Acute Myeloid Leukemia, Allogeneic Stem Cell Transplantation
Conditions
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
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.
Interventions
DRUGSiremadlin
Siremadlin was administered at a starting dose of 30 mg/day on days 1-5 of a 28-day treatment cycle (Part 1).
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Study started out a phase l/ll study but because it was terminated, it never made it to phase ll.
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Dose Limiting Toxicities (DLTs) With Siremadlin Monotherapy in Part 1 (Dose Confirmation With Siremadlin Monotherapy) | from cycle 1 day 1 (C1D1) to end of Cycle 1 (cycle = 28days) | To determine the dose and schedule of siremadlin monotherapy that are tolerable without unacceptable toxicities as defined by the incidence of DLT during the first cycle of treatment in part 1. 'A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed, by the Investigator, to be at least possibly related to study treatment (siremadlin monotherapy and/or siremadlin in combination with Donor lymphocyte infusion (DLI)), and as unrelated to disease, disease progression, inter-current illness, or concomitant medications, that occurs during the DLT observation period and meets severity criteria as per protocol. |
| Time to Dose Limiting Toxicity (DLT) With Siremadlin in Combination With Donor Lymphocyte Infusion (DLI), in Part 2 | 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 | To determine the dose and schedule of siremadlin in combination with DLI that are tolerable without unacceptable toxicities (siremadlin recommended dose for combination), defined as time from start of combination phase to first DLT observed during the entire combination phase. |
| 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) | Over 6 months from start of study treatment strategy (part 2 - siremadlin/DLI treatment strategy) | This involves evaluating the preliminary efficacy of siremadlin (as monotherapy, in priming and/or maintenance, with or without siremadlin in combination with DLI) on the prevention of hematologic relapse. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time From Start of Study Treatment to the Date of Death From Any Cause | From start of study treatment to up to 36 months from last patient first treatment | Assessment of Overall survival (OS) in part 2 |
| Incidence of Graft Versus Host Disease (GvHD) | From start of study treatment up to approx. 8 months | Incidence of grade III or IV acute GvHD, and moderate to severe chronic GvHD in part 1. Part 2 never started. |
| Percentage of Participants With Permanent Study Treatment Discontinuation Due to GvHD or Other Adverse Events | From start of study treatment up to approx. 8 months | Percentage of participants with permanent discontinuation of study treatment due to GvHD or other adverse events in part 1. As part 2 was not started, there were no participants to analyze in part 2. |
| 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 | From start of treatment up to approx. 8 months | Assessment of GvHD-free/relapse-free survival (GRPF) in Part 1 and 2. According to the study protocol, time-to-event endpoints in Part 1 were planned to be analyzed using Kaplan-Meier method only for participants who received siremadlin at the recommended dose for Part 2. |
| 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 ) | Over 6 months from start of siremadlin monotherapy (part 1) | This involves evaluating the preliminary efficacy of siremadlin monotherapy at the recommended dose for part 2 on prevention of hematologic relapse |
| PK Characteristic Cmax of Siremadlin | 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] | The maximum (peak) observed plasma drug concentration following drug administration (mass x volume\^-1) in part 1. Part 2 did not open for enrollment due to recruitment halt and so no data was analyzed. |
| PK Characteristic Tmax of Siremadlin | 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] | The time to reach maximum (peak) plasma drug concentration after drug administration (time) in part 1. Part 2 did not open for enrollment due to recruitment halt and so no data was analyzed. |
| PK Characteristic Ctrough of Siremadlin | Cycle 1 Day 1, Cycle 1 Day 5 in part 1; [each cycle is 28 days] | Concentration that is just prior to the beginning of, or at the end of a dosing interval; corresponding to the pre-dose concentration in part 1 and 2. Part 2 never started. |
| Pharmacokinetic (PK) Characteristic AUC of Siremadlin | 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] | AUC is the area under the concentration vs. time curve in part 1 and was based on plasma concentration. Part 2 did not open for enrollment due to recruitment halt and so no data was analyzed. AUClast: The AUC from time zero to the last quantifiable concentration point (Tlast) (mass x time x volume-1). AUC0-t: The area under the concentration vs. time Curve (AUC) from time zero to specified time point. |
| Time From Start of Study Treatment to the Date of First Documented Hematologic Relapse or Death Due to Any Cause, Whichever Occurs First | From start of study treatment to up to 36 months from last patient first treatment | Assessment of relapse free survival (RFS) in part 2 |
| Cumulative Incidence of AML Relapse at 1 Year and 2 Years After Start of Study Treatment | 1 year and 2 years after start of study treatment | Cumulative incidence of Acute Myeloid Leukemia (AML) relapse at one year and 2 years after the start of study treatment in part 1 and 2. Cumulative incidence of relapse (CIR) is defined as the time from start of study treatment to the date of first documented hematologic relapse. CIR was to be analyzed in the FAS population who initiated priming phase at siremadlin recommended dose (RD) in Part 2 and participants at the RD in Part 1. |
Countries
Germany, Italy, Spain
Participant flow
Recruitment details
38 participants were planned to be enrolled; 12 participants in Part 1 and 26 participants in Part 2; however, due to permanent recruitment halt, the enrollment was stopped after the 1st dose escalation meeting. The study was conducted in 6 centers in 3 countries: Germany, Italy and Spain.
