 6 mL injection vial. The total amount of copanlisib per vial is 60 mg. The solution for IV infusions is obtained after reconstitution with normal saline solution. For patients on R-B dosing of copanlisib will be administered on Days 1, 8 and 15 of each 28-day cycle. Copanlisib will be administered and then rituximab followed by bendamustine. For patients on R-CHOP dosing of copanlisib will be administered on Days 1 and 8 of each 21-day cycle. Copanlisib will be administered before rituximab followed by cyclophosphamide, doxorubicin and vincristine infusions. Prednisone/prednisolone tablets to be taken for 5 days.
Drug: Rituximab
Rituximab is administered as an infusion at a dose of 375 mg/m2 body surface on Day 1 of each 28-day cycle for patients assigned to R-B and on Day 2 of each 21-day cycle for patients assigned to R-CHOP.
Drug: Cyclophosphamide
Cyclophosphamide is administered as an infusion at a dose of 750 mg/m2 body surface on Day 2 of each 21-day cycle for patients assigned to R-CHOP
Drug: Doxorubicin
Doxorubicin is administered as an infusion at a dose of 50 mg/m2 body surface on Day 2 of each 21-day cycle for patients assigned to R-CHOP
Drug: Vincristine
Vincristine is administered as an infusion at a dose of 1.4 mg/m2 body surface (maximum dose 2.0 mg) on Day 2 of each 21-day cycle for patients assigned to R-CHOP
Drug: Bendamustine
Bendamustine is administered as an infusion at a dose of 90 mg/m2 body surface on Day 1 and Day 2 for patients assigned to R-B
Drug: Prednisone
Prednisone is given as 100 mg tablets daily from Day 2 to Day 6 for patients assigned to R-CHOP
Placebo Comparator: Placebo + R-B or R-CHOP / Arm 2
Combination of placebo and R-B or R-CHOP (phase III only)
Drug: Placebo
Placebo is supplied as lyophilized preparation in a 6 mL injection vial. The developed placebo lyophilisate is equivalent to the 60 mg copanlisib formulation, with regard to the composition of excipients and the instructions for reconstitution and dose preparation. Placebo dosing will be administered as per copanlisib described above. Applies to the phase III part of the study only.
Drug: Rituximab
Rituximab is administered as an infusion at a dose of 375 mg/m2 body surface on Day 1 of each 28-day cycle for patients assigned to R-B and on Day 2 of each 21-day cycle for patients assigned to R-CHOP.
Drug: Cyclophosphamide
Cyclophosphamide is administered as an infusion at a dose of 750 mg/m2 body surface on Day 2 of each 21-day cycle for patients assigned to R-CHOP
Drug: Doxorubicin
Doxorubicin is administered as an infusion at a dose of 50 mg/m2 body surface on Day 2 of each 21-day cycle for patients assigned to R-CHOP
Drug: Vincristine
Vincristine is administered as an infusion at a dose of 1.4 mg/m2 body surface (maximum dose 2.0 mg) on Day 2 of each 21-day cycle for patients assigned to R-CHOP
Drug: Bendamustine
Bendamustine is administered as an infusion at a dose of 90 mg/m2 body surface on Day 1 and Day 2 for patients assigned to R-B
Drug: Prednisone
Prednisone is given as 100 mg tablets daily from Day 2 to Day 6 for patients assigned to R-CHOP

Detailed Description:

Patients should be in need of and fit for immunochemotherapy and should not be resistant to rituximab (resistance defined as lack of response, or progression within 6 months of the last course of treatment with a rituximab containing regimen). This study will be composed of two parts: Safety run-in and phase III part.

The purpose of the safety run-in part of this study is to assess whether the drug being tested (copanlisib) in combination with standard immunochemotherapy (R-B or R-CHOP) is safe and at what dose level of the study drug (copanlisib - 45mg or 60 mg) patients are able to tolerate the study treatment combination. In addition to finding a safe and tolerable dose level for the phase III part of the study, efficacy will also be evaluated for patients that stay on the study treatment during the safety run-in. The phase III part of the study will start when the recommended dose of copanlisib in combination with R-CHOP and R-B has been defined and confirmed by sponsor, principal investigator and Data Monitoring Committee.

A maximum of 24 patients will take part in the safety run-in part of this study. In the phase III part approximately 676 patients will be randomly assigned to blinded treatment arms of copanlisib plus R-B or R-CHOP or placebo plus R-B or R-CHOP.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed diagnosis of CD20 positive iNHL with histological subtype limited to:

    • Follicular lymphoma G1-2-3a
    • Small lymphocytic lymphoma with absolute lymphocyte count <5x10E9/L at study entry
    • Lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM)
    • Marginal zone lymphoma (splenic, nodal, or extranodal)
  • Patients must have relapsed after at least 1 but at most 3 prior lines of therapy, including rituximab and alkylating agents. A previous regimen is defined as one of the following: at least 2 months of single-agent therapy; at least 2 consecutive cyclesof polychemotherapy; autologous transplant; radioimmunotherapy. Previous exposure to other PI3Ki is acceptable provided there is no resistance.
  • Non-WM must have at least one bi-dimensionally measurable lesion (that has not been previously irradiated) according to the Lugano Classification.
  • Patients affected by WM who do not have at least one bi-dimensionally measurable lesion in the baseline radiologic assessment must have measurable disease, defined as presence of immunoglobulin M (IgM) paraprotein with a minimum IgM level ≥ 2 x upper limit of normal (ULN) and positive immunofixation test.
  • Male or female patients ≥ 18 years of age
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
  • Life expectancy of at least 3 months
  • Availability of fresh tumor tissue and/or archival tumor tissue at Screening
  • Adequate baseline laboratory values collected within 7 days of starting the study treatment
  • Left ventricular ejection fraction (LVEF) ≥ 50%

Exclusion Criteria

  • Histologically confirmed diagnosis of follicular lymphoma grade 3b or transformed disease, or chronic lymphocytic leukemia.
  • Rituximab resistance at any line of therapy (resistance defined as lack of response, or progression within 6 months of the last course of treatment with a rituximab containing regimen
  • History or concurrent condition of interstitial lung disease and/or severely impaired lung function (as judged by the investigator)
  • Known lymphomatous involvement of the central nervous system
  • HbA1c > 8.5% at Screening
  • Known history of human immunodeficiency virus (HIV) infection
  • Hepatitis B (HBV) or hepatitis C (HCV) infection. Patients positive for Hepatitis B surface antigen (HBsAg or HBcAb) will be eligible if they are negative for HBV-DNA, these patients should receive prophylactic antiviral therapy. Patients positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA.
  • Uncontrolled hypertension despite optimal medical management (per investigator´s assessment)
  • Congestive heart failure > New York Heart Association (NYHA) class 2
  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: NCT02626455

Contacts
Contact: Bayer Clinical Trials Contact clinical-trials-contact@bayer.com
Contact: Bayer US toll-free number (+)1-888-84 22937

  Show 170 Study Locations
Sponsors and Collaborators
Bayer
Investigators
Study Director: Bayer Study Director Bayer
  More Information

Additional Information:
Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT02626455     History of Changes
Other Study ID Numbers: 17833
2015-001088-38 ( EudraCT Number )
Study First Received: November 3, 2015
Last Updated: June 13, 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Bayer:
Clinical trial, Phase III
Phosphatidylinositol-3-kinase
Non-Hodgkin's lymphoma
Indolent B-cell 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
Doxorubicin
Liposomal doxorubicin
Prednisone
Cyclophosphamide
Rituximab
Vincristine
Bendamustine Hydrochloride
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents

ClinicalTrials.gov processed this record on June 23, 2017