| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Children, adolescents, and young adults up to the age of 21 years with acute myeloid leukemia with a documented negative test for FLT3/ITD mutation and either:
- Untreated second relapse, who are sufficiently fit to undergo another round of intensive chemotherapy or
- Untreated first relapse who per investigator discretion cannot tolerate additional anthracycline containing chemotherapy.
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| E.1.1.1 | Medical condition in easily understood language |
| Pediatric patients, adolescentes and adults up to the age of 21 years who suffer from acute myeloid leukemia (a type of blood cancer) who have relapsed (returned after treatment). |
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| 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 | 10001941 |
| E.1.2 | Term | AML |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
| To assess if venetoclax combined with FLA+GO (fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin) will improve overall survival of children with relapsed acute myeloid leukemia (AML) compared to FLA+GO. |
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| E.2.2 | Secondary objectives of the trial |
To compare event free survival (EFS) in patients receiving FLA+GO with and without venetoclax. All other secondary objectives refer to this same population
To compare the flow-based overall response rate (ORR) comprising ped-flow CR, ped-flow CRi, ped-flow CRp
To compare the morphological overall response rate (ORR) comprising ped-morph CR, ped-morph CRi, ped-morph CRp
To assess the duration of response (DOR)
To assess the cumulative incidence of relapse (CIR)
To assess relapse and non-relapse mortality (NRM) as competing events in patients receiving FLA+GO with and without venetoclax.
To describe the hematopoietic stem cells transplant (HSCT) rate
To describe the safety and tolerability of FLA+GO with and without venetoclax
To describe the pharmacokinetics of venetoclax in combination with FLA+GO
To describe the MRD-negative overall response rate (CR/CRi/CRp) rate
To compare the morphological International Working Group complete response (IWG-CR) rate |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patient must have the following:
a. Children, adolescents, and young adults with acute myeloid leukemia without demonstrated FLT3/ITD mutation. Ideally, the status of the mutation needs to be proven in the current relapse. Nevertheless, patients with previous FLT3/ITD negative test from prior lines can be included based on local results in order to not delay the start of treatment.
b. And patients must have AML which is either:
- untreated second relapse, in patients who are sufficiently fit to undergo another round of intensive chemotherapy, or
- untreated first relapse, in patients who cannot tolerate additional anthracycline containing chemotherapy per investigator discretion.
Patients must have a performance status corresponding to ECOG scores of 0, 1 or 2 (≥ 50% Lansky or Karnofsky score)
Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the minimum duration from prior anti-cancer directed therapy prior to enrolment (more details in the protocol).
Cytotoxic chemotherapy: Must not have received cytotoxic chemotherapy within 14 days prior to start of protocol treatment, except for corticosteroids, low dose cytarabine or hydroxyurea (see below) that can be given up to 24 hours prior to start of protocol treatment.
Antibodies: ≥ 21 days must have elapsed from infusion of last dose of an antibody-drug conjugate prior to start of protocol treatment.
Interleukins, Interferons and Cytokines : ≥ 21 days after the completion of interleukins, interferon or cytokines
Hematopoietic growth factors: ≥ 14 days after the last dose of a long-acting growth factor or ≥7 days for short-acting growth factor prior to start of protocol treatment.
Radiation therapy (RT): Between 14 and 84 days depeding on the extent of radiation fields
Stem Cell Infusions: ≥ 84 days since allogeneic bone marrow or stem cell transplant or boost infusion. No evidence of active graft versus host disease
Patients must be off medications to treat or prevent either graft-versus-host disease post bone marrow transplant or organ rejection post-transplant for at least 14 days
Cellular Therapy: ≥ 42 days after the completion of any type of cellular therapy
Adequate organ function . a.Adequate Renal Function defined as: •Calculated eGFR (based on Schwartz formula) or radioisotope GFR ≥ 60ml/min/1.73 m2, OR •A serum creatinine based on age/sex b.Adequate Liver Function defined as: •Total or direct (conjugated) bilirubin ≤ 1.5xULN, AND •Alkaline phosphatase ≤ 2.5xULN, AND •SGPT (ALT) ≤ 2.5xULN oIf liver abnormality is due to radiographically identifiable leukemia infiltrate, the patient will remain eligible. c.Cardiac performance: Minimum cardiac function defined as: •No history of congestive heart failure in need of medical treatment •No pre-treatment diminished left ventricular function on echocardiography (FS <25% or EF <40%) •No signs of congestive heart failure at presentation of relapse Informed consent: Patient, parent or legal guardian must sign and date informed consent and pediatric assent (when required), prior to the initiation of screening or study specific procedures
Patient, parent or legal guardian must sign and date informed consent and pediatric assent (when required), prior to the initiation of screening or study specific procedures, according to local law and legislation |
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| E.4 | Principal exclusion criteria |
Patients who in the opinion of the investigator may not be able to comply with the study requirements of the study, are not eligible.
