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SNCTP000002252 | NCT02950051 | BASEC2017-00372

CLL 13
Eine prospektive, randomisierte, unverblindete, multizentrische Phase-III-Studie zum Vergleich von Standard-Chemoimmuntherapie (FCR/BR) gegen Rituximab plus Ventoclax (RVe) gegen Obinutuzumab plus Venetoclax (GVe) gegen Obinutuzumab plus Ibrutinib plus Venetoclax bei körperlich fitten Patienten mit bislang unbehandelter chronisch lymphatischer Leukämie (CLL) ohne del(17p) oder TP53 Mutation

Data source: BASEC (Imported from 05.03.2021), WHO (Imported from 07.03.2021)
Changed: 02.03.2021
Disease category: Leukemia

Brief description of trial (Data source: BASEC)

Bei dieser klinischen Studie werden vier Behandlungsarme miteinander verglichen.
Es wird getestet, ob bei körperlich fitten Patienten mit CLL eine Erstlinienbehandlung ohne Chemotherapie, nämlich mit der Kombination aus Venetoclax plus Rituximab oder Venetoclax plus Obinutuzumab oder Venetoclax plus Obinutuzumab plus Ibrutinib wirksamer und weniger nebenwirkungsreich ist als die Standardbehandlung mit Chemoimmuntherapie.
Mit Hilfe eines Computerprogramms werden alle Patienten zufällig einem Behandlungsarm zugeteilt. Die Wahrscheinlichkeit die von den Gesundheitsbehörden zugelassene und auch in der Routine eingesetzte Behandlung mit Chemoimmuntherapie zu erhalten beträgt 25% (ein Viertel). Die Wahrscheinlichkeit ohne Chemotherapie, also mit einer Art bzw. zwei Arten von Tabletten bzw. Kapseln in Kombination mit einem Antikörper behandelt zu werden beträgt somit 75% (drei Viertel).

Health conditions investigated (Data source: BASEC)

bislang unbehandelte chronisch lymphatische Leukämie (CLL) ohne del(17p) oder TP53 Mutation, körperlich fitte Patienten

Health conditions (Data source: WHO)

Chronic Lymphocytic Leukemia

Rare disease (Data source: BASEC)

No

Intervention investigated (e.g. drug, therapy or campaign) (Data source: BASEC)

Alle 4 möglichen Therapien werden in sogenannten Behandlungszyklen durchgeführt. Ein Zyklus umfasst 28 Tage.
Falls Sie der Standard-Chemoimmuntherapie zugeordnet werden, erhalten Sie sechs Behandlungszyklen.
In den anderen Behandlungsarmen (Kombination aus Venetoclax plus Rituximab oder Venetoclax plus Obinutuzumab oder Venetoclax plus Obinutuzumab plus Ibrutinib) erhaltne Sie mindestens 12 Zyklen.
Es ist allerdings auch möglich, dass die Therapie aus medizinischen Gründen vorzeitig beendet werden muss, z.B. weil die Standard- oder Studienmedikamente zu Nebenwirkungen führen, die Krankheit trotz Behandlung voranschreitet und anders behandelt werden muss oder weil eine Schwangerschaft eintritt.
Nach Beendigung der Therapie schließt sich eine Nachbeobachtungsphase mit regelmäßigen Besuchen im Prüfzentrum alle drei Monate an.
Sofern Ihre CLL zurückkehrt und eine neue Behandlung durchgeführt werden muss wird lediglich eine jährliche Nachbeobachtung durchgeführt.

Interventions (Data source: WHO)

Drug: Fludarabine;Drug: Cyclophosphamide;Biological: Rituximab;Drug: Bendamustine;Drug: Venetoclax;Biological: Obinutuzumab;Drug: Ibrutinib

Criteria for participation in trial (Data source: BASEC)

- behandlungsbedürftige CLL-Erkrankung
- mindestens 18 Jahre alt
- die Lebenserwartung ist mindestens 6 Monate

Exclusion criteria (Data source: BASEC)

Es dürfen keine behandlungsbedürftigen Krebserkrankungen oder Infektionen, insbesondere keine Hepatitis oder HIV-Infektion vorliegen. Des Weiteren darf wegen möglichen Wechselwirkungen mit der Studientherapie keine gleichzeitige Einnahme von sogenannten CYP3A4-und CYP3A5 Inhibitoren/-Induktoren, den Gerinnungshemmern Warfarin oder Phenprocoumon (Marcoumar®) oder anderen neuen Medikamenten (z.B. in klinischen Studien) erfolgen.
Ebenfalls von einer Studienteilnahme ausgeschlossen sind schwangere und stillende Frauen, um das (noch ungeborene) Kind nicht zu gefährden.
Patienten, bei denen bestimmte Veränderungen der CLL-Zellen vorliegen, nämlich die sogenannte del(17p) oder eine TP53-Mutation, dürfen ebenfalls nicht an dieser Studie teilnehmen, da sie eine schlechtere Prognose haben, frühzeitig einen Rückfall zu erleiden, und für diese die Standardbehandlung mit Chemoimmuntherapie nicht ausreichend ist.

Inclusion/Exclusion Criteria (Data source: WHO)


Inclusion Criteria:

1. Documented CLL requiring treatment according to iwCLL criteria

2. Age at least 18 years

3. Life expectancy = 6 months

4. Ability and willingness to provide written informed consent and to adhere to the study
visit schedule and other protocol requirements

5. Adequate bone marrow function indicated by a platelet count >30 x10^9/l (unless
directly attributable to CLL infiltration of the bone marrow, proven by bone marrow
biopsy)

6. Creatinine clearance =70ml/min directly measured with 24hr urine collection or
calculated according to the modified formula of Cockcroft and Gault (for men: GFR ˜
((140 - age) x bodyweight) / (72 x creatinine), for women x 0, 85). For patients with
creatinine values within the normal range the calculation of the clearance is not
necessary. Dehydrated patients with an estimated creatinine clearance less than 70
ml/min may be eligible if a repeat estimate after adequate hydration is > 70 ml/min

7. Adequate liver function as indicated by a total bilirubin= 2 x, AST/ALT = 2.5 x the
institutional ULN value, unless directly attributable to the patient's CLL or to
Gilbert's Syndrome

8. Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative;
patients positive for anti-HBc may be included if PCR for HBV DNA is negative and
HBV-DNA PCR is performed every month until 12 months after last treatment cycle),
negative testing for hepatitis C RNA within 6 weeks prior to registration

9. Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0-2

Exclusion Criteria:

1. Any prior CLL-specific therapies (except corticosteroid treatment administere due to
necessary immediate intervention; within the last 10 days before start of study
treatment, only dose equivalents of 20 mg prednisolone are permitted).

2. Transformation of CLL (Richter transformation)

3. Decompensated hemolysis, defined as ongoing hemoglobin drop in spite of three more
concurrent treatments being administered for hemolysis

4. Detected del(17p) or TP53 mutation

5. Patients with a history of PML

6. Any comorbidity or organ system impairment rated with a single CIRS (cumulative
illness rating scale) score of 4 (excluding the eyes/ears/nose/throat/larynx organ
system), a total CIRS score of more than 6 or any other life-threatening illness,
medical condition or organ system dysfunction that, in the investigator´s opinion,
could comprise the patients safety or interfere with the absorption or metabolism of
the study drugs (e.g, inability to swallow tablets or impaired resorption in the
gastrointestinal tract)

7. Urinary outflow obstruction

8. Malignancies other than CLL currently requiring systemic therapies, not being treated
in curative intention before (unless the malignant disease is in a stable remission
due to the discretion of the treating physician) or showing signs of progression after
curative treatment

9. Uncontrolled or active infection

10. Patients with known infection with human immunodeficiency virus (HIV)

11. Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers

12. Anticoagulant therapy with warfarin or phenoprocoumon, (rotation to alternative
anticoagulation is allowed, but note that patients being treated with NOAKs can be
included, but must be properly informed about the potential risk of bleeding under
treatment with ibrutinib)

13. History of stroke or intracranial hemorrhage within 6 months prior to registration

14. Use of investigational agents which might interfere with the study drug within 28 days
prior to registration

15. Vaccination with live vaccines 28 days prior to registration

16. Major surgery less than 30 days before start of treatment

17. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal
antibodies, known sensitivity or allergy to murine products

18. Known hypersensitivity to any active substance or to any of the excipients of one of
the drugs used in the trial

19. Pregnant women and nursing mothers (a negative pregnancy test is required for all
women of childbearing potential within 7 days before start of treatment; further
pregnancy testing will be performed regularly)

20. Fertile men or women of childbearing potential unless:

1. surgically sterile or = 2 years after the onset of menopause

2. willing to use two methods of reliable contraception including one highly
effective contraceptive method (Pearl Index <1) and one additional effective
(barrier) method during study treatment and for 18 months after the end of study
treatment

21. Legal incapacity

22. Prisoners or subjects who are institutionalized by regulatory or court order

23. Persons who are in dependence to the sponsor or an investigator

Further information on the trial in WHO primary registry

https://clinicaltrials.gov/show/NCT02950051

Further information on the trial from WHO database (ICTRP)

http://apps.who.int/trialsearch/Trial2.aspx?TrialID=NCT02950051

Further information on trial

Date trial registered

27.10.2016

Incorporation of the first participant

13.12.2016

Recruitment status

Active, not recruiting

Academic title (Data source: WHO)

A Phase 3 Multicenter, Randomized, Prospective, Open-label Trial of Standard Chemoimmunotherapy (FCR/BR) Versus Rituximab Plus Venetoclax (RVe) Versus Obinutuzumab (GA101) Plus Venetoclax (GVe) Versus Obinutuzumab Plus Ibrutinib Plus Venetoclax (GIVe) in Fit Patients With Previously Untreated Chronic Lymphocytic Leukemia (CLL) Without Del(17p) or TP53 Mutation

Type of trial (Data source: WHO)

Interventional

Design of the trial (Data source: WHO)

Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).

Phase (Data source: WHO)

Phase 3

Primary end point (Data source: WHO)

Progression free survival (PFS);Miminimal residual disease (MRD) negativity rate in peripheral blood (PB)

Secundary end point (Data source: WHO)

MRD negativity rate in PB;MRD levels in PB;MRD levels in bone marrow (BM);Overall response rate (ORR);Rate of complete responses (CR) / complete responses with incomplete bone marrow recovery(CRi);PFS

Contact information (Data source: WHO)

Please refer to primary and secondary sponsors

Trial results (Data source: WHO)

Results summary

no information available yet

Link to the results in the primary register

no information available yet

Information on the availability of individual participant data

no information available yet

Trial sites

Trial sites in Switzerland (Data source: BASEC)

Aarau, Baden, Basel, Bellinzona, Bern, Chur, Frauenfeld, Geneva, Liestal, Luzern, Münsterlingen, Olten, St. Gallen, Winterthur, Zurich

Countries (Data source: WHO)

Austria, Belgium, Denmark, Finland, Germany, Ireland, Israel, Netherlands, Sweden, Switzerland

Contact for further information on the trial

Details of contact in Switzerland (Data source: BASEC)

Sandra Thierstein
+41 31 389 91 91
trials@sakk.ch

Contact for general information (Data source: WHO)

Barbara Eichhorst, MD, PD
Department I of Internal Medicine, University Hospital Cologne

Contact for scientific information (Data source: WHO)

Barbara Eichhorst, MD, PD
Department I of Internal Medicine, University Hospital Cologne

Principal Sponsor/Investigator

Principal sponsor (Data source: WHO)

German CLL Study Group

Additional sponsors (Data source: WHO)

Janssen-Cilag Ltd.;Hoffmann-La Roche;AbbVie;Stichting Hemato-Oncologie voor Volwassenen Nederland;Nordic CLL Study Group (NCLLSG);Swiss Group for Clinical Cancer Research;Cancer Trials Ireland;Israeli CLL Study Group

Authorisation by the ethics committee (Data source: BASEC)

Name of the authorising ethics committee (for multicentre studies only the lead committee)

Ethikkommission Nordwest- und Zentralschweiz EKNZ

Date of authorisation by the ethics committee

07.06.2017

Further trial identification numbers

Trial identification number of the ethics committee (BASEC-ID) (Data source: BASEC)

2017-00372

Secondary ID (Data source: WHO)

2015-004936-36
CLL13