| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Acute Lymphoblastic Leukemia (ALL)
Lymphoblastic Lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
Primary Objectives:
a) Evaluate the safety of venetoclax in combination with navitoclax
b) Evaluate the safety of venetoclax in combination with navitoclax and chemotherapy
c) Determine dose limiting toxicities (DLT) of venetoclax, navitoclax, and chemotherapy
d) Assess the pharmacokinetics (PK) of venetoclax in combination with navitoclax |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
a) Determine the anti-tumor activity of venetoclax in combination with navitoclax
b) Determine the anti-tumor activity of venetoclax, navitoclax and chemotherapy, after the first cycle of chemotherapy
c) Determine the number of subjects who proceed to stem cell transplantation or CAR-T therapy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
nclusion Criteria:
a) Must have relapsed or refractory acute lymphoblastic leukemia (ALL) or relapsed or refractory lymphoblastic lymphoma (LL). Refractory is defined as persistent disease after at least 2 courses of chemotherapy.
- Participants with ALL with Philadelphia chromosome or with an ABL class targetable fusion are eligible.
- Participants with LL must have radiographic evidence of disease
b) Participants <= 18 years of age who do not have a standard of care treatment option available.
c) Must weigh greater than or equal to 20 kg.
d) Must be able to swallow pills.
e) Must have adequate hepatic and kidney function.
f) Must have adequate performance status:
- Participants less than or equal to 16 years of age: Lansky greater than or equal to 50
- Participants greater than 16 years of age: Karnofsky greater than or equal to 50 or Eastern Cooperative Oncology Group (ECOG) less than 3. |
|
| E.4 | Principal exclusion criteria |
a) Participant has central nervous system (CNS) disease with cranial involvement that requires radiation.
b) Participants who are less than 100 days post-transplant, or greater than 100 days post-transplant with active graft versus host disease (GVHD), or are still continuing post-transplant immunosuppressant therapy within 7 days prior to the first dose of study drug.
c) Participants who have received any of the following prior to the first dose of study drug:
- Inotuzumab within 30 days (if participant received inotuzumab > 30 days prior to Day 1, must have ALT, AST and bilirubin < ULN).
- A biologic agent (i.e., monoclonal antibodies) for anti-neoplastic intent within 30 days
- CAR-T infusion or other cellular therapy within 30 days
- Any anti-cancer therapy including blinatumomab, chemotherapy, radiation therapy targeted small molecule agents or investigational agents within 14 days, or 5 half-lives, whichever is shorter
d) Exception: Philadelphia Chromosome (Ph)+ ALL subjects on TKIs at Screening may enroll and remain on Tyrosine Kinase Inhibitor (TKI) therapy to control disease. Participants on venetoclax at screening may enroll and remain on venetoclax.