Patients with Down syndrome.
Patients with Acute promyelocytic leukemia (APL) or Juvenile myelomonocytic leukemia (JMML).
Patients with isolated CNS3 disease or symptomatic CNS3 disease.
Patients with malabsorption syndrome or any other condition that precludes enteral administration of venetoclax.
Patients who are currently receiving an investigational drug other than those specified for this study (venetoclax and GO are considered investigational in this study).
Patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known congenital bone marrow failure syndrome.
Patients with known prior allergy to any of the medications used in protocol therapy.
Patients with documented active, uncontrolled infection at the time of study entry.
Known hepatitis C virus (HCV), hepatitis B virus (HBV) (known positive hepatitis B virus (HBV) surface antigen (HBsAg) result) or human immunodeficiency virus (HIV) infection. Note: For the countries under EU CTR, these tests are required at screening. For other countries, HCV, HBV, and HIV testing does not need to be conducted at screening unless it is required per local guidelines or local regulations.
Concomitant Medications
- Patients who have received strong and moderate CYP3A inducers such as rifampin, carbamazepine, phenytoin, and St. John’s wort within 7 days of the start of study treatment.
- Patients who have consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or starfruit within 3 days of the start of study treatment.
- Patients who are hypersensitive to the active substance or to any of the excipients listed in SPC.
Pregnancy or Breast-Feeding:
- Patients who are pregnant or breast-feeding.
- Patients of reproductive potential may not participate unless they have agreed to use a highly effective contraceptive method per CTFG guidelines for the duration of study therapy and at least 30 days after last dose of venetoclax, or 7 months after gemtuzumab ozogamicin treatment, or for 6 months after the completion of all study therapy , whichever is longer.
- Male patients must use a condom during intercourse and agree not to father a child or donate sperm during therapy and for the duration of study therapy and at least 30 days after last dose of venetoclax or 4 months after last dose of gemtuzumab ozogamicin, 6 months from the last dose of cytarabine, or 90-days after last exposure to any other chemotherapy, whichever is longer.
Gemtuzumab ozogamicin should not be given:
• to patients with history of veno-occlusive disease (VOD)/Sinusoidal obstruction syndrome (SOS) grade 3 or 4
• to patients with CD33 negative leukemic blasts (determined at local lab)
These patients are eligible for the study but will not be treated with gemtuzumab ozogamicin. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of the study is overall survival (OS). OS is defined as time from randomization until death of any cause. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 28 days, 12 months, 24 months, 36 months, 48 months, 50 months |
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| E.5.2 | Secondary end point(s) |
Morphology and flow-based event-free survival (EFS): days from date of randomization to the first event (subsequent relapse after ped-flow and ped- morph CR, death of any cause, failure to achieve remission (ped-flow and ped-morph CR, CRp or CRi) after 2 cycles of treatment, or secondary malignancy). Patients who are event-free will be censored at date of last adequate disease assessment. Pediatric flow and morphologic treatment failure (defined by morphology and flow as not achieving remission after two cycles in separate analyses) is calculated as an event at day 1.
Flow-based overall response rate (ORR)
Morphological ORR
Duration of response (DOR): Time from documentation of disease response (ped-flow CR/CRp/CRi or ped-morph CR/CRp/CRi) to disease progression or death of disease, whichever occurs earlier
Cumulative incidence of relapse (CIR): estimate of the risk that a patient will develop a relapse during a specified period of time
Non-relapse mortality (NRM): death without recurrent or progression during treatment
Hematopoietic stem cell transplantation (HSCT) Rate: The rate of those proceeding to subsequent hematopoietic stem cell transplantation as consolidation therapy is calculated as the number of patients who receive a hematopoietic stem cell infusion divided by the total number of patients enrolled
Safety
Pharmacokinetics (PK) of venetoclax in blood in combination with intensive chemotherapy and GO
Pediatric MRD (Ped-MRD) negative ped-flow CR/CRp/CRi: CR/CRp/CRi with no detectable residual disease defined as <0.1% leukemic blasts in a cellular BM by central flow cytometry
To compare the morphological International Working Group complete response (IWG-CR) rate in patients receiving FLA+GO with and without venetoclax.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 28 days, 12 months, 24 months, 36 months, 48 months, 50 months |
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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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| Switzerland |
| Australia |
| Canada |
| Israel |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| Czechia |
| Denmark |
| Finland |
| France |
| Ireland |
| Italy |
| Netherlands |
| Norway |
| Portugal |
| Spain |
| Sweden |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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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| Last Subject Last Visit (LVLS) |
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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 | 10 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
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