Clinical trial NCT01660451: Open-label, Uncontrolled Phase II Trial of Intravenous PI3K Inhibitor BAY80-6946 in Patients With Relapsed, Indolent or Aggressive Non-Hodgkin's Lymphomas
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Lymphoma, Non-Hodgkin
Keywords: Clinical trial, phase II
Phosphatidylinositol 3-Kinase
Class I, Non-Hodgkin's lymphoma
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2012-08-08
Enrollment: 227
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Objective Response Rate (ORR) Based on Independent Review-Part A
timeFrame: Baseline up to the last patient has completed the 16 weeks of treatment
measure: ORR Based on Independent Review-Part B
timeFrame: Baseline up to the last patient has completed the 16 weeks of treatment
measure: ORR Based on Investigator Assessment-Part A
timeFrame: Baseline up to the last patient has completed the 16 weeks of treatment
measure: ORR Based on Investigator Assessment-Part B
timeFrame: Baseline up to the last patient has completed the 16 weeks of treatment
Secondary outcomes:
measure: Duration of Response (DOR) Based on Independent Review-Part A
timeFrame: Baseline up to approximately 6 years
measure: DOR Based on Independent Review-Part B
timeFrame: Baseline up to approximately 9 years 7 months
measure: DOR Based on Investigator Assessment-Part A
timeFrame: Baseline up to approximately 6 years
measure: DOR Based on Investigator Assessment-Part B
timeFrame: Baseline up to approximately 9 years 7 months
measure: Progression Free Survival (PFS) Based on Independent Review-Part A
timeFrame: Baseline up to approximately 6 years
measure: PFS Based on Independent Review-Part B
timeFrame: Baseline up to approximately 9 years 7 months
measure: PFS Based on Investigator Assessment-Part A
timeFrame: Baseline up to approximately 6 years
measure: PFS Based on Investigator Assessment-Part B
timeFrame: Baseline up to approximately 9 years 7 months
measure: Overall Survival (OS)-Part A
timeFrame: Baseline up to approximately 6 years
measure: OS-Part B
timeFrame: Baseline up to approximately 9 years 7 months
measure: Functional Assessment of Cancer Therapy - Lymphoma Lymphoma Subscale (FACT-Lym LymS) at Week 16 - Part B
timeFrame: Baseline up to week 16
measure: Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) Total Score at Week 16 - Part B
timeFrame: Baseline up to week 16
Other outcomes:
Locations:
city: Birmingham
country: United States
state: Alabama
city: Gilbert
country: United States
state: Arizona
city: Anaheim
country: United States
state: California
city: Aurora
country: United States
state: Colorado
city: Englewood
country: United States
state: Colorado
city: Fort Collins
country: United States
state: Colorado
city: Seattle
country: United States
state: Florida
city: Louisville
country: United States
state: Kentucky
city: Detroit
country: United States
state: Michigan
city: Saint Louis Park
country: United States
state: Minnesota
city: Westbury
country: United States
state: New York
city: Clinton
country: United States
state: North Carolina
city: Canton
country: United States
state: Ohio
city: San Antonio
country: United States
state: Texas
city: Spokane
country: United States
state: Washington
city: Garran
country: Australia
state: Australian Capital Territory
city: Linz
country: Austria
city: Bruxelles - Brussel
country: Belgium
city: Bruxelles
country: Belgium
city: Gent
country: Belgium
city: Leuven
country: Belgium
city: Turnhout
country: Belgium
city: Wilrijk
country: Belgium
city: Sofia
country: Bulgaria
city: Saint John
country: Canada
state: New Brunswick
city: Montreal
country: Canada
state: Quebec
city: Montreal
country: Canada
state: Quebec
city: Helsinki
country: Finland
city: Oulu
country: Finland
city: Tampere
country: Finland
city: Turku
country: Finland
city: Brest
country: France
city: Creteil
country: France
city: La Roche Sur Yon
country: France
city: Lille
country: France
city: PARIS cedex
country: France
city: Pessac
country: France
city: Pierre Benite
country: France
city: Poitiers
country: France
city: Rouen
country: France
city: Vandoeuvre-les-nancy
country: France
city: München
country: Germany
state: Bayern
city: Potsdam
country: Germany
state: Berlin
city: Münster
country: Germany
state: Nordrhein-Westfalen
city: Recklinghausen
country: Germany
state: Nordrhein-Westfalen
city: Mainz
country: Germany
state: Rheinland-Pfalz
city: Dresden
country: Germany
state: Sachsen
city: Berlin
country: Germany
city: Berlin
country: Germany
city: Athens
country: Greece
city: Hong Kong
country: Hong Kong
city: Shatin
country: Hong Kong
city: Budapest
country: Hungary
city: Budapest
country: Hungary
city: Kaposvar
country: Hungary
city: Galway
country: Ireland
city: Petach Tikva
country: Israel
city: Ramat Gan
country: Israel
city: Zerifin
country: Israel
city: Napoli
country: Italy
state: Campania
city: Bologna
country: Italy
state: Emilia-Romagna
city: Roma
country: Italy
state: Lazio
city: Brescia
country: Italy
state: Lombardia
city: Milano
country: Italy
state: Lombardia
city: Torino
country: Italy
state: Piemonte
city: Busan
country: Korea, Republic of
state: Busan Gwang''yeogsi
city: Seoul
country: Korea, Republic of
state: Seoul Teugbyeolsi
city: Seoul
country: Korea, Republic of
city: Christchurch
country: New Zealand
city: Gdynia
country: Poland
city: Krakow
country: Poland
city: Lisboa
country: Portugal
city: Lisboa
country: Portugal
city: Kemerovo
country: Russian Federation
city: Moscow
country: Russian Federation
city: Nizhny Novgorod
country: Russian Federation
city: Omsk
country: Russian Federation
city: Saratov
country: Russian Federation
city: St. Petersburg
country: Russian Federation
city: Singapore
country: Singapore
city: Singapore
country: Singapore
city: Majadahonda
country: Spain
state: Madrid
city: Marbella
country: Spain
state: Málaga
city: Barcelona
country: Spain
city: Madrid
country: Spain
city: Sevilla
country: Spain
city: Valencia
country: Spain
city: Uddevalla
country: Sweden
city: Ankara
country: Turkey
city: Istanbul
country: Turkey
city: Izmir
country: Turkey
city: Izmir
country: Turkey
city: Cambridge
country: United Kingdom
state: Cambridgeshire
city: Plymouth
country: United Kingdom
state: Devon
city: Southampton
country: United Kingdom
state: Hampshire
city: Harrow
country: United Kingdom
state: London
city: Liverpool
country: United Kingdom
state: Merseyside
city: Sutton
country: United Kingdom
state: Surrey
city: Birmingham
country: United Kingdom
state: West Midlands
city: Leeds
country: United Kingdom
city: Manchester
country: United Kingdom
city: Romford
country: United Kingdom
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.