- Steroid therapy for anti-neoplastic intent within 5 days
- Hydroxyurea that is ongoing (hydroxyurea is permitted up to the first dose)
- A strong or moderate CYP3A inhibitor or inducer within 7 days
- Aspirin within 7 days, or 5 half-lives, whichever is longer
- An excluded antiplatelet/anticoagulant drug or a herbal supplement that affects platelet function within 7 days, or 5 half-lives, whichever is longer
e) Participants with malabsorption syndrome or any other condition that precludes enteral administration |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
a) Cmax of Venetoclax + Navitoclax [ Time Frame: Up to approximately 9 months ]
Maximum observed plasma concentration (Cmax) of venetoclax + navitoclax
b) AUC of Venetoclax + Navitoclax [ Time Frame: Up to approximately 9 months ]
Area under the plasma concentration-time curve (AUC) of venetoclax + navitoclax
c) Tmax of Venetoclax + Navitoclax [ Time Frame: Up to approximately 9 months ]
Time to Cmax (Tmax) of Venetoclax + Navitoclax
d) CL/F of Venetoclax + Navitoclax [ Time Frame: Up to approximately 9 months ]
Apparent oral clearance (CL/F) of venetoclax + navitoclax
e) Number of participants with dose-limiting toxicities (DLT) [ Time Frame: Up to approximately 28 days after initial dose of study drug ]
A DLT is any Grade 3 or higher non-hematologic adverse event (AE) with exceptions outlined in the protocol. AEs and toxicities that occur beyond the DLT assessment period will also be evaluated by the investigator and AbbVie and may be considered as dose-limiting. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
a) Cmax of Venetoclax + Navitoclax [ Time Frame: Up to approximately 9 months ]
b) AUC of Venetoclax + Navitoclax [ Time Frame: Up to approximately 9 months ]
c) Tmax of Venetoclax + Navitoclax [ Time Frame: Up to approximately 9 months ]
d) CL/F of Venetoclax + Navitoclax [ Time Frame: Up to approximately 9 months ]
e) Number of participants with dose-limiting toxicities (DLT) [ Time Frame: Up to approximately 28 days after initial dose of study drug ]
|
|
| E.5.2 | Secondary end point(s) |
a) Progression-free survival (PFS) [Time Frame: Up to 9 months after the last subject has enrolled into the study]
PFS is defined as the number of days from the date of enrollment to the date of earliest disease progression or death.
b) Partial Response (PR) rate [Time Frame: Up to 9 months after the last subject has enrolled into the study]
PR defined as no peripheral blasts or peripheral blood absolute blast count decreased by ≥ 50% from baseline, bone marrow with 5 - 25% blasts and at least a 50% decrease in bone marrow blast percent from baseline, no evidence of extramedullary disease.
c) Number of Participant who Proceed to Stem Cell Transplantation or Chimeric antigen receptor T-cell (CAR-T) Therapy [ Time Frame: Up to 9 months after the last subject has enrolled into the study ]
Determine the number of participants who proceed to stem cell transplantation or CAR-T therapy.
d) Overall survival (OS) [ Time Frame: Up to 9 months after the last subject has enrolled into the study ]
OS is defined as the number of days from the date of enrollment to the date of death.
e) Objective response rate (ORR) [ Time Frame: Up to 9 months after the last subject has enrolled into the study ]
The proportion of subjects with objective response rate (complete response [CR] + CR incomplete recovery [CRi] + CR without platelet recovery [CRp]) for ALL subjects and (CR+PR) for LL subjects.
f) Complete Response (CR) rate [ Time Frame: Up to 9 months after the last subject has enrolled into the study ]
CR defined as hematologic recovery (absolute neutrophil count [ANC] greater than or equal to 500/μL; platelet counts greater than or equal to 75,000/μL), evidence of trilineage hematopoiesis in the bone marrow and less than 5% blasts in the bone marrow, absence of circulating blasts, and no evidence of extramedullary disease. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
a) Progression-free survival (PFS) [Time Frame: Up to 9 months after the last subject has enrolled into the study]
b) Partial Response (PR) rate [Time Frame: Up to 9 months after the last subject has enrolled into the study]
c) Number of Participant who Proceed to Stem Cell Transplantation or Chimeric antigen receptor T-cell (CAR-T) Therapy [ Time Frame: Up to 9 months after the last subject has enrolled into the study ]
d) Overall survival (OS) [ Time Frame: Up to 9 months after the last subject has enrolled into the study ]
e) Objective response rate (ORR) [ Time Frame: Up to 9 months after the last subject has enrolled into the study ]
f) Complete Response (CR) rate [ Time Frame: Up to 9 months after the last subject has enrolled into the study ] |
|
| 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 | 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| 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 | Yes |
| 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) | Yes |
| 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 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
|
| 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 study is defined as the date of the last subject's last visit, which does not include subjects receiving treatment beyond Week 37. Subjects receiving treatment beyond Week 37 will cease study treatment upon last subject last visit |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 16 |
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