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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT05155709




Registration number
NCT05155709
Ethics application status
Date submitted
20/10/2021
Date registered
14/12/2021
Date last updated
13/09/2023

Titles & IDs
Public title
A Study of Siremadlin in Combination With Venetoclax Plus Azacitidine in Adult Participants With Acute Myeloid Leukemia (AML) Who Are Ineligible for Chemotherapy.
Scientific title
A Phase Ib/II Open Label Dose Confirmation, Proof of Concept Study of Siremadlin in Combination With Venetoclax Plus Azacitidine in Unfit Adult AML Participants Who Responded Sub-optimally to First-line Venetoclax Plus Azacitidine Treatment and in Participants With Newly Diagnosed Unfit AML Presenting With High-risk Clinical Features
Secondary ID [1] 0 0
2021-001165-21
Secondary ID [2] 0 0
CHDM201I12201
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukemia 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - siremadlin
Treatment: Drugs - venetoclax
Treatment: Drugs - azacitidine

Experimental: Arm 1: Unfit adult participants with AML who responded sub-optimally to standard of care - Unfit adult participants with AML who responded sub-optimally to at least 2 and not more than 4 cycles ( 1 cycle=28 days) of first-line venetoclax plus azacitidine therapy

Experimental: Arm 2: Newly diagnosed unfit adult participants with high-risk AML - Unfit adult participants with newly diagnosed AML and with adverse genetic risk stratification (according to ELN 2022)(Except TP53 mutation positive participants).


Treatment: Drugs: siremadlin
Siremadlin is a capsule taken orally once a day (QD) and comes in 10 mg, 20 mg and 30 mg strengths

Treatment: Drugs: venetoclax
Venetoclax is a tablet taken orally once a day (QD) and comes in 10 mg, 50 mg and 100 mg strengths.

Treatment: Drugs: azacitidine
Azacitidine is a powder for suspension for injection or powder for solution for infusion taken intravenously or subcutaneously according to standard local clinical practice
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Percentage of participants with Dose Limiting Toxicities (DLTs) as per investigator assessment reported during the first cycle (separately in Arm 1 & Arm 2)
Timepoint [1] 0 0
From Cycle 1 Day 1 to Cycle 1 Day 28 (28 days)
Primary outcome [2] 0 0
Percentage of participants treated at the recommended dose for expansion, achieving a complete remission (CR) as per investigator assessment (Arm 1 only)
Timepoint [2] 0 0
At least 7 cycles (196 days)
Secondary outcome [1] 0 0
Percentage of participants treated at the recommended dose for expansion, achieving CR as per investigator assessment (Arm 2 only; for Arm 1 assessment of CR is a primary outcome measure))
Timepoint [1] 0 0
up to 3 years
Secondary outcome [2] 0 0
Time of the date of the first documented CR to the date of the first documented relapse or death due to any cause, whichever occurs first (Arm 1 and Arm 2)
Timepoint [2] 0 0
up to 3 years
Secondary outcome [3] 0 0
Percentage of participants achieving CR or complete remission with partial hematological recovery (CRh) and percentage of participants achieving CR or complete remission with incomplete hematological recovery (CRi) (Arm 1 and Arm 2)
Timepoint [3] 0 0
up to 3 years
Secondary outcome [4] 0 0
Time from the date of the first documented CR/CRh and CR/CRi to the date of first documented relapse or death due to any cause, whichever occurs first (Arm 1 and Arm 2)
Timepoint [4] 0 0
up to 3 years
Secondary outcome [5] 0 0
The time from start of treatment to death due to any cause (Arm 1 and Arm 2)
Timepoint [5] 0 0
up to 3 years
Secondary outcome [6] 0 0
Percentage of participants died due to any cause from start of treatment until 30- and 60-day (Arm 1 and Arm 2)
Timepoint [6] 0 0
30 days & 60 days from start of study treatment
Secondary outcome [7] 0 0
Pharmacokinetic (PK) parameters: AUCs of siremadlin, venetoclax and azacitidine (Arm 1 and Arm 2)
Timepoint [7] 0 0
up to 3 years
Secondary outcome [8] 0 0
PK parameter: Cmax of siremadlin, venetoclax and azacitidine (Arm 1 and Arm 2)
Timepoint [8] 0 0
up to 3 years
Secondary outcome [9] 0 0
PK parameter: Tmax of siremadlin, venetoclax and azacitidine (Arm 1 and Arm 2)
Timepoint [9] 0 0
up to 3 years
Secondary outcome [10] 0 0
Percentage of CR- Measurable Residual Disease (MRD) negative overall and in participants achieving a CR, CR/CRh, and CR/CRi (Arm 1 and Arm 2)
Timepoint [10] 0 0
up to 3 years

Eligibility
Key inclusion criteria
- Age at the date of signing the informed consent form (ICF): Arm 1 and Arm 2: = 18 years

- Participants diagnosed with AML based on WHO 2016 classification (Arber et al 2016) who
are ineligible for standard induction chemotherapy and: Arm 1 : have received at least 2
cycles and not more than 4 cycles of first-line venetoclax plus azacitidine treatment and
have not achieved a CR, CRi, CRh or MLFS.

Arm 2 : newly diagnosed AML with adverse genetic risk stratification (according to ELN
2022) (except TP53 mutation positive participants).

- Participant must be considered ineligible for standard of care intensive induction
chemotherapy defined by the following:

- 75 years of age; OR

- 18 to 74 years of age with at least one of the following co-morbidities: Eastern
Cooperative Oncology Group (ECOG) Performance Status of 2 or 3; Cardiac history
of congestive heart failure (CHF) requiring treatment or Ejection Fraction = 50%
or chronic stable angina; DLCO = 65% or FEV1 = 65%.

- Participants must have an ECOG performance status:

0 to 2 for participants = 75 years of age. OR 0 to 3 for participants = 18 to 74 years
of age.

- WBC < 25x109/L

- AST and ALT = 3 × ULN

- Estimated Glomerular Filtration Rate (eGFR)= 60 mL/min/1.73 m2
Minimum age
18 Years
Maximum age
99 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Prior exposure to MDM2-inhibitor therapy at any time.

- Participants with TP53 mutation positive.

- Participants with del17p.

- Participants with AML-M3 / APL (Acute promyelocytic leukemia) with PML-RARA
(Promyelocytic leukemia/retinoic acid receptor alpha) or with AML secondary to Down's
syndrome.

- Participants treated with FLT3 inhibitors

- Participants who require treatment with moderate or strong CYP3A4 inducers within 14
days prior to starting study treatment, or are expected to receive moderate or strong
CYP3A4 inducers during the entire study

- Participants who require treatment with substrates of CYP3A4/5 with a narrow
therapeutic index.

Other protocol-defined inclusion/exclusion criteria may apply at the end

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1/Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
17/05/2022
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
13/11/2026
Actual
Sample size
Target
56
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 0 0
Novartis Investigative Site - Perth
Recruitment postcode(s) [1] 0 0
6000 - Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Colorado
Country [3] 0 0
United States of America
State/province [3] 0 0
Massachusetts
Country [4] 0 0
United States of America
State/province [4] 0 0
New York
Country [5] 0 0
United States of America
State/province [5] 0 0
Ohio
Country [6] 0 0
United States of America
State/province [6] 0 0
Oregon
Country [7] 0 0
United States of America
State/province [7] 0 0
Pennsylvania
Country [8] 0 0
United States of America
State/province [8] 0 0
Texas
Country [9] 0 0
United States of America
State/province [9] 0 0
Virginia
Country [10] 0 0
United States of America
State/province [10] 0 0
Wisconsin
Country [11] 0 0
Hong Kong
State/province [11] 0 0
Hong Kong
Country [12] 0 0
Hungary
State/province [12] 0 0
Budapest
Country [13] 0 0
Israel
State/province [13] 0 0
Beer-Sheva
Country [14] 0 0
Israel
State/province [14] 0 0
Jerusalem
Country [15] 0 0
Italy
State/province [15] 0 0
BO
Country [16] 0 0
Italy
State/province [16] 0 0
BR
Country [17] 0 0
Italy
State/province [17] 0 0
MI
Country [18] 0 0
Malaysia
State/province [18] 0 0
Kedah
Country [19] 0 0
Malaysia
State/province [19] 0 0
Kuala Lumpur
Country [20] 0 0
Malaysia
State/province [20] 0 0
Selangor
Country [21] 0 0
Spain
State/province [21] 0 0
Catalunya
Country [22] 0 0
Spain
State/province [22] 0 0
Comunidad Valenciana
Country [23] 0 0
Switzerland
State/province [23] 0 0
Bern
Country [24] 0 0
Switzerland
State/province [24] 0 0
Lausanne
Country [25] 0 0
Turkey
State/province [25] 0 0
Yenimahalle
Country [26] 0 0
Turkey
State/province [26] 0 0
Izmir

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
A study of siremadlin in combination with venetoclax plus azacitidine in adult participants
with AML who are ineligible for chemotherapy.
Trial website
https://clinicaltrials.gov/ct2/show/NCT05155709
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Country 0 0
Phone 0 0
1-888-669-6682
Fax 0 0
Email 0 0
novartis.email@novartis.com
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT05155709