Venetoclax in children with relapsed AML

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Prinses Maxima Centrum voor Kinderoncologie B.V.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

16 Aug 2022 → ongoing

Decision date (initial)

2024-07-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Leukemia & Lymphoma Society, Princess Máxima Center, AbbVie, Roche/Genentech

External identifiers

EU CT number

2023-510160-12-00

EudraCT number

2021-003212-11

ClinicalTrials.gov

NCT05183035

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Pharmacokinetic, Efficacy, Pharmacodynamic

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.

Conditions and MedDRA coding

acute myeloid leukemia

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-002018-PIP02-16

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. 1. 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.
2. 2. Patients must have a performance status corresponding to ECOG scores of 0, 1 or 2 (≥ 50% Lansky or Karnofsky score)
3. 3. 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).
4. 4. 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.
5. 5. Antibodies: ≥ 21 days must have elapsed from infusion of last dose of an antibody-drug conjugate prior to start of protocol treatment.
6. 6. Interleukins, Interferons and Cytokines : ≥ 21 days after the completion of interleukins, interferon or cytokines.
7. 7. 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.
8. 8. Radiation therapy (RT): Between 14 and 84 days depeding on the extent of radiation fields.
9. 9. Stem Cell Infusions: ≥ 84 days since allogeneic bone marrow or stem cell transplant or boost infusion. No evidence of active graft versus host disease.
10. 10. 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.
11. 11. Cellular Therapy: ≥ 42 days after the completion of any type of cellular therapy.
12. 12. 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 o if higher transaminases outside these ranges (up to 5x ULN) are due to a radiographically identifiable leukemia infiltrate, the patient will remain eligible. Transaminase elevation up to 5x ULN is also allowed in case of steatosis on echography. 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
13. 13. 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.

Exclusion criteria 13

1. 1. Patients who in the opinion of the investigator may not be able to comply with the study requirements of the study, are not eligible.
2. 2. Patients with Down syndrome.
3. 3. Patients with Acute promyelocytic leukemia (APL) or Juvenile myelomonocytic leukemia (JMML).
4. 4. Patients with isolated CNS3 disease or symptomatic CNS3 disease.
5. 5. Patients with malabsorption syndrome or any other condition that precludes enteral administration of venetoclax.
6. 6. 1.6 Patients who are currently receiving an investigational drug other than those specified for this study (Venetoclax, Fludarabine, Cytarabine, GO and Azacitidine are considered investigational in this study in the countries under EU CTR. For other countries not under EU CTR, please refer to section 9).
7. 7. Patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known congenital bone marrow failure syndrome.
8. 8. Patients with known prior allergy to any of the medications used in protocol therapy.
9. 9. Patients with documented active, uncontrolled infection at the time of study entry.
10. 10. 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 not under EU CTR, HCV, HBV, and HIV testing does not need to be conducted at screening unless it is required per local guidelines or local regulations.
11. 11. 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.
12. 12. 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.
13. 13. Gemtuzumab ozogamicin should not be given: - to patients with history of veno-occlusive disease (VOD/SOS)/ 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint of the study is overall survival (OS). OS is defined as time from randomization until death of any cause.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 12

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Prinses Maxima Centrum voor Kinderoncologie B.V.

Sponsor organisation

Prinses Maxima Centrum voor Kinderoncologie B.V.

Address

Heidelberglaan 25

City

Utrecht

Postcode

3584 CS

Country

Netherlands

Scientific contact point

Organisation

Prinses Maxima Centrum voor Kinderoncologie B.V.

Contact name

Princess Máxima Center for Pediatric Oncology

Public contact point

Organisation

Prinses Maxima Centrum voor Kinderoncologie B.V.

Contact name

Princess Máxima Center for Pediatric Oncology

Third parties 10

Locations

14 EU/EEA countries · 29 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 189 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications