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NCT03886649 | SNCTP000003333

SAKK 66/18
Copanlisib in Kombination mit Venetoclax bei Patienten mit einem rückfälligen/therapieresistenten B-Zell Non-Hodgkin Lymphom. Eine multizentrische (an vielen Behandlungszentren durchgeführte) Phase-Ib-Studie mit zwei Erweiterungskohorten

Data source: BASEC (Imported from 16.10.2019), WHO (Imported from 13.10.2019)
Changed: 08.10.2019
Disease category: Non-Hodgkin-Lymphom

Brief description of trial (Source of data: BASEC)

IIn dieser Studie untersuchen wir eine neue Therapieform für Patienten mit einem B-Zell Non-Hodgkin-Lymphom, die nach den bisherigen Behandlungen einen Rückfall erlitten haben oder die auf die üblichen Behandlungen nicht mehr ansprechen. Die Studientherapie besteht aus einer Kombination der Medikamente Copanlisib und Venetoclax. Diese Kombination wurde noch nie in diesen Patienten getestet. Wir möchten in einen ersten Teil der Studie herausfinden, wie hoch diese Medikamente dosiert werden müssen, ohne dass die behandelten Patienten unter nicht tolerierbaren Nebenwirkungen leiden. In einen zweiten Studienteil untersuchen wir zusätzlich, wie sicher und verträglich die Behandlung ist und wie sie bei den Patienten auf den Verlauf der Lymphom-Erkrankung wirkt.

Health conditions investigated (Source of data: BASEC)

rückfälliges/therapieresistentes B-Zell Non-Hodgkin Lymphom

Health conditions (Source of data: WHO)

Non-Hodgkin Lymphoma

Rare disease (Source of data: BASEC)

Yes

Intervention investigated (e.g. drug, therapy or campaign) (Source of data: BASEC)

In der Studie werden die Medikamente in sogenannten Zyklen verabreicht; ein Zyklus umfasst 4 Wochen respektive 28 Tage. Die Studientherapie dauert maximal 12 Zyklen, also rund ein Jahr. Sofern ein(e) Patient(in) gut auf die Therapie anspricht, kann er/sie – in Absprache mit dem Studienleiter - die Medikamente auch nach Ablauf dieser 12 Zyklen so lange anwenden, bis die Krankheit weiter fortschreitet oder der Patient/die Patientin die Medikamente nicht mehr verträgt. In jedem Zyklus erhält der Patient/die Patientin an den Tagen 1, 8 und 15 eine intravenöse Infusion mit Copanlisib. Ab dem Tag 2 des ersten Zyklus wird zusätzlich täglich die vom Arzt vorgeschriebene Dosis Venetoclax (bis zu 8 Tabletten) eingenommen.

Interventions (Source of data: WHO)

Drug: Copanlisib;Drug: Venetoclax

Criteria for participation in trial (Source of data: BASEC)

- An der ersten Phase der Studie können Personen teilnehmen, die an einem B-Zell Non-Hodgkin-Lymphom (ausgenommen Mantelzelllymphom und Kleinzelliges B-Zell-Lymphom), erkrankt sind und die nach den bisherigen Behandlungen einen Rückfall erlitten haben oder die auf die üblichen Behandlungen nicht mehr ansprechen.
- Bei den Patienten, die an der zweiten Phase der Studie teilnehmen, muss ein follikuläres Lymphom oder ein Marginalzonen-Lymphom vorliegen.
- Die teilnehmenden Personen müssen über 18 Jahre alt sein und müssen in einem guten gesundheitlichen Allgemeinzustand sein, eine ausreichende Herz-, Leber- und Nierenfunktion haben und ihre Blutwerte (Anzahl der Blutplättchen sowie der roten und weissen Blutkörperchen) dürfen nicht zu niedrig sein.

