| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Physically fit and unfit patients with TP53 deletion (17p-) and/or mutation and previously untreated CLL requiring therapy |
|
| E.1.1.1 | Medical condition in easily understood language |
| Physically fit and unfit patients with TP53 deletion (17p-) and/or mutation and previously untreated CLL requiring therapy |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008957 |
| E.1.2 | Term | Chronic lymphatic leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| 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 the GIVe regimen in patients with TP53 deletion (17p-) and/or mutation and previously untreated CLL requiring treatment.
For this, the CR rate at cycle 15 (d1; final restaging) will be used as primary parameter for efficacy. The CR rate is defined as the proportion of patients having achieved a CR or a CR with incomplete recovery of the bone marrow (CRi) as best response (according to iwCLL criteria) until cycle 15 (d1; final restaging) from start of therapy.
Efficacy of the regimen will be further assessed by evaluation of the proportion of patients free of disease progression (PD-free rate) after 12 cycles of therapy, overall response rate (ORR), minimal residual disease (MRD) and overall survival as well as other time to event endpoints as outlined below. |
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| E.2.2 | Secondary objectives of the trial |
| secondary objective of the study is to evaluate the safety of ibrutinib, venetoclax and obinutuzumab. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Have documented CLL according to iwCLL criteria and measurable disease (lymphocytosis > 5x109 with/without measurable lymph nodes and/or organomegaly) assessed by physical exam and/or CT
2. Subjects must have untreated CLL, i.e. no prior chemotherapy, antibody therapy or non-chemotherapeutic agent (BTK, PI3K, BCL2 inhibitor or similar). Local irradiation or short term (up to 1 month) corticosteroid treatment for autoimmune phenomena are allowed
3. Subjects must have TP53 deletion (17p-) and/or mutation (in bone marrow or peripheral blood), with pre-existing local test results confirmed by central laboratory in Ulm
4. CLL requiring treatment (“active disease”) according to the iwCLL criteria
5. ECOG ≤ 2
6. Creatinine clearance ≥ 50 ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured after 24 h urine collection
7. Adequate liver function as indicated by a total bilirubin ≤ 2 x, AST, and ALT ≤ 3 x the institutional ULN value, unless directly attributable to the patient’s CLL or to Gilbert’s Syndome
8. No cardiovascular disability of New York Heart Association (NYHA) Class > 2. Class 2 is defined as comfortabilty at rest but moderate physical activity causes dyspnoea, angina pain or fatigue
9. Adequate bone marrow function (unless directly attributable to CLL, BM examination required):
• ANC ≥ 1000/µl or
• ANC < 1000/µl, if attributable to the underlying CLL (growth factor support may be administered after screening)
• Platelets > 30.000/µl (unless directly attributable to the
underlying CLL)
10 Hemoglobin ≥ 8g/dl (unless directly attributable to the
underlying CLL)
11. Negative serological testing for hepatitis B (i.e. HBsAg negative and anti-HBc negative, patients positive for anti-HBc may be included if PCR for HBV DNA is negative) negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration.
[Patients who are HBsAg negative/anti-HBc positive with undetectable serum HBV DNA should be monitored closely (every month) for HBV DNA by a real-time PCR quantification assay with a lower limit of detection of the order of 10 WHO IU/mL until at least 24 months after the last treatment cycle with obinutuzumab. If the HBV DNA assay becomes positive, patients should pre-emptively be treated with a nucleoside analogue (i.e. lamivudine) for at least 24 months after the last cycle of therapy with obinutuzumab or be referred to a gastroenterologist for management.]
12. Age at least 18 years
13. Life expectancy ≥ 6 months
14. Must be able to adhere to the study visit schedule and other protocol requirements
15. Able and willing to provide written informed consent and to comply with the study protocol procedures
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|
| E.4 | Principal exclusion criteria |
1. Transformation of CLL (i.e. Richter’s transformation, prolymphocyctic leukemia)
2. One or more individual organ / system impairment score of 4 as assessed by the CIRS definition, excluding the Eyes, Ears, Nose, Throat and Larynx organ system
3. Known central nervous system (CNS) involvement
4. Patients with a history of PML
5. Impairment of plasmatic coagulation as indicated by "Quick" ≤ 60% and / or PTT ≥ 50 sec. unless explicabledue to by iatrogenic measure
6. Active malignancies other than CLL within the past 2 years prior to study entry, with the exception:
• Adequately treated in situ carcinoma of the cervix uteri
• Adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin
• Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent and in remission at time of screening
7. Use of agents which would interfere with the study drug within 28 days prior to registration
8. Uncontrolled infection requiring systemic treatment
9. History of severe infusion-related reaction to humanized or murine monoclonal antibodies, and/ or known sensitivity or allergy to murine products or allergy to xanthin oxidase and rasburicase or glucose-6-phosphate dehydrogenase deficiency
10. Requires treatment with the following drugs:
• Within 7 days prior to the first dose of study drug: No steroid therapy higher than 20 mg Prednisolone for anti-neoplastic intent; No CYP3A inhibitors (e.g. fluconazole, ketoconazole, clarithromycin); No potent CYP3A inducers (e.g., rifampin, phenytoin or carbamazepine);
• Within 3 days prior to the first dose of study drug: Grapefruit or grapefruit products; Seville oranges (including marmalade); Star fruit.
11. History of stroke or intracranial hemorrhage within 6 months prior to registration
12. Pregnant women and nursing mothers
13. Fertile men or women of childbearing potential unless:
a. surgically sterile or ≥ 2 years after the onset of menopause
b. willing to use two highly effective contraceptive methods (Pearl Index <1) during study treatment and for 18 months after end of study treatment.
14. Vaccination with a live vaccine a minimum of 28 days prior to registration
15. Legal incapacity
16. Prisoners or subjects who are institutionalized by regulatory or court order
17. Persons who are in dependence to the sponsor or an investigator |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Complete response (CR) rate at cycle 15 (d1; at final restaging) (according to iwCLL criteria) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| after Follow up period of all patients |
|
| E.5.2 | Secondary end point(s) |
• Proportion of patients free of disease progression (PD-free rate) after 12 cycles of therapy
• Overall response rate (ORR) (including all patients achieving a complete response (CR), a complete response with incomplete recovery of the bone marrow (CRi), a partial response (PR) and a PR with lymphocytosis)
• ORR after end of maintenance treatment
• MRD levels (measured in peripheral blood after cycle 9, after cycle 12, at the beginning of cycle 15 (d1), at the beginning of cycle 36 (d1), as well as in bone marrow at the beginning of cycle 15)
• Progression-free survival (PFS)
• Event-free survival (EFS)
• Overall survival (OS)
• Duration of response in patients with (clinical) CR/CRi, PR
• Treatment-free survival (TFS) and time to next CLL treatment (TTNT)
• Evaluation of subsequent treatment for CLL (including proportion receiving allogeneic SCT as consolidation or in relapse) including response to treatment
• Safety parameters: Type, frequency, and severity of adverse events (AEs) and adverse events of special interest (AESI) and their relationship to study treatment
• Incidence of Richter’s transformation
• Exploratory: Evaluation of relationship between baseline markers and clinical outcome parameters
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| after Follow up period of all patients |
|
| 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 | 10 |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
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