Pharmacokinetics and Safety Study of Siremadlin (HDM201) in Participants With Mild, Moderate and Severe Hepatic Impairment

NCT05599932 | Completed Phase 1 FDA Drug

• 1 other identifier: CHDM201X2105
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 3

Brief Summary

The main purpose of this study is to evaluate the effect of varying degrees of impaired hepatic function (by Child Pugh classification) on the plasma PK of siremadlin after a single oral dose. In addition, safety and tolerability of siremadlin after a single oral dose will be evaluated. The results of this study will inform the decision whether a dose adjustment may be recommended when treating patients with various degrees of impaired hepatic function.

Conditions

Hepatic Impairment

Keywords

Hepatic Impairment; Solids tumors; Hematological malignancies; Child-Pugh classification; HDM201; Siremadlin

Outcome Measures

Primary Outcomes (10)

• Pharmacokinetics (PK): Cmax

  Maximum Observed Blood Concentrations (Cmax) for siremadlin. Blood samples will be collected to measure Cmax at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.

  pre-dose, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, and 144 hours

• Pharmacokinetics (PK): AUClast

  Area Under Plasma Concentration-time Curve from time zero to the last measurable concentration sampling time (AUClast) for siremadlin. Blood samples will be collected to measure AUClast at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.

  pre-dose, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, and 144 hours

• Pharmacokinetics (PK): AUC0-t

  Area Under Plasma Concentration from time zero to time "t" (AUC0-t). The definition of "t" may be data driven post-hoc to mitigate bias in the exposure comparision due to between-group differences in Tlast for siremadlin. Blood samples will be collected to measure AUC0-t at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.

  pre-dose, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, and 144 hours

• Pharmacokinetics (PK): AUC0-24h

  Area Under Plasma Concentration from time zero to 24-hour post-dose sampling time (AUC0-24h) for siremadlin. Blood samples will be collected to measure AUC0-24h at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.

  pre-dose, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, and 144 hours

• Pharmacokinetics (PK): Tlast

  Last measurable plasma concentration (Tlast) for siremadlin. Blood samples will be collected to measure Tlast at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.

  pre-dose, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, and 144 hours

• Pharmacokinetics (PK): Tmax

  Time to Reach Maximum Blood Concentrations (Tmax) for siremadlin. Blood samples will be collected to measure Tmax at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.

  pre-dose, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, and 144 hours

• Pharmacokinetics (PK): CL/F

  Apparent total body clearance of siremadlin from plasma (CL/F). Blood samples will be collected to measure CL/F at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.

  pre-dose, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, and 144 hours

• Pharmacokinetics (PK): Vz/F

  Apparent volume of distribution during terminal elimination phase (Vz/F) of siremadlin. Blood samples will be collected to estimate Vz/F at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.

  pre-dose, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, and 144 hours

• Pharmacokinetics (PK): T1/2

  Terminal Elimination Half-life (T1/2) for siremadlin. Blood samples will be collected to measure T1/2 at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.

  pre-dose, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, and 144 hours

• Pharmacokinetics (PK): AUCinf

  Area Under Plasma Concentration from time zero to infinity (AUCinf). Blood samples will be collected to measure AUCinf at indicated timepoints. Pharmacokinetic (PK) parameters will be calculated based on siremadlin blood concentrations.

  pre-dose, 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, and 144 hours

Study Arms (4)

Group 1: Healthy Control

EXPERIMENTAL

Each healthy participant will receive a single dose of HDM201

Drug: Siremadlin

Group 2: Mild; Child-Pugh A

EXPERIMENTAL

Each participant with mild Child-Pugh will receive a single dose of HDM201

Drug: Siremadlin

Group 3: Moderate; Child-Pugh B

EXPERIMENTAL

Each participant with moderate Child-Pugh will receive a single dose of HDM201

Drug: Siremadlin

Group 4: Severe; Child-Pugh C

EXPERIMENTAL

Each participant with severe Child-Pugh will receive a single dose of HDM201

Drug: Siremadlin

Interventions

Siremadlin DRUG

HDM201 capsule

Also known as: HDM201

Group 1: Healthy Control; Group 2: Mild; Child-Pugh A; Group 3: Moderate; Child-Pugh B; Group 4: Severe; Child-Pugh C

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All participants:
• Male and non-child-bearing potential females between 18 and 75 years of age, inclusive, at Screening.
• Participant must have been a non-smoker or moderate smoker (up to 10 cigarettes or equivalent nicotine containing products per day) at Screening. Participant must have agreed to maintain the same smoking status (i.e., smoker or non-smoker) from Screening until after Study Completion evaluations.
• Participants must have weighed at least 50.0 kg and must have had a BMI within the range of 18.0 to 38.0 kg/m2, inclusive at Screening.
• Participants with no clinically significant abnormalities as determined by past medical history, physical examination, ECG and clinical laboratory test at Screening.
• Participants must have weighed at least 50.0 kg and must have had a BMI within the range of 18.0 to 38.0 kg/m2, inclusive at Screening. For participants without overt ascites, the BMI must have been within the range of 18.0 to 40.0 kg/m2, inclusive. For participants with overt ascites, the BMI must have been within the range of 18.0 to 45.0 kg/m2, inclusive.
• Participant must have satisfied the criteria for HI as evidenced by a Child-Pugh class of A, B, or C at Screening and Baseline (see Table 8-2 Child-Pugh classification criteria):
• Group 2: Class A; Mild; Child-Pugh score 5-6, inclusive
• Group 3: Class B; Moderate; Child-Pugh score 7-9, inclusive
• Group 4: Class C; Severe; Child-Pugh score 10-15, inclusive. If the results of the assessments at Screening and Baseline indicated different Child-Pugh class, a third assessment must have been conducted. If the results of the 2 most recent assessments (the second and third) were in agreement with regard to the participant's Child-Pugh class, the participant may have been enrolled at the Child-Pugh class determined by the most recent assessment. If the second and third measurements differ, the participant would not be eligible for the study on the basis that their liver function was not stable.
• Participants with impaired hepatic function and other stable medical disorders such as diabetes, hypertension, hyperlipidemia, hypothyroidism etc., may have been eligible, as long as they were considered appropriate for enrollment, as determined by past medical history, physical examination, vital signs, ECG, and clinical laboratory tests at Screening.

You may not qualify if:

• All participants (Groups 1-4):
• Contraindication or hypersensitivity to the investigational compound/compound class or excipients being used in this study.
• History or presence of clinically significant ECG abnormalities or a family history or presence of prolonged QT-interval syndrome.
• History of malignancy of any organ system, treated or untreated, within 3 years prior to Screening, regardless of whether there were recurrence or metastases. Those with localized basal cell carcinoma of the skin, in-situ cervical cancer, or hepatocellular cancer treated with local ablative therapy more than 6 months prior to Screening may have been enrolled.
• Use of investigational drugs, other than siremadlin (i.e., participation in any clinical investigation) within 4 weeks prior to dosing or longer if required by local regulation, or within 5 half-lives of the investigational agent taken prior to dosing (whichever was longer).
• Clinically significant illness within 2 weeks prior to dosing that may have jeopardized safety of the study participant and/or alter the study results as judged by the Investigator.
• Any single parameter of ALT, AST, GGT, or ALP that exceeded 1.2 x ULN or ≥ 1.5 x ULN TBL or any elevation above ULN of more than one parameter of ALT, AST, GGT, ALP, or serum TBL at Screening.
• Participants known to have Gilbert's syndrome.
• Participants with abnormal laboratory values for the following parameters at Screening:
• Hemoglobin levels \< 12.0 g/dL (males) or \< 11.0 g/dL (females).
• WBC count outside the range of 3.5 x 109-10.7 x 109 /L (unless deemed not clinically significant by the Investigator).
• Platelet count \< 100 x 109 /L (unless deemed not clinically significant by the Investigator).
• Presence of impaired renal function as indicated by serum creatinine \> ULN or abnormal urinary constituents at Screening.
• Participants with abnormal laboratory values for the following parameters at Screening:
• Hemoglobin \< 9 g/dL.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (3)

Clinical Pharmacology of Miami LLC

Miami, Florida, 33014-3616, United States

Location

Orlando Clinical Research Center

Orlando, Florida, 32809, United States

Location

Texas Liver Institute

San Antonio, Texas, 78215, United States

Location

Related Links

• Results for CHDM201X2105 can be found on the Novartis Clinical Trial Results Website

MeSH Terms

Conditions

Hematologic Neoplasms

Interventions

siremadlin

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 26, 2022
• First Posted: October 31, 2022
• Study Start: December 2, 2022
• Primary Completion: September 18, 2023
• Study Completion: September 18, 2023
• Last Updated: July 9, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)