| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Lymphocytic Leukemia 17 p Deletion |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the blood and bone marrow |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10024340 |
| E.1.2 | Term | Leukemia lymphocytic chronic |
| 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 |
Main Cohort Primary Objective:
To evaluate the efficacy of venetoclax monotherapy in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL) harboring the 17p deletion. Efficacy will be measured by overall response rate (ORR).
Safety Expansion Cohort Primary Objectives:
A safety expansion cohort is being added with the primary objective of evaluating the safety of ABT-199 in approximately 50 subjects with relapsed or refractory CLL harboring 17p deletion per the updated TLS prophylaxis and management measures. |
|
| E.2.2 | Secondary objectives of the trial |
Main Cohort Primary Secondary Objective: The secondary objectives are to evaluate the complete remission rate (CR rate), partial remission rate (PR rate), duration of overall response (DOR), progression-free survival (PFS), event-free survival, time to progression (TTP), time to first response, time to 50%
reduction in ALC, overall survival (OS) and percent of subjects who move on to stem cell transplant.
The secondary objectives are to evaluate ORR, CR rate, PR rate, duration of overall response, progression-free survival, event-free survival, time to progression, time to first response, time to 50% reduction in ALC, overall survival, and percent of subjects who move on to stem cell transplant.
(Note : All study objectives, with the exception of Safety and MRD analyses, will cease to be evaluated beyond 2 years after last subject first dose.) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject must be ≥ 18 years of age
2. Subject must have diagnosis of CLL that meets published 2008 Modified IWCLL NCI-WG Guidelines.
• Subject has clinically measurable disease;
● Subject must have relapsed/refractory CLL or previously untreated CLL;
○ Refractory or relapsed CLL subjects must meet the following requirements:
- Refractory or relapsed after receiving at least one prior line of therapy (subjects that have progressed after 1 cycle of treatment or have completed at least 2 cycles of treatment for a given line of therapy);
○ Previously untreated CLL subjects must meet the following requirements (previously untreated chronic lymphocytic leukemia harboring 17p deletion patients will not be enrolled in Germany):
- Received no prior chemotherapy or immunotherapy. Subjects with a history of emergency, loco-regional radiotherapy (e.g., for relief of compressive signs or symptoms) are eligible.
- CLL diagnostic criteria above and must have > 5 × 109/L B-Lymphocytes in the peripheral blood.
• Subjects must have 17p deletion, assessed by local laboratory (in bone marrow or peripheral blood) or assessed by central laboratory (peripheral blood).
3. Subject has an ECOG performance score of ≤ 2
4. Subjects must meet the following laboratory parameters, per laboratory reference range:
- ANC ≥ 1000/μL
For subjects with an ANC < 1000/μL at Screening and bone marrow heavily infiltrated with underlying disease (unless cytopenia is clearly due to marrow involvement of CLL), growth factor support may be administered after Screening and prior to the first dose of venetoclax to achieve the ANC eligibility criteria (≥ 1000/μL);
- Platelets ≥ 30,000/mm3
- Hemoglobin ≥ 8.0 g/dL;
- aPTT and PT ≤ 1.5 × ULN;
- Calculated creatinine clearance> 50 mL/min;
- AST and ALT ≤ 3 × ULN;
- Total bilirubin ≤ 1.5 × ULN (Subjects with Gilbert's Syndrome may have bilirubin > 1.5 × ULN per correspondence between the investigator and AbbVie medical monitor).
5. For high risk subjects a pre approval by the AbbVie medical monitor is required prior to enrolment |
|
| E.4 | Principal exclusion criteria |
1-Subject has undergone an allogeneic stem cell transplant
2-Subjects has developed Richter's transformation confirmed by biopsy.
3-Subject has prolymphocytic leukemia.
4-Subject has active and uncontrolled autoimmune cytopenias (for 2 weeks prior to Screening), including autoimmune hemolytic anemia (AIHA) and idiopathic thrombocytopenic purpura (ITP) despite low dose corticosteroids.
5-Subject is known to be positive for HIV, due to potential drug-drug interactions as well as anticipated mechanism-based lymphopenia that may increase the risk of opportunistic infections).
6-Subject has received the following within 30 days prior to the first dose of study drug:
●A biologic agent (i.e., monoclonal antibodies) for anti-neoplastic intent.
7-Subject has received radiotherapy within 14 days or 5 half-lives as applicable prior to the first dose of study drug, or has not recovered to less than CTC grade 2 clinically significant adverse effect(s)/toxicity(s) of the previous therapy:
●Any anti-cancer therapy including chemotherapy, or radiotherapy;
●Investigational therapy, including targeted small molecule agents.
8-Subject has known allergy to both xanthine oxidase inhibitors and rasburicase.
9-Cardiovascular disability status of New York Heart Association Class ≥ 2.
10- Subjects exhibits evidence of other clinically significant uncontrolled condition(s), including, but not limited to:
- Uncontrolled and/or active systemic infection (viral, bacterial, or fungal).
- Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment.
- Febrile neutropenia
11-Subject has a significant history of renal, pulmonary, neurologic, psychiatric, endocrinologic, metabolic, immunologic, cardiovascular, or hepatic disease that in the opinion of the investigator would adversely affect his/her participating in this study. For subjects who have required an intervention for any above diseases within the past 6 months correspondence with the investigator and the AbbVie medical monitor must occur.
12-Subject has a significant history of other active malignancies other than CLL within the past 3 years prior to study entry, with the following exceptions: Adequately treated in situ carcinoma of the cervix uteri; Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin; Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent. |
|
| 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 |
| Every month through Week 36, then every 3 months thereafter. Survival data will be collected every 3 months for a period of 5 years after the subject has enrolled in the study. |
|
| E.5.2 | Secondary end point(s) |
| Complete remission rate (CR), partial remission rate (PR), duration of overall response (DOR), progression free survival (PFS), time to progression (TTP), overall survival (OS) and percent of subjects who move on to stem cell transplant. The safety and tolerability of venetoclax in subjects with relapsed or refractory CLL harboring 17p deletion will also be evaluated. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Every month through Week 36, then every 3 months thereafter. The safety and tolerability of venetoclax will be assessed at every study visit through the safety follow up period. Survival data will be collected every 3 months for a period of 5 years after the subject has enrolled in the study.
Safety and MRD-PCR data will continue to be collected for those subjects who remain on venetoclax into the Survival-Extended Access portion of the trial. All other end points will be abandoned 2 years following LSFD. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 31 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| France |
| Germany |
| Poland |
| United Kingdom |
| United States |
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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