| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with relapsed/refractory CLL requiring treatment |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with relapsed chronic lymphocytic leukaemia in need of 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 primary objective of the study is to evaluate the efficacy of a sequential regimen of two cycles of bendamustine, followed by a combination therapy of GA101 (obinutuzumab), acalabrutinib (ACP-196) and ABT-199 (venetoclax) in patients with relapsed/refractory CLL.
|
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| E.2.2 | Secondary objectives of the trial |
| The secondary objective is to evaluate the safety of a sequential regimen of two cycles of bendamustine, followed by a combination therapy of GA101 (obinutuzumab), acalabrutinib (ACP-196) and ABT-199 (venetoclax) in patients with relapsed/refractory CLL. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Relapsed/refractory CLL in need of treatment according to iwCLL criteria
In case of a recent previous treatment, patients must have recovered from acute toxicities and treatment regimen must be stopped within the following time periods before start of the study treatment in the CLL2-BAAG trial:
- chemotherapy ≥ 28 days
- antibody treatment ≥ 14 days
- kinase inhibitors, BCL2-antagonists or immunomodulatory agents ≥ 3 days
- corticosteroids may be applied until the start of the BAAG-regimen, these have to be reduced to an equivalent of ≤ 20mg prednisolone per day during treatment
Please note: Patients with a progression during previous treatment with venetoclax, ibrutinib or another BTK inhibi-tor, as well as patients with a known resistance mutation (e.g. BTK-/PLCg2) are excluded from study participation. However, patients who progressed after termination of treatment with venetoclax, ibrutinib, other BTK inhibitors and/or obinutuzumab or who stopped treatment due to in-tolerance to ibrutinib are eligible for participation.
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 neutro-phil count ≥ 1.0 x 109/L, a hemoglobin value ≥8.0 g/dL and a platelet count ≥ 25 x 109/L, unless directly attributable to the patient´s CLL (e.g. bone marrow infiltration), in this case, platelet count should be ≥ 10 × 109/L.
4. Adequate liver function as indicated by a total bilirubin ≤2x, AST/ALT ≤2.5x the institutional ULN value, unless di-rectly attributable to the patient’s CLL or to Gilbert’s Syn-drome
5. 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 4 weeks until one year after last dosage of GA101 (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 |
|
| E.4 | Principal exclusion criteria |
1. (Suspicion of) transformation of CLL (i.e. Richter’s trans-formation, pro-lymphocytic leukemia) or central nervous system (CNS) involvement
2. Progression during previous treatment with venetoclax, ibrutinib or another BTK inhibitor, and/or presence of known mutations associated with resistance to therapy, e.g. Bruton´s Tyrosine Kinase and Phospholipase C Gamma 2 (PLCg2)
3. Confirmed progressive multifocal leukoencephalopathy (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, exclud-ing 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 gastrointestinal tract)
7. Significantly increased risk of bleeding according to the investigator´s evaluation, e.g. due known bleeding diathe-sis (e.g. von-Willebrandt´s disease or hemophilia), major surgical procedure ≤ 4 weeks or stroke/intracranial hem-orrhage ≤ 6 months.
8. Requirement of therapy with strong CYP3A4 inhibi-tors/inducers or anticoagulant with phenprocoumon (mar-cumar) or other vitamin K-antagonists
9. Use of investigational agents ≤ 28 days prior to start of study treatment, however, kinase inhibitors, BCL2-antagonists and antibody treatment are allowed in ac-cordance with inclusion criterion number 1 (see above).
10. Known hypersensitivity to obinutuzumab (GA101), venetoclax (ABT-199), acalabrutinib (ACP-196) 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
11. Pregnant women and nursing mothers (a negative preg-nancy test is required for all women of childbearing potential within 7 days before start of treatment)
12. 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.
13. Vaccination with a live vaccine ≤ 28 days prior to registration
14. Legal incapacity
15. Prisoners or subjects who are institutionalized by regulatory or court order
16. Persons who are in dependence to the sponsor or an investigator |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Negativity rate of minimal residual disease (MRD) in peripheral blood (PB) measured by 4-color flow cytometry at final restaging (RE) at the end of induction treatment (12 weeks after the start of the last induction cycle) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint can be analysed as soon as all enrolled patients who did not discontinue prematurely have achieved the final restaging 12 weeks after last cycle of induction therapy. This will trigger the time point of the analysis of the primary endpoint. |
|
| E.5.2 | Secondary end point(s) |
- Overall response rate (ORR) according to iwCLL criteria at RE 12 weeks after the start of the last cycle of induction therapy including all patients achieving: a complete response (CR), CR with incomplete recovery of the bone marrow (CRi), or a partial response (PR).
- CR / CRi rate at RE 12 weeks after the start of the last cycle of induction therapy
- Differentiation of patients with a PR according to iwCLL crite-ria into patients achieving an unconfirmed (clinical) CR/CRi lacking a CT/MRI scan and/or a bone marrow biopsy a PR due to residual lymphadenopathy and/or hepatosplenomegaly, or a PR due to residual bone marrow infiltration
- Safety parameters: Type, frequency and severity of adverse events (AE), serious adverse events (SAE) and adverse events of particular interest (AEPI)
- MRD in PB measured by 4-color flow therapy at: every 12 weeks (= approx. 3 months) during the maintenance phase and every 24 weeks (= approx. 6 months) during the follow-up.
- MRD in PB measured by 4-color flow cytometry for the assessment of the kinetics of response to the different treat-ment phases at screening/baseline, staging after debulking (if applicable), before start with acalabrutinib (cycle 2, d1), before start with venetoclax (cycle 3, d1), interim staging (after 3 induction cycles), initial response assessment (after 6 induction cycles)
- MRD in bone marrow measured by 4-color flow cytometry optionally in patients with (clin.) CR/CRi (or PR almost fulfilling CR criteria, e.g. with residual splenomegaly) 12 weeks after achievement of MRD negativity in PB
- Best response rate (BRR) until 6 months after RE
- ORR after debulking
- ORR after end of maintenance treatment
- Progression-free survival (PFS)
- Event-free survival (EFS)
- Overall survival (OS)
- Duration of response in patients with a complete response (CR), a CR with incomplete recovery of the bone marrow (CRi), a partial remission (PR) (including patients with a PR due to residual lymphadenopathy and/or hepatosple-nomegaly or due to residual bone marrow infiltration as well as patients with an unconfirmed (clinical) CR/CRi lacking a CT/MRI scan and/or a bone marrow biopsy).
- Treatment-free survival (TFS) and time to next CLL treatment (TTNT)
Exploratory endpoints:
- Evaluation of relationship between various baseline markers and clinical outcome parameters
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint can be analysed as soon as all enrolled patients who did not discontinue prematurely have achieved the final restaging 12 weeks after last cycle of induction therapy. This will trigger the time point of the analysis of the primary and secondary endpoints. |
|
| 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 | No |
| 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.8.3 |
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 | 9 |
| 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
|
| The end of the clinical trial is defined as the time point once the last patient has completed the maintenance phase and at least 2 follow up visits (with an interval of 3 months) thereafter. This will take place approximately 40 months after the last patient entered the trial. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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