Pre-assignment details
Prior to dosing at Cycle 1 Day 1, participants who fulfilled all the inclusion/exclusion criteria were enrolled via IRT and a treatment number was provided for the study treatment siremadlin.
Participants by arm
| Arm | Count |
|---|---|
| Siremadlin (HDM201) 30mg Participants with AML post allogeneic stem cell transplantation (allo-SCT) received 30mg siremadlin monotherapy | 8 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 2 |
| Overall Study | Study terminated by Sponsor | 5 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Siremadlin (HDM201) 30mg |
|---|---|
| Age, Continuous | 52.0 years STANDARD_DEVIATION 17.96 |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 7 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 8 |
| other Total, other adverse events | 8 / 8 |
| serious Total, serious adverse events | 2 / 8 |
Outcome results
Primary
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)
This involves evaluating the preliminary efficacy of siremadlin (as monotherapy, in priming and/or maintenance, with or without siremadlin in combination with DLI) on the prevention of hematologic relapse.
Time frame: Over 6 months from start of study treatment strategy (part 2 - siremadlin/DLI treatment strategy)
Population: Part 2 did not open for enrollment due to recruitment halt, so no data was analyzed hence no data to report.
Primary
Rate of Dose Limiting Toxicities (DLTs) With Siremadlin Monotherapy in Part 1 (Dose Confirmation With Siremadlin Monotherapy)
To determine the dose and schedule of siremadlin monotherapy that are tolerable without unacceptable toxicities as defined by the incidence of DLT during the first cycle of treatment in part 1. 'A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed, by the Investigator, to be at least possibly related to study treatment (siremadlin monotherapy and/or siremadlin in combination with Donor lymphocyte infusion (DLI)), and as unrelated to disease, disease progression, inter-current illness, or concomitant medications, that occurs during the DLT observation period and meets severity criteria as per protocol.
Time frame: from cycle 1 day 1 (C1D1) to end of Cycle 1 (cycle = 28days)
Population: Dose Determining Set (DDS): The Dose Determining Set (DDS) includes participants in the dose determination phase who met specific treatment cycles, exposure criteria, follow-up/DLT observation, and safety evaluations, or experienced a DLT during the observation period. Only the 30 mg siremadlin arm was opened for enrollment, and patients needing dose reduction during Cycle 1 were not analyzed separately.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Siremadlin (HDM201) 30mg | Rate of Dose Limiting Toxicities (DLTs) With Siremadlin Monotherapy in Part 1 (Dose Confirmation With Siremadlin Monotherapy) | 1 Participants |
Primary
Time to Dose Limiting Toxicity (DLT) With Siremadlin in Combination With Donor Lymphocyte Infusion (DLI), in Part 2
To determine the dose and schedule of siremadlin in combination with DLI that are tolerable without unacceptable toxicities (siremadlin recommended dose for combination), defined as time from start of combination phase to first DLT observed during the entire combination phase.
Time frame: 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
Population: Part 2 did not open for enrollment due to recruitment halt, so no data was analyzed hence no data to report.
Secondary
Cumulative Incidence of AML Relapse at 1 Year and 2 Years After Start of Study Treatment
Cumulative incidence of Acute Myeloid Leukemia (AML) relapse at one year and 2 years after the start of study treatment in part 1 and 2. Cumulative incidence of relapse (CIR) is defined as the time from start of study treatment to the date of first documented hematologic relapse. CIR was to be analyzed in the FAS population who initiated priming phase at siremadlin recommended dose (RD) in Part 2 and participants at the RD in Part 1.
