Trial Review

Technical difficulties have been reported by some users of the search function and is being investigated by technical staff. Thank you for your patience and apologies for any inconvenience caused.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT05447663




Registration number
NCT05447663
Ethics application status
Date submitted
28/06/2022
Date registered
7/07/2022
Date last updated
20/12/2023

Titles & IDs
Public title
A Study of Siremadlin Alone and in Combination With Donor Lymphocyte Infusion in Acute Myeloid Leukemia Post-allogeneic Stem Cell Transplant
Scientific title
A Phase Ib/II, Open Label Study of Siremadlin Monotherapy and in Combination With Donor Lymphocyte Infusion as a Treatment for Patients With Acute Myeloid Leukemia Post-allogeneic Stem Cell Transplantation Who Are in Complete Remission But at High Risk for Relapse.
Secondary ID [1] 0 0
2021-003596-34
Secondary ID [2] 0 0
CHDM201K12201
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukemia 0 0
Allogeneic Stem Cell Transplantation 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

Experimental: Siremadlin (HDM201) - Participants with AML post allogeneic stem cell transplantation (allo-SCT) will receive siremadlin monotherapy in part 1 and siremadlin monotherapy as well as in combination with donor lymphocyte infusion in part 2


Treatment: Drugs: Siremadlin
30-40 mg QD siremadlin capsules, orally (1-5 days of 28 or 42 days cycle)
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Incidence of Dose Limiting Toxicities (DLTs) with siremadlin monotherapy in part 1 (dose confirmation with siremadlin monotherapy)
Timepoint [1] 0 0
28 days
Primary outcome [2] 0 0
Time to Dose Limiting Toxicity (DLT) with siremadlin in combination with Donor Lymphocyte Infusion (DLI), in part 2
Timepoint [2] 0 0
From Day 1 of combination Cycle 1 to Day 42 of the last cycle of combination phase (up to 3 cycles of siremadlin/DLI combination). Cycle duration: 42 days
Primary outcome [3] 0 0
Percentage of participants who are alive and maintained complete remission (CR) or complete response with incomplete hematological recovery (CRi) with no evidence of hematologic relapse
Timepoint [3] 0 0
Over 6 months from start of study treatment strategy (part 2 - siremadlin/DLI treatment strategy)
Secondary outcome [1] 0 0
Participants who are alive and maintained CR or CRi with no evidence of hematologic relapse
Timepoint [1] 0 0
Over 6 months from start of siremadlin monotherapy (part 1)
Secondary outcome [2] 0 0
Time from start of study treatment to the date of first documented hematologic relapse or death due to any cause, whichever occurs first
Timepoint [2] 0 0
From start of study treatment to up to 36 months from last patient first treatment
Secondary outcome [3] 0 0
Cumulative incidence of AML relapse
Timepoint [3] 0 0
at 1 year and at 2 years after start of study treatment
Secondary outcome [4] 0 0
Time from start of study treatment to the date of death from any cause
Timepoint [4] 0 0
From start of study treatment to up to 36 months from last patient first treatment
Secondary outcome [5] 0 0
Incidence of Graft versus Host Disease (GvHD)
Timepoint [5] 0 0
From start of study treatment to up to 24 months from last patient first treatment
Secondary outcome [6] 0 0
Percentage of participants with permanent study treatment discontinuation due to GvHD or other adverse events
Timepoint [6] 0 0
From start of study treatment to up to 24 months from last patient first treatment
Secondary outcome [7] 0 0
Time from start of study treatment to the date of first documented occurrence or worsening of treatment emergent grade III or IV acute GvHD, or chronic GvHD requiring initiation of systemic immunosuppressive treatment
Timepoint [7] 0 0
From start of treatment to up to 36 months from last patient first treatment
Secondary outcome [8] 0 0
Pharmacokinetic (PK) characteristic AUC of siremadlin
Timepoint [8] 0 0
From Cycle 1 Day 1 to Cycle 24 Day 1 in part 1 or from Cycle 1 Day 1 safety confirmation to Cycle 21 Day 1 maintenance in part 2; [each cycle is 28 days for monotherapy, and 42 days for combination]
Secondary outcome [9] 0 0
PK characteristic Cmax of siremadlin
Timepoint [9] 0 0
From Cycle 1 Day 1 to Cycle 24 Day 1 in part 1 or from Cycle 1 Day 1 safety confirmation to Cycle 21 Day 1 maintenance in part 2; [each cycle is 28 days for monotherapy, and 42 days for combination]
Secondary outcome [10] 0 0
PK characteristic Tmax of siremadlin
Timepoint [10] 0 0
From Cycle 1 Day 1 to Cycle 24 Day 1 in part 1 or from Cycle 1 Day 1 safety confirmation to Cycle 21 Day 1 maintenance in part 2; [each cycle is 28 days for monotherapy, and 42 days for combination]
Secondary outcome [11] 0 0
PK characteristic Ctrough of siremadlin
Timepoint [11] 0 0
From Cycle 1 Day 1 to Cycle 24 Day 1 in part 1 or from Cycle 1 Day 1 safety confirmation to Cycle 21 Day 1 maintenance in part 2; [each cycle is 28 days for monotherapy, and 42 days for combination]

Eligibility
Key inclusion criteria
- Participants with AML diagnosis, who underwent one allo-SCT to treat AML and are
currently at = Day 60 but no later than Day 120 (= Day 120) post allo-SCT.

- Pre-allo-SCT - Participants must have any of the following risk factors that put them
at high risk for relapse:

• AML in first CR (CR1) prior to allo-SCT with one of the following:

- Adverse risk genetic abnormalities per 2017 ELN risk stratification. Patients with
TP53 mutant AML at diagnosis are eligible if they meet eligibility criteria.

- Therapy-related AML (t-AML).

- Secondary AML (sAML) [AML secondary to antecedent myelodysplastic syndrome (MDS) or
AML secondary to myeloproliferative neoplasm (MPN)].

• AML in second or greater CR (=CR2) prior to allo-SCT.

- Allo-SCT must have the following characteristics:

- Unmanipulated/T cell-replete bone marrow or peripheral blood stem cells as a
graft source.

- Matched related (family) donor (MFD) or matched unrelated donor (MUD): Human
Leukocyte Antigen (HLA) matching of donor and recipient should be at a minimum of
8/8 antigen or allele matched at HLA-A, -B, -C, -DRB1 loci.

- Any conditioning regimen intensity is permitted, the use of anti-thymocyte
globulin (ATG) or alemtuzumab or post-transplant cyclophosphamide as a part of
conditioning is allowed.

- Donor lymphocytes are collected, cryopreserved and available for infusion (DLI), or
obtaining donor lymphocytes for DLI is feasible (applicable only for part 2)

- Post-allo-SCT, participants must have achieved CR or CRi with no current evidence of
hematologic relapse

- Eastern Cooperative Oncology Group (ECOG ) performance status 0, 1 or 2.

- Laboratory test results indicating adequate liver and kidney function laboratory test
results

- Evidence of adequate engraftment: Absolute Neutrophil Count (ANC) = 1.0x109/L,
Platelets (PLT) = 75x109/L, Hemoglobin (Hgb) = 8 g/dL (within 14 days prior to start
of study treatment)
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria:

- Prior exposure to MDM-inhibitor

- Active acute GvHD (aGvHD) of any grade (per Harris et al 2016) and/or active chronic
GvHD (cGvHD ) of any grade (per NIH criteria (Jagasia et al 2015)) requiring systemic
therapy at time of study treatment initiation

- Past history of grade III or IV aGvHD and/or past history of moderate or severe cGvHD.
History of lower grades of GvHD is permitted if GvHD resolved to grade 0 for at least
4 weeks prior to start of study treatment.

- Recipient of allo-SCT from MUD with =1 antigen or allele mismatch at HLA-A, -B, -C,
-DRB1 locus (HLA matching < 8/8 antigens)

- Recipient of allo-SCT from a haploidentical family donor; and recipients of cord blood
transplant as a graft source

- Prior systemic AML-directed treatments given at any time after allo-SCT (including
DLI)

- Prior systemic cancer-directed treatments or investigational modalities = 5 half-lives
or 4 weeks prior to starting study, whichever is longer

- GI disorders that may prevent the intake and absorption of oral siremadlin (eg,
diarrhea, uncontrolled nausea/vomiting, GI bleeding, etc).

- Any concurrent severe and/or active uncontrolled bacterial, viral or fungal infection
requiring parenteral antibacterial, antiviral or antifungal therapy. Prophylactic
antimicrobial use (oral or parenteral) is allowed.

- Participants who require treatment with moderate or strong CYP3A inducers within 14
days prior to starting study treatment, or are expected to receive moderate or strong
CYP3A inducers during the entire study

- Cardiac or cardiac repolarization abnormality, that are clinically significant

Other protocol defined inclusion/exclusion criteria may apply.

Study design
Purpose of the study
Treatment
Allocation to intervention
N/A
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
23/02/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
11/01/2028
Actual
Sample size
Target
38
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 0 0
Novartis Investigative Site - Murdoch
Recruitment postcode(s) [1] 0 0
6150 - Murdoch
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
Florida
Country [3] 0 0
United States of America
State/province [3] 0 0
Ohio
Country [4] 0 0
Germany
State/province [4] 0 0
Augsburg
Country [5] 0 0
Germany
State/province [5] 0 0
Freiburg
Country [6] 0 0
Israel
State/province [6] 0 0
Haifa
Country [7] 0 0
Israel
State/province [7] 0 0
Tel Aviv
Country [8] 0 0
Italy
State/province [8] 0 0
BG
Country [9] 0 0
Italy
State/province [9] 0 0
BO
Country [10] 0 0
Spain
State/province [10] 0 0
Andalucia
Country [11] 0 0
Spain
State/province [11] 0 0
Valencia
Country [12] 0 0
United Kingdom
State/province [12] 0 0
Cardiff

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

Ethics approval
Ethics application status

Summary
Brief summary
The purpose of this study is to confirm a safe dose and schedule as well as the preliminary
efficacy of siremadlin alone, and in combination with donor lymphocyte infusion (DLI), in
adult participants with AML who are in remission following allogeneic stem cell
transplantation (allo-SCT) but are at high risk for relapse based on the presence of
pre-transplant risk factors.
Trial website
https://clinicaltrials.gov/ct2/show/NCT05447663
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/NCT05447663