Randomized Phase III Study of Standard Intensive Chemotherapy versus Intensive Chemotherapy with CPX-351 in Adult Patients with Newly Diagnosed AML and Intermediate- or Adverse Genetics

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitaetsklinikum Ulm AöR

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

28 Aug 2019 → ongoing

Decision date (initial)

2024-02-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-503670-21-00

EudraCT number

2018-002678-34

ClinicalTrials.gov

NCT03897127

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

To evaluate the impact of CPX-351 vs standard intensive chemotherapy on overall survival (OS) in the restricted set of de novo patients

Secondary objectives 6

1. To evaluate the impact of CPX-351 vs standard intensive chemotherapy on EFS with CRi considered as response to induction therapy in the restricted set of de novo patients
2. To evaluate the impact of CPX-351 vs standard intensive chemotherapy on overall survival (OS) in the extended set of patients
3. To evaluate the impact of CPX-351 vs standard intensive chemotherapy on event-free survival (EFS) with CRi considered as response to induction therapy in the extended set of patients
4. To evaluate the impact of CPX-351 vs standard intensive chemotherapy on EFS with CRi considered as failure of induction therapy in the restricted set of de novo patients
5. To evaluate the impact of CPX-351 vs standard intensive chemotherapy on response rate (CR or CRi after induction therapy) in the restricted set of de novo patients
6. To evaluate the impact of CPX-351 vs standard intensive chemotherapy on response rate (CR or CRi without measurable residual disease (CRMRD-/CRiMRD-) after induction therapy) in the restricted set of de novo patients

Conditions and MedDRA coding

Patients with newly diagnosed AML and intermediate- or adverse-risk genetics (according to 2017 ELN criteria), including AML with myelodysplasia-related changes (AML-MRC) and therapy-related AML according to the World Health Organization (WHO) classification

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Patients with newly diagnosed AML and intermediate- or adverse-risk genetics (according to 2017 ELN criteria [Appendix B]), including AML with myelodysplasia-related changes (AML-MRC) and therapy-related AML according to the World Health Organization (WHO) classification
2. Age ≥ 18 years, no upper age limit
3. Patient considered eligible for intensive chemotherapy
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 at screening
5. Genetic assessment in AMLSG central laboratory
6. Adequate renal function as evidenced by serum creatinine ≤ 2.0 × ULN or creatinine clearance >40 mL/min based on the Cockcroft-Gault glomerular filtration rate (GFR)
7. Adequate hepatic function as evidenced by: Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN) unless considered due to Gilbert’s disease, or leukemic involvement following approval by the Coordinating Investigator or Co-Coordinating Investigator; Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvement following approval by the Coordinating Investigator or Co-Coordinating Investigator
8. No prior chemotherapy for acute leukemia except hydroxyurea for up to 14 days during the diagnostic screening phase for the control of peripheral leukemic blasts in patients with leukocytosis (e.g., white blood cell [WBC] counts >30x10^9/l); prior treatment of myelo-dysplastic syndrome with hypomethylating agents is allowed
9. Non-pregnant and non-nursing women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within a sensitivity of at least 25 mIU/mL within 72 hours prior to randomization (“Women of childbearing potential” is defined as a sexually active mature woman who has not undergone a hysterectomy or bilateral oophorectomy or who has had menses at any time in the preceding 24 consecutive months)
10. Female patients of childbearing potential must agree to avoid getting pregnant while on therapy and for 27 weeks after the last dose of study drug
11. Women of childbearing potential must either commit to continued abstinence from heterosexual intercourse or apply one highly effective method of birth control (such as IUD, bilateral tubal ligation, or partner’s vasectomy) in combination with one acceptable method of birth control at the same time (such as hormonal contraception or the male partner has to use a latex condom coated with spermicide lubricant or combined with spermicide gel or foam) while on therapy and for 27 weeks after the last dose of study drug. Hormonal contraception is only a highly effective method of birth control in case of combined (estrogen and progestogen containing) associated with inhibition of ovulation or progestogen-only hormonal contraception associated with inhibition of ovulation is used
12. Men must use a latex condom coated with a spermicide lubricant or combined with spermicide gel or foam during any sexual contact with women of childbearing potential, even if they have undergone a successful vasectomy and must agree to avoid to father a child (while on therapy and for 6 months after the last dose of study drug). In addition, their female partners of childbearing potential have to use a highly effective method of birth control
13. Able to understand and willing to sign an informed consent form (ICF)

Exclusion criteria 19

1. AML with favorable-risk genetics according to 2017 ELN criteria [Appendix B]: - AML with t(8;21)(q22;q22.1), RUNX1-RUNX1T1; - AML with inv(16)(p13.1q22)/t(16;16)(p13.1;q22), CBFB-MYH11; - AML with mutated NPM1 without FLT3-ITD or with FLT3-ITDlow; - AML with biallelic CEBPA mutation
2. AML with FLT3 mutation as assessed by DNA fragment analysis PCR for FLT3-ITD and FLT3-TKD mutation. Positivity is defined as a FLT3-ITD or FLT3-TKD / FLT3-WT ratio of ≥ 0.05 (5%).
3. Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12); PML-RARA; or one of the other pathognomonic variant chromosomal translocations/ fusion genes
4. AML with BCR-ABL1
5. Prior treatment of myelodysplastic syndrome (MDS) with intensive chemotherapy or bone marrow transplant with a curative intent
6. Significant active cardiac disease within 6 months prior to the start of study treatment, including New York Heart Association (NYHA) class III or IV congestive heart failure; myocardial infarction, unstable angina and/or stroke; severe cardiac arrhythmias, or left ventricular ejection fraction (LVEF) <50% by ultrasound obtained within 28 days prior to the start of study treatment
7. Severe obstructive or restrictive ventilation disorder
8. Uncontrolled infection
9. Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required, if there is a clinical suspicion of CNS involvement by leukemia during screening
10. Evidence of active hepatitis B or C infection or known Human Immunodeficiency Virus (HIV) infection
11. Patients with a “currently active” second malignancy. Patients are not considered to have a currently active malignancy, if they have completed therapy and are considered by their physician to be at < 30% risk of relapse within one year. However, subjects with the following history/concurrent conditions are allowed: - Basal or squamous cell carcinoma of the skin; - Carcinoma in situ of the cervix; - Carcinoma in situ of the breast, - Incidental histologic finding of prostate cancer
12. Severe neurological or psychiatric disorder interfering with ability to give an informed consent
13. No consent for registration, storage and processing of the individual disease characteristics and course as well as information of the family physician about study participation
14. No consent for biobanking of patient’s biological specimens
15. Current participation in any other interventional clinical trial within 30 days before the first administration of the investigational product or at any time during the trial
16. Patients with prior cumulative anthracycline exposure of daunorubicin (or equivalent) can be included but the maximum of daunorubicin (or equivalent) dose of 550 mg/m2 must not be exceeded. Anthracycline-based therapy should be avoided until exposure to the previous cardiotoxic agents is negligible. If this is not possible, the patient's cardiac function should be carefully monitored and an absolute cumulative dose of 400 mg/m² in adults can be exceeded only with great caution. In patients who received radiation therapy to the mediastinum the maximum of daunorubicin (or equivalent) dose of 400 mg/m2 must not be exceeded.
17. Known or suspected hypersensitivity to cytarabine, daunorubicin or liposomal products and/or any excipients
18. History of Wilson’s disease or other copper-metabolism disorder
19. Receipt of live, attenuated vaccine within 30 days prior to the inclusion in the clinical trial (NOTE: Subjects, if enrolled, should not receive live vaccine during the trial and until 6 months after the therapy).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Overall survival (OS) in the restricted set of de novo patients

Secondary endpoints 4

1. Overall survival (OS) in the extended set of patients
2. Event-free survival (EFS) with CRi considered as response to induction therapy in both, the restricted set of de novo patients and the extended set of patients
3. Event-free survival (EFS) with CRi considered as failure of induction therapy in the restricted set of de novo patients
4. Rate of objective responses (complete remission [CR], CR with incomplete hematologic recovery [CRi], CRi without measurable residual disease [CRiMRD-], CR without measurable residual disease [CRMRD-]) in the restricted set of de novo patients

Investigational products

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

Test 1

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitaetsklinikum Ulm AöR

Sponsor organisation

Universitaetsklinikum Ulm AöR

Address

Albert-Einstein-Allee 29, Eselsberg Eselsberg

City

Ulm

Postcode

89081

Country

Germany

Scientific contact point

Organisation

Universitaetsklinikum Ulm AöR

Contact name

Verena Gaidzik

Public contact point

Organisation

Universitaetsklinikum Ulm AöR

Contact name

Verena Gaidzik

Third parties 8

Locations

2 EU/EEA countries · 63 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 18 files

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

Application history

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