Time frame: 1 year and 2 years after start of study treatment
Population: Participants who received siremadlin at the recommended dose (RD) for Part 2 and had available efficacy data at 1 year and 2 years after start of study treatment. The RD for Part 2 could not be determined and there were no patients with efficacy data collected at 1 year and 2 years after start of study treatment. Therefore, there were no patients meeting the reporting criteria for this endpoint.
Secondary
Incidence of Graft Versus Host Disease (GvHD)
Incidence of grade III or IV acute GvHD, and moderate to severe chronic GvHD in part 1. Part 2 never started.
Time frame: From start of study treatment up to approx. 8 months
Population: Safety Set: Safety set includes all participants from the Full Analysis Set (FAS), i.e. all participants who received any study drug (i.e., at least one dose of siremadlin with or without DLI). Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Siremadlin (HDM201) 30mg | Incidence of Graft Versus Host Disease (GvHD) | Grade 3 acute GvHD | 2 Participants |
| Siremadlin (HDM201) 30mg | Incidence of Graft Versus Host Disease (GvHD) | Moderate chronic GvHD | 1 Participants |
Secondary
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 )
This involves evaluating the preliminary efficacy of siremadlin monotherapy at the recommended dose for part 2 on prevention of hematologic relapse
Time frame: Over 6 months from start of siremadlin monotherapy (part 1)
Population: Participants who received siremadlin monotherapy at the recommended dose for Part 2. The recommended dose for Part 2 could not be determined and therefore there were no patients meeting the reporting criteria for this endpoint.
Secondary
Percentage of Participants With Permanent Study Treatment Discontinuation Due to GvHD or Other Adverse Events
Percentage of participants with permanent discontinuation of study treatment due to GvHD or other adverse events in part 1. As part 2 was not started, there were no participants to analyze in part 2.
Time frame: From start of study treatment up to approx. 8 months
Population: Safety Set: Safety set includes all participants from the Full Analysis Set (FAS), i.e. all participants who received any study drug (i.e., at least one dose of siremadlin with or without DLI). Only the siremadlin 30 mg arm was opened for enrollment, and patients requiring any dose reduction throughout the study were not analyzed separately.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Siremadlin (HDM201) 30mg | Percentage of Participants With Permanent Study Treatment Discontinuation Due to GvHD or Other Adverse Events | 3 Participants |
Secondary
Pharmacokinetic (PK) Characteristic AUC of Siremadlin
AUC is the area under the concentration vs. time curve in part 1 and was based on plasma concentration. Part 2 did not open for enrollment due to recruitment halt and so no data was analyzed. AUClast: The AUC from time zero to the last quantifiable concentration point (Tlast) (mass x time x volume-1). AUC0-t: The area under the concentration vs. time Curve (AUC) from time zero to specified time point.
Time frame: 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]
Population: Pharmacokinetic Analysis Set (PAS): PAS includes all participants in the safety set who provide at least one evaluable PK concentration of siremadlin. One participant from the 30mg cohort received a siremadlin reduced dose of 10 mg due to coadministration of a strong CYP3A4 inhibitor as per protocol.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Siremadlin (HDM201) 30mg | Pharmacokinetic (PK) Characteristic AUC of Siremadlin | AUClast: Cycle 1 Day 1 | 1497 hr*ng/mL | — |
| Siremadlin (HDM201) 30mg | Pharmacokinetic (PK) Characteristic AUC of Siremadlin | AUC0-8hr: Cycle 1 Day 1 | 446 hr*ng/mL | — |
| Siremadlin (HDM201) 30mg | Pharmacokinetic (PK) Characteristic AUC of Siremadlin | AUClast: Cycle 1 Day 1 | 3077 hr*ng/mL | Geometric Coefficient of Variation 39.7 |
| Siremadlin (HDM201) 30mg | Pharmacokinetic (PK) Characteristic AUC of Siremadlin | AUC0-8hr: Cycle 1 Day 1 | 1187.1 hr*ng/mL | Geometric Coefficient of Variation 39.8 |
| Siremadlin (HDM201) 30mg | Pharmacokinetic (PK) Characteristic AUC of Siremadlin | AUClast: Cycle 1 Day 5 | 1880.7 hr*ng/mL | Geometric Coefficient of Variation 31.2 |
| Siremadlin (HDM201) 30mg | Pharmacokinetic (PK) Characteristic AUC of Siremadlin | AUC0-8hr: Cycle 1 Day 5 | 1894 hr*ng/mL | Geometric Coefficient of Variation 30.3 |
Secondary
PK Characteristic Cmax of Siremadlin
The maximum (peak) observed plasma drug concentration following drug administration (mass x volume\^-1) in part 1. Part 2 did not open for enrollment due to recruitment halt and so no data was analyzed.
Time frame: 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]
Population: Pharmacokinetics Analysis Set (PAS): PAS includes all participants in the safety set who provide at least one evaluable PK concentration of siremadlin. One participant from the 30mg cohort received a siremadlin reduced dose of 10 mg due to coadministration of a strong CYP3A4 inhibitor as per protocol.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Siremadlin (HDM201) 30mg | PK Characteristic Cmax of Siremadlin | Cycle 1 Day 1 | 73.6 ng/mL | — |
| Siremadlin (HDM201) 30mg | PK Characteristic Cmax of Siremadlin | Cycle 1 Day 1 | 207.68 ng/mL | Geometric Coefficient of Variation 36.2 |
| Siremadlin (HDM201) 30mg | PK Characteristic Cmax of Siremadlin | Cycle 1 Day 5 | 296.92 ng/mL | Geometric Coefficient of Variation 30.4 |
Secondary
PK Characteristic Ctrough of Siremadlin
Concentration that is just prior to the beginning of, or at the end of a dosing interval; corresponding to the pre-dose concentration in part 1 and 2. Part 2 never started.
Time frame: Cycle 1 Day 1, Cycle 1 Day 5 in part 1; [each cycle is 28 days]
Population: Pharmacokinetics Analysis Set (PAS): PAS includes all participants in the safety set who provide at least one evaluable PK concentration of siremadlin. One participant from the 30mg cohort received a siremadlin reduced dose of 10 mg due to coadministration of a strong CYP3A4 inhibitor as per protocol.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Siremadlin (HDM201) 30mg | PK Characteristic Ctrough of Siremadlin | Cycle 1 Day 1 (Pre-dose) | 0 ng/mL | Standard Deviation 0 |
| Siremadlin (HDM201) 30mg | PK Characteristic Ctrough of Siremadlin | Cycle 1 Day 1 (Pre-dose) | 0 ng/mL | Standard Deviation 0 |
| Siremadlin (HDM201) 30mg | PK Characteristic Ctrough of Siremadlin | Cycle 1 Day 5 (Pre-dose) | 146.77 ng/mL | Standard Deviation 79.726 |
Secondary
PK Characteristic Tmax of Siremadlin
The time to reach maximum (peak) plasma drug concentration after drug administration (time) in part 1. Part 2 did not open for enrollment due to recruitment halt and so no data was analyzed.
Time frame: 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]
Population: Pharmacokinetics Analysis Set (PAS): PAS includes all participants in the safety set who provide at least one evaluable PK concentration of siremadlin. One participant from the 30mg cohort received a siremadlin reduced dose of 10 mg due to coadministration of a strong CYP3A4 inhibitor as per protocol.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Siremadlin (HDM201) 30mg | PK Characteristic Tmax of Siremadlin | Cycle 1 Day | 3.00 hour (hr) |
| Siremadlin (HDM201) 30mg | PK Characteristic Tmax of Siremadlin | Cycle 1 Day | 5.95 hour (hr) |
| Siremadlin (HDM201) 30mg | PK Characteristic Tmax of Siremadlin | Cycle 1 Day 5 | 4.50 hour (hr) |
Secondary
Time From Start of Study Treatment to the Date of Death From Any Cause
Assessment of Overall survival (OS) in part 2
Time frame: From start of study treatment to up to 36 months from last patient first treatment
Population: Part 2 did not open for enrollment due to recruitment halt, so no data was analyzed hence no data to report.
Secondary
Time From Start of Study Treatment to the Date of First Documented Hematologic Relapse or Death Due to Any Cause, Whichever Occurs First
Assessment of relapse free survival (RFS) in part 2
Time frame: From start of study treatment to up to 36 months from last patient first treatment
Population: Part 2 did not open for enrollment due to recruitment halt, so no data was analyzed hence no data to report.
Secondary
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
Assessment of GvHD-free/relapse-free survival (GRPF) in Part 1 and 2. According to the study protocol, time-to-event endpoints in Part 1 were planned to be analyzed using Kaplan-Meier method only for participants who received siremadlin at the recommended dose for Part 2.
Time frame: From start of treatment up to approx. 8 months
Population: Participants who received siremadlin monotherapy at the recommended dose for Part 2, and participants enrolled in Part 2. The recommended dose for Part 2 could not be determined and Part 2 was not opened, and therefore there were no patients meeting the reporting criteria for this endpoint.