| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Acute Myeloid Leukemia (AML) |
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| E.1.1.1 | Medical condition in easily understood language |
| Reoccurring or resistant cancer of the white blood cells |
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| 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 |
Groupe A
To demonstrate the overall safety of ENTO in combination with standard dose cytarabine and daunorubicin chemotherapy (7+3) in subjects with previously untreated AML who are candidates for chemotherapy (fit subjects) and to assess the efficacy of ENTO at the recommended Phase 2 dose (RP2D)
Groupe B
To demonstrate the overall safety of ENTO in combination with hypomethylating agents (decitabine or azacitidine) in subjects with previously untreated AML who are not candidates for 7+3 (unfit subjects) and to assess the efficacy of ENTO at the RP2D
Group C
To demonstrate the overall safety of ENTO monotherapy in subjects with previously untreated AML who are not candidates for chemotherapy or in subjects with relapsed/refractory AML with or without mixed-lineage leukemia (MLL) and to assess the efficacy of ENTO at the RP2D |
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| E.2.2 | Secondary objectives of the trial |
To assess the qualitative and quantitative toxicities of ENTO monotherapy or ENTO in combination with chemotherapy in subjects with AML
To document therapeutic response of subjects with AML treated with ENTO monotherapy or ENTO in combination with chemotherapy
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Groupe A
- Subjects age ≥ 18 with previously untreated AML by WHO criteria, excluding acute promyelocytic leukemia (M3), who are able and should receive up to 2 cycles of induction chemotherapy with 7+3 as determined by the treating physician
Groupe B
- Subjects age > 70 years with previously untreated AML by WHO criteria, excluding acute promyelocytic leukemia (M3)
- Subjects age ≤ 70 years with previously untreated AML by WHO criteria, excluding acute promyelocytic leukemia (M3), who refuse or are unable to receive 7+3 as determined by the treating physician
Groupe C Phase 1b
- Subjects age ≥ 18 years with relapsed/refractory AML by WHO criteria, excluding acute promyelocytic leukemia (M3)
- Subjects with previously untreated AML by WHO criteria, excluding acute promyelocytic leukemia (M3), and who would have met disease eligibility criteria for Group A or B but refuse or are unable to receive 7+3 or decitabine chemotherapy as determined by the treating physician
Group C Phase 2 (Dose Expansion)
- Cohort C1A: Subjects age ≥ 18 years with relapsed/refractory AML by WHO criteria, excluding acute promyelocytic leukemia (M3)
- Cohort C2: Subjects age ≥ 18 years with relapsed/refractory AML with MLL
- Cohort C3: Subjects with previously untreated AML by WHO criteria, excluding acute promyelocytic leukemia (M3), and who would have met disease eligibility criteria for Group A or B but refuse or are unable to receive chemotherapy and hypomethylating agent as determined by the treating physician
ALL patients must meet all of the following inclusion criteria to be eligible for participation in this study:
1) Male or female ≥ 18 years of age with a diagnosis AML (M0-M7, except M3).
2) All acute toxic effects of any prior anti-leukemia therapy resolved to Grade ≤ 1 before the start of study treatment (with the exception of alopecia [any grade permitted], or bone marrow parameters [any grade permitted] due to leukemia in the investigators opinion).
3) ECOG performance status less than or equal to 2.
4) Life expectancy of at least 3 months.
5) Meet required screening laboratory criteria unless leukemia related.
6) Left Ventricular Ejection Fraction (LVEF) ≥ 45% confirmed by ECHO and no clinical evidence of congestive heart failure.
7) For female subjects of childbearing potential, willingness to abstain from heterosexual intercourse or use a protocol-recommended method of contraception from the screening visit throughout the study treatment period and for 30 days following the last dose of ENTO or as recommended in the prescribing information for other co-administered study drugs (whichever is later).
For male subjects of childbearing potential having intercourse with females of childbearing potential, willingness to abstain from heterosexual intercourse or use a protocol recommended method of contraception from the start of study treatment throughout the study treatment period and for 90 days following the last dose of ENTO or as recommended in the prescribing information for other co-administered study drugs (whichever is later), and to refrain from sperm donation from the start of study treatment throughout the study treatment period and for 90 days following the last dose of ENTO or as recommended in the prescribing information for other co-administered study drugs (whichever is later).
Note: See Appendix 4 for definition of childbearing potential and information regarding recommendations for contraception.
8) Willingness to comply with scheduled visits, drug administration plan, imaging studies, laboratory tests, other study procedures, and study restrictions .
9) Have the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures. |
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| E.4 | Principal exclusion criteria |
1) Patients with acute promyelocytic leukemia (M3)
2) Known active central nervous system or leptomeningeal leukemic involvement. Note: Central nervous system testing (CSF analysis) is only required in patients with suspected involvement based on symptoms or signs.
3) Treatment with proton pump inhibitors (PPIs) within 7 days prior to enrollment. Note: PPIs are likely to interfere with ENTO absorption, thus requiring a 7-day washout period. H2 blockers and antacids will be allowed for use during the protocol
4) History of active non-myeloid malignancy except for the following: adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate specific antigen for > 1 year prior to start of study therapy, or any other cancer that has been in complete remission without treatment for ≥ 5 years prior to enrolment. Subjects who are on prophylaxis with long-term adjuvant hormonal therapy and are ≥ 5 years from therapy for their primary tumor are eligible for enrollment.
5) Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection at the time of start of study treatment. Note: Patients with localized fungal infections of skin or nails are eligible.
6) Ongoing, drug-induced liver injury, known chronic active hepatitis C Virus (HCV), chronic active hepatitis B Virus (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension.
7) Ongoing (within the past 6 weeks) hepatic encephalopathy.
8) Ongoing drug-induced pneumonitis.
9) Ongoing inflammatory bowel disease.
10) Ongoing alcohol or drug addiction as determined by investigator.
11) Pregnancy or breastfeeding.
12) History of prior allogeneic bone marrow progenitor cell or solid organ transplantation. Note: prior allogeneic bone marrow progenitor cell or solid organ transplantation is NOT an exclusion criteria for Cohort C2 ie, MLL cohort.
13) Ongoing immunosuppressive therapy, including systemic chemotherapy for treatment of leukemia. Patients may not have received AML-directed therapy prior to enrollment other than Hydrea or apheresis, if de-novo or for current relapse, except for patients defined as refractory disease at study enrollment. Concurrent use of methotrexate for rheumatologic conditions is permitted.
Note: Patients may use topical, enteric, or inhaled corticosteroids as therapy for comorbid conditions and systemic steroids for autoimmune anemia and/or thrombocytopenia. Ongoing use of low dose systemic corticosteroids (<5 mg/day of methylprednisolone or equivalent) for rheumatologic conditions is permitted. During study participation, patients may receive systemic or other corticosteroids needed for treatment-emergent comorbid conditions.
14) Concurrent participation in an investigational drug trial with therapeutic intent defined as prior study therapy within 14 days prior to study treatment.
15) Any other prior or ongoing condition that, in the opinion of the investigator, could adversely affect the safety of the patient or impair the assessment of study results .
16) Inability to tolerate oral medications, symptomatic disease significantly affecting gastrointestinal function manifested from resection of the stomach or small bowel or active ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction.
17) Uncontrolled intercurrent illness including, but not limited to:
a) unstable angina pectoris
b) psychiatric illness/social situations that would limit compliance with study requirements
c) patients with active infection are permitted to enroll provided that the infection is documented to be under control
18) Known hypersensitivity to ENTO, decitabine, azacitidine, cytarabine and daunorubicin, the metabolites, or formulation excipient
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety
- Occurrence of adverse events and laboratory abnormalities defined as DLTs for Entospletinib in combination with standard dose cytarabine and daunorubicin in patients with previously untreated AML (Group A).
- Occurrence of adverse events and laboratory abnormalities defined as DLTs for Entospletinib in combination with decitabine or azacitidine in patients with previously untreated AML who are unable to receive intensive chemotherapy (Group B).
- Occurrence of adverse events and laboratory abnormalities defined as DLTs for Entospletinib as a single agent or in combination with mitoxantrone, etoposide and cytosine arabinoside (MEC) in patients with relapsed or refractory AML (Group C).
Efficacy
- Complete remission rate at induction completion: defined as the proportion of subjects who achieved morphologic complete remission (CR) at induction completion. Note: CR includes a subcategory of cytogenetic CR (CRc).
- Composite complete remission rate at induction completion: defined as the proportion of subjects who achieved morphologic complete remission (CR) or morphologic complete remission with incomplete blood count recovery (CRi) at induction completion.
- Overall response rate at induction completion: defined as the proportion of subjects who achieved CR, CRi, or partial remission (PR) at induction completion .
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety: at laboratory clinic visits as describe in the Appendix 2 "Study procedures tables" of the protocol.
Efficacy: at induction completion. |
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| E.5.2 | Secondary end point(s) |
Exposure
- Drug administration and duration of exposure of study treatment.
Safety
- Occurrence of AEs and laboratory abnormalities not defined as DLTs.
Efficacy
- Event free survival (EFS) - defined for all patients and it is measured from the start of the study therapy until the date of treatment failure, AML relapse or death from any cause, whichever occurs first.
- Overall survival (OS) – defined as the interval from the start of the study therapy to the death from any cause.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety: at laboratory clinic visits as describe in the Appendix 2 "Study procedures tables" of the protocol.
Efficacy: at the date of treatment failure and time of death. |
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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 | 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 | 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.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| 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 | Yes |
| 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 |
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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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 24 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 44 |
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