Clinical trial NCT05447663: A Study of Siremadlin Alone and in Combination With Donor Lymphocyte Infusion in Acute Myeloid Leukemia Post-allogeneic Stem Cell Transplant
Official 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.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Acute Myeloid Leukemia
Allogeneic Stem Cell Transplantation
Keywords: Acute Myeloid Leukemia
Acute myeloid leukemia post allogeneic stem cell transplantation
AML
allogeneic stem cell transplantation
HDM201
siremadlin
donor lymphocyte infusion
DLI
MDM2
p53
allo-SCT
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2022-07-07
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Study started out a phase l/ll study but because it was terminated, it never made it to phase ll.
Primary purpose: TREATMENT

Brief summary: The purpose of this study was 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 Acute Myeloid Leukemia (AML) who were in remission following allogeneic stem cell transplantation (allo-SCT) but were at high risk for relapse based on the presence of pre-transplant risk factors.

Detailed description: This is a Phase Ib/II, single arm, open label, multi-center study of siremadlin as monotherapy and in combination with DLI, in adult participants with AML.

The primary purpose of the study was to confirm the safe dose and schedule of siremadlin monotherapy and in combination with DLI. The study is also designed to assess the preliminary efficacy in preventing hematologic relapse.

The study was initially planned to enroll approximately 38 participants starting with a dose confirmation of siremadlin monotherapy (part 1) to determine the siremadlin recommended dose, followed by a treatment strategy of siremadlin/DLI (Part 2).

After enrolling 8 participants (at the starting dose 30 mg/day on days 1-5 of a 28-day treatment cycle) in part 1, Novartis took the decision to put the enrollment in permanent halt and terminate the siremadlin program. For that reason, the enrollment in part 2 will not be open. The Novartis decision was not driven by any safety concerns.

In part 1 approximately 12 participants were planned to be enrolled in 2 cohorts (starting dose 30 mg/day on days 1-5 of a 28-day treatment cycle, dose level +1 at 40 mg/day and dose level -1 at 20 mg/day) and participants were planned to be treated for a maximum of 24 cycles.

In part 2, participants were planned to follow a treatment strategy, which contains three consecutive phases for a maximum of 24 cycles in total:

* A priming phase with siremadlin monotherapy at the recommended dose determined in Part 1 (for at least 2 cycles). Participants who were not eligible for the combination phase of siremadlin/DLI could continue priming phase with siremadlin monotherapy.
* A combination phase of siremadlin in combination with DLI (siremadlin/DLI) for participants who were eligible to receive DLI (up to a total of 3 combination cycles).
* A maintenance phase with siremadlin monotherapy.

Eligibility criteria: 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)

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

Primary outcomes:
measure: Rate of Dose Limiting Toxicities (DLTs) With Siremadlin Monotherapy in Part 1 (Dose Confirmation With Siremadlin Monotherapy)
timeFrame: from cycle 1 day 1 (C1D1) to end of Cycle 1 (cycle = 28days)
measure: Time to Dose Limiting Toxicity (DLT) With Siremadlin in Combination With Donor Lymphocyte Infusion (DLI), in Part 2
timeFrame: 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
measure: 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 (Part 2)
timeFrame: Over 6 months from start of study treatment strategy (part 2 - siremadlin/DLI treatment strategy)
Secondary outcomes:
measure: Participants Who Are Alive and Maintained CR or CRi With no Evidence of Hematologic Relapse (Part 1 -Siremadlin Monotherapy at the Recommended Dose for Part 2 )
timeFrame: Over 6 months from start of siremadlin monotherapy (part 1)
measure: Time From Start of Study Treatment to the Date of First Documented Hematologic Relapse or Death Due to Any Cause, Whichever Occurs First
timeFrame: From start of study treatment to up to 36 months from last patient first treatment
measure: Cumulative Incidence of AML Relapse at 1 Year and 2 Years After Start of Study Treatment
timeFrame: 1 year and 2 years after start of study treatment
measure: Time From Start of Study Treatment to the Date of Death From Any Cause
timeFrame: From start of study treatment to up to 36 months from last patient first treatment
measure: Incidence of Graft Versus Host Disease (GvHD)
timeFrame: From start of study treatment up to approx. 8 months
measure: Percentage of Participants With Permanent Study Treatment Discontinuation Due to GvHD or Other Adverse Events
timeFrame: From start of study treatment up to approx. 8 months
measure: 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
timeFrame: From start of treatment up to approx. 8 months
measure: Pharmacokinetic (PK) Characteristic AUC of Siremadlin
timeFrame: AUC from time 0 to 8hr postdose, AUC0- 8hr (Cycle 1 Day 1, Cycle 1 Day 5) in part 1 [each cycle is 28 days for monotherapy]
measure: PK Characteristic Cmax of Siremadlin
timeFrame: from 0 to 24 hrs post-dose (Cycle 1 Day 1), from 0 to 8 hr post-dose (Cycle 1 Day 5) in part 1 [each cycle is 28 days for monotherapy]
measure: PK Characteristic Tmax of Siremadlin
timeFrame: from 0 to 24 hrs post-dose (Cycle 1 Day 1), from 0 to 8 hr post-dose (Cycle 1 Day 5) in part 1 [each cycle is 28 days for monotherapy]
measure: PK Characteristic Ctrough of Siremadlin
timeFrame: Cycle 1 Day 1, Cycle 1 Day 5 in part 1; [each cycle is 28 days]
Other outcomes:
Locations:
city: Augsburg
country: Germany
facility: Novartis Investigative Site
city: Freiburg
country: Germany
facility: Novartis Investigative Site
city: Bergamo
country: Italy
facility: Novartis Investigative Site
state: BG
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Valencia
country: Spain
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: