Clinical trial NCT05387616: A Prospective Multicenter Phase 2 Study of the Chemotherapy-Free Combination of the Intravenous Phosphatidylinositol-3-Kinase (PI3K) Inhibitor Copanlisib in Combination With Obinutuzumab in Patients With Previously Untreated Follicular Lymphoma (FL) and a High Tumor Burden
Official title: A Prospective Multicenter Phase 2 Study of the Chemotherapy-Free Combination of the Intravenous Phosphatidylinositol-3-Kinase (PI3K) Inhibitor Copanlisib in Combination With Obinutuzumab in Patients With Previously Untreated Follicular Lymphoma (FL) and a High Tumor Burden
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Follicular Lymphoma
Lead sponsor: Ludwig-Maximilians - University of Munich
Sponsor class: OTHER
Collaborators: name: Roche Pharma AG
name: Bayer
First posted: 2022-05-24
Enrollment: 98
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The Alternative-C Trial is a prospective, multicenter Phase 2 Study to evaluate the efficacy of the chemotherapy-free combination of copanlisib and obinutuzumab in patients with previously untreated follicular lymphoma (FL) and a high tumor burden. Additionally, the combination should be evaluated in terms of secondary efficacy endpoints, treatment compliance, safety and patient-reported symptoms. The study Population includes Patients \> 18 years of age with histologically confirmed follicular lymphoma grade 1, 2 or 3A with Ann Arbor Stage III/IV or stage II not suitable for radiotherapy and in need of therapy.


Eligibility criteria: Inclusion Criteria:

* Subjects will only be included in the study, if they meet all of the following criteria:
* Histologically confirmed follicular lymphoma grade 1, 2 or 3A with a biopsy performed within 12 months before study entry and with material available for central review and complementary scientific analyses
* Ann Arbor stage III/IV, or stage II not suitable for radiotherapy, or stage II bulky disease
* Age ≥ 18 years
* No prior lymphoma therapy
* Need for start of therapy as defined by at least one of the following criteria:

  * bulky disease at study entry according to the GELF criteria (nodal or extranodal mass \> 7 cm in its greatest diameter)
  * B symptoms (fever, drenching night sweats, or unintentional weight loss of \> 10% of normal body weight over a period of 6 months or less)
  * hematopoietic insufficiency (granulocytopenia \< 1500/µl, Hb \< 10 g/dl, thrombocytopenia \< 100000/µl)
  * compressive syndrome or high risk for compression syndrome
  * pleural/peritoneal effusion
  * symptomatic extranodal manifestations
* At least one bi-dimensionally measurable lesion (\> 2 cm in its largest dimension by CT scan or MRI)
* Performance status ≤ 2 on the ECOG scale
* Adequate hematologic function (unless abnormalities are related to NHL), defined as follows:

  * Hemoglobin ≥ 9.0 g/dL
  * Absolute neutrophil count ≥ 1500/µl
  * Platelet count ≥ 75000/µl
* Women are not breast feeding, are using highly effective contraception (see section 11.4.1), are not pregnant, and agree not to become pregnant during participation in the study and during the 18 months thereafter (pregnancy testing is mandatory for premenopausal women).
* Men agree not to father a child during participation in the study and during the 18 months thereafter.
* Written informed consent

Exclusion criteria:

Subjects will not be included in the study if any of the following criteria apply:

* Transformation to high-grade lymphoma (secondary to "low grade" FL)
* Grade 3B follicular lymphoma
* Presence or history of CNS disease (either CNS lymphoma or leptomeningeal lymphoma)
* Known hypersensitivity to any of the study drugs
* Known sensitivity to murine products
* Patients with HbA1c \> 8.5 % at Screening
* Uncontrolled arterial hypertension despite optimal medical management (per investigator's assessment)
* Regular use of corticosteroids during the last 4 weeks, unless administered at a dose equivalent to \< 20 mg/day prednisone or administered as prephase treatment according to study protocol (see section 7.2 of study protocol)
* Concomitant use of strong CYP3A4 inhibitors and/or inducers
* Prior or concomitant malignancies except:

  * non-melanoma skin cancer or adequately treated in carcinoma in situ of the cervix
  * other malignant diseases not specified above which have been curatively treated by surgery alone and from which subject is disease-free for ≥ 5 years without further treatment
* Serious disease interfering with a regular therapy according to the study protocol:

  * Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification
  * pulmonary (e.g. chronic lung disease with hypoxemia)
  * endocrine (e.g. severe, not sufficiently controlled diabetes mellitus)
  * renal insufficiency (unless caused by the lymphoma): creatinine \> 2x normal value and/or creatinine clearance \< 50 ml/min)
  * impairment of liver function (unless caused by the lymphoma): transaminases \> 3x normal or bilirubin \> 2.0 mg/dl (unless caused by known Morbus Meulengracht \[Gilbert-Meulengracht-Syndrome\])
* Positive test results for chronic HBV infection (defined as positive HBsAg serology) Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) may be included if HBV DNA is undetectable, provided that they are willing to undergo monthly DNA testing.

Patients who have protective titers of hepatitis B surface antibody (HBsAb) after vaccination or prior but cured hepatitis B are eligible.

* Positive test results for hepatitis C (hepatitis C virus \[HCV\] antibody serology testing) Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.
* Clinically significant history of liver disease, including viral or other hepatitis, or cirrhosis
* Known history of HIV seropositive status
* Patients with a history of confirmed PML
* Vaccination with a live vaccine within 28 days prior to registration
* Recent major surgery (within 4 weeks prior to the start of Cycle 1)
* History of stroke or intracranial hemorrhage within 6 months prior to registration
* Serious underlying medical conditions, which could impair the ability of the patient to undergo the treatment offered in the study (e.g. ongoing infection, gastric ulcers, active autoimmune disease)
* Treatment within another clinical study within 30 days prior to study entry
* Prior organ, bone marrow, or peripheral blood stem cell transplantation
* Known or persistent abuse of medication, drugs, or alcohol
* Any other co-existing medical or psychological condition that will preclude participation in the study or compromise ability to give informed consent

Primary outcomes:
measure: One-year progression-free survival (PFS) probability from study registration
timeFrame: 1 year
Secondary outcomes:
measure: Complete remission (CR) rates and overall response (CR or partial remission, PR) rates
timeFrame: at end of induction (month 6), at end of consolidation (month 12), and at end of maintenance (month 30)
measure: Progression free survival from registration
timeFrame: continuous observation up to 78 months
measure: Duration of response
timeFrame: from end of induction to progression or death assessed up to 72 months
measure: Cumulative incidence of progression
timeFrame: from registration to end of study assessed up to 78 months
measure: Failure-free survival
timeFrame: from start of therapy assessed up to 78 months
measure: Time to next anti-lymphoma therapy and time to next chemotherapy based treatment
timeFrame: from start of first-line therapy up to 78 months
measure: Overall survival
timeFrame: from registration up to 78 months
measure: Treatment associated adverse events
timeFrame: continuous observation up to 78 months
measure: Percentage of MRD-negative patients
timeFrame: therapy (month 12), and at end maintenance therapy (month 30)
measure: Duration of molecular remission for MRD negative patients
timeFrame: from end of induction therapy up to 72 months
measure: Cumulative incidence of secondary transformations to aggressive lymphoma
timeFrame: ongoing observation up to 78 months
measure: Cumulative incidence of secondary malignancies
timeFrame: ongoing observation up to 78 months
measure: Percentage of patients with compliance to therapy
timeFrame: after 6, 12, and 30 months
measure: Frequency of patient-reported lymphoma symptoms and concerns (FACT-Lym)
timeFrame: Baseline, End of Induction, End of Consolidation, End of Maintenance, and every 6 months during FU for at least 2 years until end of the whole study
Other outcomes:
Locations:
city: München
country: Germany
facility: LMU Klinikum
state: Bavaria
city: Amberg
country: Germany
facility: Gesundheitszentrum St. Marien GmbH
city: Bad Saarow
country: Germany
facility: HELIOS Klinikum Bad Saarow
city: Berlin
country: Germany
facility: Vivantes Netzwerk für Gesundheit GmbH - Vivantes Klinikum am Urban
city: Berlin
country: Germany
facility: Charité Campus Benjamin Franklin
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz gGmbH
city: Cottbus
country: Germany
facility: Carl-Thiem-Klinikum Cottbus gGmbH
city: Dachau
country: Germany
facility: Cancer Center Dachau
city: Dessau
country: Germany
facility: Städtisches Klinikum Dessau
city: Dresden
country: Germany
facility: Gemeinschaftspraxis Dr. med. J. Mohm und Dr. med. G. Prange-Krex
city: Düsseldorf
country: Germany
facility: Marien Hospital Düsseldorf
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Frankfurt am Main
country: Germany
facility: Centrum für Hämatologie und Onkologie Bethanien
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Jena
country: Germany
facility: Universitätsklinikum Jena
city: Kassel
country: Germany
facility: Klinikum Kassel
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein
city: Koblenz
country: Germany
facility: Praxis für Hämatologie und Onkologie
city: Ludwigshafen
country: Germany
facility: Klinikum der Stadt Ludwigshafen gGmbH
city: Magdeburg
country: Germany
facility: Schwerpunktpraxis für Hämatologie und Onkologie
city: Magdeburg
country: Germany
facility: Universitätsklinikum Magdeburg A.ö.R.
city: Mannheim
country: Germany
facility: Universitätsklinik Mannheim
city: Mutlangen
country: Germany
facility: Stauferklinikum Schwäbisch Gmünd
city: Mönchengladbach
country: Germany
facility: Kliniken Maria Hilf GmbH, Krankenhaus St. Franziskus
city: München
country: Germany
facility: Klinikum rechts der Isar der TU München
city: Münster
country: Germany
facility: Gemeinschaftspraxis für Hämatologie und Onkologie
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Neumünster
country: Germany
facility: Friedrich Ebert Krankenhaus
city: Neuss
country: Germany
facility: Rheinland Klinikum, Lukaskrankenhaus Neuss
city: Paderborn
country: Germany
facility: Brüderkrankenhaus St. Josef Paderborn
city: Rostock
country: Germany
facility: Universitätsmedizin Rostock
city: Rostock
country: Germany
facility: Klinikum Südstadt Rostock
city: Saarbrücken
country: Germany
facility: Gemeinschaftspraxis Dr. med. G.A. Jacobs
city: Trier
country: Germany
facility: Klinikum Mutterhaus der Borromäerinnen gGmbH
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Wuppertal
country: Germany
facility: Petrus Kankenhaus
city: Würzburg
country: Germany
facility: Hämatologisch-Onkologische Schwerpunktpraxis
Study officials:
affiliation: LMU Klinikum, Medical department III
name: Christian Schmidt, Dr.
role: PRINCIPAL_INVESTIGATOR
References: