| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Fit and unfit patients with previously untreated or relapsed/refractory CLL requiring treatment |
|
| E.1.1.1 | Medical condition in easily understood language |
| Fit and unfit patients with previously untreated or relapsed/refractory CLL requiring treatment |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008958 |
| E.1.2 | Term | Chronic lymphocytic leukaemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The results of the CLL2-BAG trial, evaluating an optional debulking with bendamustine followed by an induction and a maintenance treatment with obinutuzumab and venetoclax were promising: Overall response rate was 95% and additionally, the minimal residual disease negativity rate in peripheral blood was 87%.Toxicity was generally acceptable and manageable. It is scientifically important to collect further data in this study, to analyze the duration of response and the further course of MRD. Risk factors for early progression may be identified. Consecutive blood samples will be analyzed for venetoclax resistance and clonal evolution.
The planned re-treatment with venetoclax and obinutuzumab in case of a progression will investigate the efficacy of a re-treatment. Up to 20 patients from both strata may be re-treated with obinituzumab and venetoclax. Start of the re-treatment should not be later than 2.5 years before the planned end of the trial.
|
|
| E.2.2 | Secondary objectives of the trial |
| Secondary endpoints to assess the efficacy of the re-treatment are: ORR and (clinical) CR/CRi rate at the final restaging of re-treatment phase and at end of re-treatment maintenance phase, as well as MRD levels in peripheral blood and bone marrow. Furthermore, it is aimed to evaluate the safety of re-treatment with venetoclax and obinutuzumab by assessment of type, frequency, and severity of AEs and their relationship to study treatment. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Documented CLL requiring treatment (irrespective if first or relapse treatment) according to iwCLL criteria
In case of previously treated patients, these must have recovered from acute toxicities and treatment regimen must be stopped within the following time periods before start of study treatment in the CLL2-BAG trial:
• chemotherapy within ≥ 28 days
• antibody treatment within ≥ 14 days
• kinase inhibitors, BCL2-antagonists or immunmodulatory agents within ≥ 3 days
• corticosteroids may be applied until the start of the BAG-regimen, these have to be reduced to an equivalent of ≤ 20mg prednisolone during treatment
2. Adequate renal function, as indicated by a creatinine clearance ≥30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24 hr. urine collection
3. Adequate hematologic function as indicated by a platelet count ≥ 25 x 10 9/L, a neutrophil count ≥ 1,0 x 10 9/L and a hemoglobin value ≥ 8.0 g/dL, unless directly attributable to the patient´s CLL (e.g. bone marrow infiltration)
4. Adequate liver function as indicated by a total bilirubin ≤2x, AST/ALT ≤2.5x the institutional ULN value, unless directly attributable to the patient’s CLL or to Gilbert’s Syndrome
5. Negative serological testing for hepatitis B (HBsAg nega-tive 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 1 year after last dosage of obinutuzumab), negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration
6. Age ≥ 18 years
7. ECOG 0 to 2, ECOG 3 is only permitted if related to CLL (e.g. due to anemia or severe constitutional symptoms)
8. Life expectancy ≥ 6 months
9. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements
Inclusion criteria for extended follow-up and re-treatment (Amendment 4 and 5):
1. Patients must have participated in the CLL2-BAG trial and must have benefitted from study treatment (clinical re-lapse ≥6 months after discontinuation of treatment due to a MRD negative response or, completion of 24-months of maintenance treatment or toxicity)
2. Only patients with a confirmed progression of CLL who are in need of treatment according to iwCLL 2008 criteria4 are eligible for retreatment with venetoclax and obinutuzumab
Please note: Patients with a MRD conversion from nega-tive/intermediate to positive without clinical signs of pro-gression should not (yet) receive a retreatment in the trial |
|
| E.4 | Principal exclusion criteria |
1. Transformation of CLL (i.e. Richter’s transformation, pro-lymphocytic leukemia)
2. Known central nervous system (CNS) involvement
3. Patients with confirmed PML
4. Malignancies other than CLL currently requiring systemic therapies
5. Uncontrolled infection requiring systemic treatment
6. Any comorbidity or organ system impairment rated with a CIRS (cumulative illness rating scale) score of 4, excluding the eyes/ears/nose/throat/larynx organ system or any other life-threatening illness, medical condition or organ system dysfunction that – in the investigator´s opinion - could compromise 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 gastro-intestinal tract)
7. Requirement of therapy with strong CYP3A4 inhibitors/inducers or anticoagulant with warfarin, phenprocoumon (marcumar) or other vitamin K-antagonists
8. Use of investigational agents which would interfere with the study drug within 28 days prior to registration
9. Known hypersensitivity to obinutuzumab, venetoclax or any of the excipients
Please note: Patients with a known hypersensitivity to bendamustine are allowed to participate but will not receive a debulking with bendamustine
10. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment, on day one of every debulking and induction cycle (monthly) and on day one of every maintenance cycle (every three months))
11. Fertile men or women of childbearing potential unless:
- surgically sterile or ≥ 2 years after the onset of menopause, or
- willing to use two methods of reliable contraception including one highly effective (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 18 months after end of study treatment.
12. Vaccination with a live vaccine ≤ 28 days prior to registration
13. Legal incapacity
14. Prisoners or subjects who are institutionalized by regulatory or court order
15. Persons who are in dependence to the sponsor or an investigator
Exclusion criteria for extended follow-up and re-treatment (Amendment 4 and 5):
3.Patients who received any subsequent treatment for CLL outside the study are ineligible |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall response rate (ORR) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| at final restaging (RE) 12 weeks after the start of the last course of induction therapy |
|
| E.5.2 | Secondary end point(s) |
Type, frequency, severity of AEs + AESI
MRD in peripheral blood at
- final restaging after end of induction in patients responding to study treatment and
- every 12 weeks during maintenance if patient has achieved a (clinical) CR(i) or
- every 24 weeks during the maintenance phase if the patient has achieved a PR
- every 24 weeks during follow up
- MRD in BM optionally in patients with (clinical) CR(i) 3 months after achievement of MRD- in peripheral blood
- BRR until 6 months after RE
- ORR after debulking
- ORR after end/maintenance
- ORR in two strata of previously untreated and relapsed/refractory pats, fit + unfit patients for mentioned response definitions
- ORR in biological defined risk groups
- PFS
- EFS
- OS
- Duration of response in patients with:
- (clinical) CR,
- (clinical) CRi,
- PR with/without lymphocytosis
- Time to next CLL treatment
- relationship between baseline markers and clinical outcome parameters
- Efficacy of re-treatment with venetoclax and obinutuzumab (in case of a clinical progression after termination of mainte-nance therapy):
- ORR and (clinical) CR/CRi rate assessed by the in-vestigator at the final restaging of re-treatment phase (12 weeks after the start of the last re-treatment in-duction cycle) and at the end of re-treatment mainte-nance phase
- MRD levels measured in peripheral blood by four-color flow cytometry every 3 months during re-treatment and every 6 months during thefollow-up thereafter
- MRD levels measured in bone marrow (optionally in patients with (clinical) CR/CRi and MRD negativity in peripheral blood)
- Safety evaluation of re-treatment: Type, frequency, and severity of
- adverse events (AE) leading to dose reductions, treatment interruption and/or discontinuation,
- adverse events of special interest (AESI) and
- serious adverse events (SAEs) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| ongoing evaluation during the trial |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 20 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
Print
