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

Follicular Lymphoma Clinical Trial

— Alternative-C  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05387616
• Other study ID #: Alternative-C
• Secondary ID: 2018-004038-13
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: October 19, 2020
• Est. completion date: May 19, 2026

Study information

• Verified date: March 2024
• Source: Ludwig-Maximilians - University of Munich
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 98
• Est. completion date: May 19, 2026
• Est. primary completion date: September 16, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Follicular Lymphoma
• Lymphoma
• Lymphoma, Follicular

Intervention

Drug:
• Copanlisib
Induction therapy will comprise 6 cycles of copanlisib, administered by intravenous Infusion at a dose of 60 mg on day 1,8,15 of cycles 1-6 to be given every 28 days. Consolidation therapy will comprise another 24 weeks of copanlisib in patients with clinical Remission 28 days after the last induction cycle. It will be administered by intravenous Infusion at a dose of 60 mg on days 1 and 15 of cycles 7 - 12 to be given every 28 days. Maintenance therapy will comprise another 72 weeks of copanlisib in patients with clinical remissions 28 days after the last consolidation cycle.
• Obinutuzumab
Induction therapy will comprise 6 cycles of obinutuzumab, administered by intravenous infusion at a dose of 1000 mg on days 1,8, 15 of cycle 1 and on day 1 of cycles 2 - 6 to be given every 28 days. Consolidation therapy will comprise of another 24 weeks of obinutuzumab in patients with clinical remission 28 days after the last induction cycle. Obinutuzumab will be applied at a dose of 1000 mg by intravenous infusion every 8 weeks. Maintenance therapy will comprise another 72 weeks in patients with clinical remission 28 days after the last consolidation cycle. Obinutuzumab will be applied at a dose of 1000 mg by intravenous infusion every 8 weeks.

Locations

Country	Name	City	State
Germany	Gesundheitszentrum St. Marien GmbH	Amberg
Germany	HELIOS Klinikum Bad Saarow	Bad Saarow
Germany	Charité Campus Benjamin Franklin	Berlin
Germany	Vivantes Netzwerk für Gesundheit GmbH - Vivantes Klinikum am Urban	Berlin
Germany	Universitätsklinikum Bonn	Bonn
Germany	Klinikum Chemnitz gGmbH	Chemnitz
Germany	Carl-Thiem-Klinikum Cottbus gGmbH	Cottbus
Germany	Cancer Center Dachau	Dachau
Germany	Städtisches Klinikum Dessau	Dessau
Germany	Gemeinschaftspraxis Dr. med. J. Mohm und Dr. med. G. Prange-Krex	Dresden
Germany	Marien Hospital Düsseldorf	Düsseldorf
Germany	Universitätsklinikum Essen	Essen
Germany	Centrum für Hämatologie und Onkologie Bethanien	Frankfurt am Main
Germany	Universitätsklinikum Freiburg	Freiburg
Germany	Universitätsklinikum Heidelberg	Heidelberg
Germany	Universitätsklinikum Jena	Jena
Germany	Klinikum Kassel	Kassel
Germany	Universitätsklinikum Schleswig-Holstein	Kiel
Germany	Praxis für Hämatologie und Onkologie	Koblenz
Germany	Klinikum der Stadt Ludwigshafen gGmbH	Ludwigshafen
Germany	Schwerpunktpraxis für Hämatologie und Onkologie	Magdeburg
Germany	Universitätsklinikum Magdeburg A.ö.R.	Magdeburg
Germany	Universitätsklinik Mannheim	Mannheim
Germany	Kliniken Maria Hilf GmbH, Krankenhaus St. Franziskus	Mönchengladbach
Germany	Klinikum rechts der Isar der TU München	München
Germany	LMU Klinikum	München	Bavaria
Germany	Gemeinschaftspraxis für Hämatologie und Onkologie	Münster
Germany	Universitätsklinikum Münster	Münster
Germany	Stauferklinikum Schwäbisch Gmünd	Mutlangen
Germany	Friedrich Ebert Krankenhaus	Neumünster
Germany	Rheinland Klinikum, Lukaskrankenhaus Neuss	Neuss
Germany	Brüderkrankenhaus St. Josef Paderborn	Paderborn
Germany	Klinikum Südstadt Rostock	Rostock
Germany	Universitätsmedizin Rostock	Rostock
Germany	Gemeinschaftspraxis Dr. med. G.A. Jacobs	Saarbrücken
Germany	Klinikum Mutterhaus der Borromäerinnen gGmbH	Trier
Germany	Universitätsklinikum Tübingen	Tübingen
Germany	Universitätsklinikum Ulm	Ulm
Germany	Petrus Kankenhaus	Wuppertal
Germany	Hämatologisch-Onkologische Schwerpunktpraxis	Würzburg

Sponsors (3)

Lead Sponsor	Collaborator
Ludwig-Maximilians - University of Munich	Bayer, Roche Pharma AG

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	One-year progression-free survival (PFS) probability from study registration	The rate of patients achieving a progression free survival of more than one year after registration (one-year PFS rate) will serve as early readout for efficacy.	1 year
Secondary	Complete remission (CR) rates and overall response (CR or partial remission, PR) rates		at end of induction (month 6), at end of consolidation (month 12), and at end of maintenance (month 30)
Secondary	Progression free survival from registration		continuous observation up to 78 months
Secondary	Duration of response		from end of induction to progression or death assessed up to 72 months
Secondary	Cumulative incidence of progression		from registration to end of study assessed up to 78 months
Secondary	Failure-free survival	event defined by failure to achieve a CR/PR after 6 months or progression after CR or PR or death from any cause	from start of therapy assessed up to 78 months
Secondary	Time to next anti-lymphoma therapy and time to next chemotherapy based treatment		from start of first-line therapy up to 78 months
Secondary	Overall survival		from registration up to 78 months
Secondary	Treatment associated adverse events		continuous observation up to 78 months
Secondary	Percentage of MRD-negative patients		therapy (month 12), and at end maintenance therapy (month 30)
Secondary	Duration of molecular remission for MRD negative patients		from end of induction therapy up to 72 months
Secondary	Cumulative incidence of secondary transformations to aggressive lymphoma		ongoing observation up to 78 months
Secondary	Cumulative incidence of secondary malignancies		ongoing observation up to 78 months
Secondary	Percentage of patients with compliance to therapy		after 6, 12, and 30 months
Secondary	Frequency of patient-reported lymphoma symptoms and concerns (FACT-Lym)		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