Exclusion criteria (Source of data: BASEC)

- Von der Teilnahme ausgeschlossen sind Personen, bei denen der behandelnde Onkologe/Hämatologe den Einsatz der Studienmedikamente in der aktuellen Krankheitssituation für nicht geeignet hält.
- Personen, die schon einmal mit Copanlisib oder Venetoclax oder mit ähnlich wirkenden Medikamenten behandelt wurden, können nicht an der Studie teilnehmen.
- Auch Personen, die an folgenden spezifischen Erkrankungen leiden, können nicht teilnehmen:
o Krankheiten des Zentralen Nervensystems (auch Lymphombefall des Gehirns)
o schwerwiegende Herzerkrankungen
o unkontrollierter hoher Blutdruck
o schlecht eingestellter Diabetes mellitus
o Infektionen mit bestimmten Viren (HI-Virus, Hepatitis B- oder Hepatitis-C-Virus, Cytomegalie-Virus)
o Behandlung mit Kortison-Präparaten (Kortikosteroide) während 28 Tagen vor Einschluss in die Studie
o Behandlung mit Medikamenten, welche die Funktion des Immunsystems unterdrücken,
o Behandlung mit Blutverdünnern

Inclusion/Exclusion Criteria (Source of data: WHO)


Inclusion Criteria:

- Written informed consent according to Swiss law and ICH/GCP regulations before
registration and prior to any trial specific procedures.

- Histologically confirmed B-cell NHL lymphoma as per WHO classification for the
escalation phase. FL or MZL for the expansion phase.

- Patients with relapsed or refractory disease who have failed previous treatment
(including chemotherapy plus anti CD20) for whom no effective standard treatment is
available or refused by the patient.

- Patients with a prior malignancy and treated with curative intention are eligible if
all treatment of that malignancy was completed at least 2 years before registration
and the patient has no evidence of disease at registration. Less than 2 years is
acceptable for malignancies with low risk of recurrence and/or no late recurrence.

- > 1 two-dimensionally measurable nodal lesion in CT, PET/CT scan (preferable) or MRI,
according to Cheson et al, 2014.

- Tumor tissue (formalin fixed paraffin embedded (FFPE) slides/rolls) is available for
the mandatory translational research.

- Age = 18 years.

- WHO performance status 0-1

- Adequate bone marrow function:

1. Absolute neutrophil count (ANC) >1.5 × 109/l (1 × 109/l if due to bone marrow
involvement by lymphoma). Patient must not have received any hematologic growth
factor within 14 days prior to registration.

2. Platelet count >100 ×109/l (75 ×109/l if due to bone marrow involvement by
lymphoma)

- Adequate hepatic function:

1. total bilirubin = 1.5 × ULN (except for patients with Gilbert's disease = 3.0 ×
ULN),

2. AST and ALT = 2.5 × ULN, or = 5 × ULN under the assumption that abnormal values
are tumor related.

- Adequate renal function: estimated glomerular filtration rate (eGFR) = 50 ml/min/1.73
m2 (according to CKD-EPI formula)

- Adequate cardiac function: Left ventricular Ejection Fraction (LVEF) = 50% as
determined by echocardiography (ECHO).

- Adequate coagulation function: INR = 1.5 × ULN (the ULN for INR is defined with the
value 1.2 for all sites, in case no ULN is documented in the lab certificates/sheets),
aPTT = 1.5 × ULN.

- Women of childbearing potential (not surgically sterile or exceeding 2 years after the
onset of menopause) must use highly effective contraception, are not pregnant or
lactating and agree not to become pregnant during trial treatment and until 3 months
after the last dose of investigational drug. A negative pregnancy test before
inclusion into the trial is required for all women of childbearing potential.

- Men agree not to donate sperm or to father a child during trial treatment and until 3
months after the last dose of investigational drug.

- Patient is able and willing to swallow trial drug as whole tablet.

Exclusion Criteria:

- Patients with CLL/SLL.

- Patients that require ramp-up of venetoclax, including MCL. Other histologies will be
discussed with the coordinating investigator (CI).

- Presence or history of CNS disease (either CNS lymphoma or lymphomatous meningeosis).
Primary CNS disease.

- Prior treatment with venetoclax, copanlisib or any other bcl-2 inhibitors or PIK3
inhibitors.

- Prior allogeneic stem cell transplant (SCT), or autologous transplant less than 3
months prior to registration.

- Concomitant or recent treatment with any other experimental drug (enrollment in
another clinical trial.

- Treatment with any anti-lymphoma therapies within 21 days prior to registration -
except for local radiation therapy for palliative treatment of symptoms.

