E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Myeloid malignancies (acute myeloid leukemia [AML], myelodysplastic syndromes [MDS], and myelodysplastic syndrome/myeloproliferative neoplasms [MDS/MPN]) |
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E.1.1.1 | Medical condition in easily understood language |
Cancers of the blood (acute myeloid leukemia, myelodysplastic syndromes, and myelodysplastic syndrome/myeloproliferative neoplasms) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
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 |
Part 1 (dose regimen finding) and Part 2 (safety expansion) • To determine the safety and tolerability of BGB-11417 in combination with azacitidine in patients with myeloid malignancies • To select the dose regimens of BGB-11417 in combination with azacitidine in Part 1 to be evaluated in Part 2 • To determine the recommended Phase 2 dose (RP2D) of BGB-11417 in combination with azacitidine to be evaluated in Part 3
Part 3 (efficacy expansion) • To evaluate the antileukemic activity of BGB-11417 in combination with azacitidine as measured by response rates • To evaluate the effect of posaconazole on the pharmacokinetics of BGB-11417 when coadministered in a drug-drug interaction (DDI) cohort (Note: the DDI evaluation with posaconazole will not be conducted in Europe)
For monotherapy: to determine the safety and tolerability of BGB-11417 monotherapy in patients with R/R AML, MDS and MDS/MPN |
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E.2.2 | Secondary objectives of the trial |
Part 1 (dose regimen finding) and Part 2 (safety expansion) • To evaluate the antileukemic activity of BGB-11417 in combination with azacitidine as measured by response rates • To assess the pharmacokinetics (PK) of BGB-11417 and azacitidine when given in combination
Part 3 (efficacy expansion) • To evaluate the safety and tolerability of the selected BGB-11417 dose regimen in combination with azacitidine • To evaluate the antileukemic activity of BGB-11417 in combination with azacitidine as measured by duration of responses, time to responses, and additional time-to-event outcomes • To assess the pharmacokinetics of BGB-11417 in combination with azacitidine • To evaluate the safety of BGB-11417 when coadministered with posaconazole in a DDI cohort (Note: the DDI evaluation with posaconazole will not be conducted in Europe)
For monotherapy: to evaluate the antileukemic activity and assess PK of BGB-11417 monotherapy |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Confirmed diagnosis of one of the following by 2016 World Health Organization criteria: • AML, nonacute promyelocytic leukemia • MDS • MDS/MPN 2. Eastern Cooperative Oncology Group performance status of 0 to 2. 3. Adequate organ function defined as: • Creatinine clearance ≥ 50 milliliters/minute (mL/min) (or between 30 and 49 mL/min in unfit AML cohort) • Adequate liver function 4. Life expectancy of > 12 weeks. 5. Ability to comply with the requirements of the study.
Note: other protocol-defined inclusion criteria may apply. |
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E.4 | Principal exclusion criteria |
1. A diagnosis of acute promyelocytic leukemia. 2. Prior malignancy within the past 2 years, except for curatively treated localized skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast, or localized Gleason score ≤ 6 prostate cancer. 3. Antecedent MPN including myelofibrosis, essential thrombocytosis, polycythemia vera, or chronic myelogenous leukemia with or without BCR-ABL1 translocation and AML with BCR-ABL1 translocation. 4. Prior therapy with a B-cell lymphoma-2 inhibitor or azacitidine except for participants who meet HMA-failure criteria 5. Known central nervous system involvement by leukemia.
Note: other protocol-defined exclusion criteria may apply. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part 1 (dose regimen finding) and Part 2 (safety expansion) • Safety and tolerability of BGB-11417 in combination with azacitidine as assessed by dose-limiting toxicities (DLTs) and the incidence, timing, and severity of treatment-emergent adverse events (TEAEs), according to NCI-CTCAE v5.0.
Part 3 (efficacy expansion) • For AML: - complete remission (CR) + complete remission with partial hematologic recovery (CRh) rate; - In the DDI cohort: PK endpoints of BGB-11417, including but not limited to area under the curve (AUC) and maximum plasma concentration (Cmax), derived from the plasma concentration-time profiles • For MDS: modified overall response (mOR) rate, including CR, marrow complete remission (mCR), and partial remission (PR). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Part 1 (dose regimen finding) and Part 2 (safety expansion)
For AML: • CR + morphologic complete remission with partial hematologic recovery (CRh) rate.
For MDS: • Modified overall response (mOR) rate that is defined as achieving a CR, marrow complete remission (mCR), or partial remission (PR) at any time point during the study per modified IWG 2006 criteria for MDS/MPN (Cheson et al 2006)
Secondary pharmacokinetic (PK) endpoints for both AML and MDS: • Derived PK parameters, including: − For azacitidine: maximum observed plasma concentration (Cmax), area under plasma concentration-time curve (AUC0-t, AUC0-∞), half-life (t1/2), apparent total clearance of drug from plasma (CL/F), and apparent volume of distribution (Vz/F) as appropriate; − For BGB-11417: AUClast,ss, Cmax,ss, steady-state trough plasma concentration (Ctrough,ss) and tmax,ss.
Part 3 (efficacy expansion)
For AML: • CR rate; • CR + CR with incomplete hematologic recovery (CRi) rate; • ORR (CR + CRi + PR + morphologic leukemia-free state [MLFS]); • Duration of response of CR, CR + CRi, OR and CR + CRh; • Time to response (TTR) of CR, CR + CRi, OR and CR + CRh; • Event-free survival (EFS); • Overall survival (OS); • Transfusion independence (for at least consecutive 56-day postbaseline).
For MDS: • CR rate; • CRh rate; • Hematological improvement – erythroid (HI-E), as per IWG 2018 criteria; • Hematological improvement – platelet (HI-P), as per IWG 2018 criteria; • Hematological improvement – neutrophil (HI-N), as per IWG 2018 criteria; • Transfusion independence (for at least consecutive 56-day post-baseline); • EFS; • OS.
Safety endpoints for both AML and MDS: • Safety and tolerability of BGB-11417 in combination with azacitidine or posaconazole as assessed by the incidence, timing, and severity of TEAEs, according to NCI-CTCAE v5.0. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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 |
Dose finding and expansion study |
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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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
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 |
New Zealand |
Australia |
China |
Germany |
Spain |
United States |
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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
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LVLS (Note: includes long-term and survival follow-up which may be conducted via telephone) |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 10 |