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

A Phase 1, Open-label, Multi-center, Single-dose, Parallel Group Study to Evaluate the Pharmacokinetics of Siremadlin (HDM201) in Participants With Mild, Moderate and Severe Hepatic Impairment Compared to Matched Healthy Control Participants

ClinicalTrials.gov Identifier: NCT05599932

Novartis Reference Number: CHDM201X2105

Last Update: Jan 20, 2023

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All compounds are either investigational or being studied for (a) new use(s). Efficacy and safety have not been established. There is no guarantee that they will become commercially available for the use(s) under investigation. 

Study Description

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.

Condition 
Hepatic Impairment
Phase 
Phase 1
Overall status 
Recruiting
Start date 
Dec 02, 2022
Completion date 
Oct 02, 2023
Gender 
All
Age(s)
18 Years - 75 Years (Adult, Older Adult)

Interventions

Drug
Siremadlin
HDM201 capsule

Eligibility Criteria

Key Inclusion Criteria:

All participants:

Male and non-child-bearing potential females * between 18 and 75 years of age, inclusive, at Screening.
Participant must be a non-smoker or moderate smoker (up to 10 cigarettes or equivalent nicotine containing products per day) at Screening. Participant must agree to maintain the same smoking status (i.e., smoker or non-smoker) from Screening until after Study Completion evaluations.

Additional key inclusion criteria for healthy participants (Group 1):

Participants must weigh at least 50.0 kg and must have 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.

Additional inclusion criteria for mild, moderate and severe HI participants (Groups 2-4):

Participants must weigh at least 50.0 kg and must have a BMI within the range of 18.0 to 38.0 kg/m2, inclusive at Screening. For participants without overt ascites, the BMI must be within the range of 18.0 to 40.0 kg/m2, inclusive. For participants with overt ascites, the BMI must be within the range of 18.0 to 45.0 kg/m2, inclusive.

Participant must satisfy 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 indicate different Child-Pugh class, a third assessment must be conducted. If the results of the 2 most recent assessments (the second and third) are in agreement with regard to the participant's Child-Pugh class, the participant may be enrolled at the Child-Pugh class determined by the most recent assessment. If the second and third measurements differ, the participant will not be eligible for the study on the basis that their liver function is not stable.
Participants with impaired hepatic function and other stable medical disorders such as diabetes, hypertension, hyperlipidemia, hypothyroidism etc., may be eligible, as long as they are considered appropriate for enrollment, as determined by past medical history, physical examination, vital signs, ECG, and clinical laboratory tests at Screening.

Key Exclusion Criteria:

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 is 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 be 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 is longer).
Clinically significant illness within 2 weeks prior to dosing that may jeopardize safety of the study participant and/or alter the study results as judged by the Investigator.

Additional key exclusion criteria for healthy participants (Group 1):

Any single parameter of ALT, AST, GGT, or ALP exceeding 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.

Additional key exclusion criteria for mild and moderate HI participants (Groups 2-3):

Participants with abnormal laboratory values for the following parameters at Screening:

Hemoglobin < 9 g/dL.
Platelet count < 30 x 109/L.
WBC count < 2.5 x 109/L.
TBL > 8 mg/dL.
Serum amylase > 5 x ULN with no abdominal symptoms (> 2 x ULN with abdominal symptoms)
INR > 2.5.
Corrected serum calcium < 8.6 or > 10.2 mg/dL.
Presence of moderate to severe impaired renal function as indicated by creatinine clearance < 50 mL/min as calculated using the Cockcroft-Gault formula.
Severe complications of liver disease within the preceding 3 months prior to dosing..
Trans-jugular intrahepatic portosystemic shunt and/or have undergone portacaval shunting.

Additional key exclusion criteria for severe HI participants (Group 4):

Participants with abnormal laboratory values for the following parameters at Screening:

Hemoglobin < 8.5 g/dL.
Platelet count < 30 x 109/L.
WBC count < 2.5 x 109/L.
TBL > 8 mg/dL.
Serum amylase > 5 x ULN with no abdominal symptoms (> 2 x ULN with abdominal symptoms).
INR > 2.5.
Presence of moderate to severe impaired renal function as indicated by creatinine clearance < 50 mL/min as calculated using the Cockcroft-Gault formula.
Severe complications of liver disease within the preceding 3 months prior to dosing.
Trans-jugular intrahepatic portosystemic shunt and/or have undergone portacaval shunting.

Other protocol-defined Inclusion/Exclusion criteria may apply.

Study Locations

United States
Clinical Pharmacology of Miami LLC
Recruiting
Miami, 33014-3616 - Florida
Contact: (+1 305 817 2900) Juan Carlos Rondon
United States
Orlando Clinical Research Center
Recruiting
Orlando, 32809 - Florida
Contact: (407-472-0227) Thomas C Marbury
United States
Texas Liver Institute
Recruiting
San Antonio, 78215 - Texas
Contact: Eric J Lawitz
United States

Contacts

Name: 
Novartis Pharmaceuticals
Phone: 

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