- Not resolved grade = 2 (per NCI CTCAE v5.0 toxicity (other than alopecia) from prior
therapy at registration.

- Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or
IV; (see Appendix 4), unstable or new onset angina pectoris, history of myocardial
infarction within the last six months, serious arrhythmias requiring medication (with
exception of atrial fibrillation or paroxysmal supraventricular tachycardia),
significant QT-prolongation.

- Uncontrolled hypertension (sustained systolic blood pressure >150 mmHg and or
diastolic >90 mmHg) despite optimal medical management (per investigator's
assessment).

- Proteinuria of = CTCAE grade 3 as assessed by a 24h total urine protein quantification
or on a random urine sample, estimated by urine protein to creatinine ratio > 3.5.

- HbA1c > 8.5%.

- Lipase = 1.5 x ULN.

- History of cerebrovascular accident or intracranial hemorrhage within 6 months prior
to registration.

- Major surgery within 1 month prior to registration.

- Known history of human immunodeficiency virus (HIV) or active chronic Hepatitis C or
Hepatitis B Virus infection or any uncontrolled active systemic infection requiring
intravenous (iv) antimicrobial treatment. All patients must be screened for HIV up to
28 days prior to study drug start using a blood test for HIV according to local
regulations. All patients must be screened for hepatitis up to 28 days prior to study
drug start using the routine hepatitis virus laboratory panel. Patients positive for
hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (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.

- Active CMV infection. Patients who are CMV PCR positive at baseline will be excluded.

- Malabsorption syndrome or other condition that precludes enteral route of
administration.

- Concomitant or prior use of immunosuppressive medication within 28 days before
registration, with the exceptions of intranasal and inhaled corticosteroids, or
systemic corticosteroids which must not exceed 10 mg/day of prednisone or a dose
equivalent corticosteroid).

- Has active autoimmune disease that has required systemic treatment in past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.

- Concomitant anticoagulation treatment with warfarin or equivalent vitamin

Further information on the trial in WHO primary registry

https://clinicaltrials.gov/show/NCT03886649

Further information on the trial from WHO database (ICTRP)

http://apps.who.int/trialsearch/Trial2.aspx?TrialID=NCT03886649

Further information on trial

Date trial registered

21.03.2019

Incorporation of the first participant

01.10.2019

Recruitment status

Recruiting

Academic title (Source of data: WHO)

Copanlisib in Combination With Venetoclax in Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma. A Multicenter Phase Ib Trial With Two Expansion Cohorts

Type of trial (Source of data: WHO)

Interventional

Design of the trial (Source of data: WHO)

Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label).

Phase (Source of data: WHO)

Phase 1

Primary end point (Source of data: WHO)

Dose-limiting toxicities (DLTs) during the first cycle of treatment

Secundary end point (Source of data: WHO)

Adverse events (AEs);Complete response (CR) at 6 months and 12 months;Overall response (OR) at 6 months and 12 months;OR based on best response;Progression-free survival (PFS) at 12 months

Contact information (Source of data: WHO)

Please refer to primary and secondary sponsors

Trial sites

Trial sites in Switzerland (Source of data: BASEC)

Basel, Bellinzona, Bern, Genf, St Gallen, Zürich

Countries (Source of data: WHO)

Switzerland

Contact for further information on the trial

Details of contact in Switzerland (Source of data: BASEC)

SAKK, Nina Stojcheva
+41 31 389 91 91
trials@sakk.ch

Contact for general information (Source of data: WHO)

Anastasios Stathis, MD;Emanuele Zucca;Lena Sokol, PhD
IOSI, Ospedale San Giovanni, Bellinzona
+41 31 389 91 91
trials@sakk.ch

Contact for scientific information (Source of data: WHO)

Anastasios Stathis, MD;Emanuele Zucca;Lena Sokol, PhD
IOSI, Ospedale San Giovanni, Bellinzona
+41 31 389 91 91
trials@sakk.ch

Principal Sponsor/Investigator

Principal sponsor (Source of data: WHO)

Swiss Group for Clinical Cancer Research

Further trial identification numbers

BASEC ID (Source of data: BASEC)

2019-00672

Secondary ID (Source of data: WHO)

SAKK 66/18