Advanced Malignancies and Hepatic Impairment
Conditions
Keywords
Hepatic impairment (HI), Moderate or severe hepatic impairment, Advanced malignancies, Pharmacokinetics (PK), Bromodomain and extraterminal (BET)
Brief summary
The primary purpose of this study is to evaluate the impact of hepatic function on the pharmacokinetic (PK) profile of pelabresib in participants with advanced malignancies who have either hepatic impairment (HI) or normal liver function. To reduce participant burden and maximize benefit, the PK of pelabresib will be assessed at steady-state rather than after a single dose, avoiding treatment-free washout periods.
Detailed description
This study consists of 2 main parts: Part 1 will assess the PK characteristics of pelabresib in participants with hepatic impairment versus normal hepatic function, and during Part 2, extended treatment with pelabresib may be offered in case of clinical benefit, as assessed by the investigator. A participant is considered to have started the study and entered the screening period upon signing the informed consent form (ICF). Enrollment occurs when participant receive their first dose of study treatment via the IRT system. A participant is considered to have completed the study if they have completed all phases of the study including the end of treatment (EOT) and 30-day safety follow-up visits. Participants with hematological malignancies will be followed up every 3 months beyond EOT. Part 1: Impact of hepatic impairment on pelabresib PK In Part 1, the PK characteristics of pelabresib will be investigated in participants with advanced malignancies comprising 2 different study groups according to their hepatic function: * Group 1 includes participants with normal hepatic function * Group 2 includes participants with moderate or severe HI Following completion of Part 1, participants can directly proceed to Part 2 Part 2: Continued treatment After completing Part 1, in case of clinical benefit, participants can continue with pelabresib treatment in Part 2 until the end of study (EOS) is reached, until the participant meets discontinuation criteria, or until they receive pelabresib treatment via alternative means of access, whichever occurs first. Clinical benefit is determined by the investigator. End of treatment visit An EOT visit is required for all participants within 7 days of the last dose of pelabresib treatment (or within 7 days of the decision to discontinue treatment, if the decision was made \> 7 days after the last dose). 30-day safety follow-up All participants will be followed up for AEs and serious AEs (SAEs) for 30 days (±3 days) following the last dose of pelabresib. If the participant starts another anticancer treatment or switches to pelabresib treatment via an alternative source (e.g., in an extension study or commercially available pelabresib), the safety follow-up will end at the time of the first administration of the respective treatment. Leukemic transformation follow-up for participants with hematological malignancies After the EOT visit and the 30-Day safety follow-up visit, participants with hematological malignancies will be followed up every 3 months for leukemic transformation until the overall end of the study, confirmation of AML, withdrawal of consent, loss to follow-up, or death, whichever occurs first.
Interventions
DRUGpelabresib
pelabresib 125 mg orally (PO) once daily (QD) for 14 days, followed by a 7-day break
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Is at least 18 and not older than 75 years of age at the time of signing the informed consent. * Group 1 only: There is a matching participant in Group 2 and an enrollment slot is available for the Group 1 participant. * Has a confirmed documented diagnosis of an advanced malignancy for which no standard and/or curative treatment options are available. * Has the following acceptable laboratory assessments prior to the first dose of study treatment: 1. Platelet count ≥ 150 × 109 /L in the absence of thrombopoietic factors or transfusions within 2 weeks of the screening assessment 2. Absolute neutrophil count (ANC) ≥ 1 × 109 /L in the absence of granulocyte growth factors 3. Adequate renal function (creatinine clearance of ≥30 mL/min, calculated using Cockcroft-Gault formula) 4. Peripheral blood blast count \< 5%. Assessment of blasts in bone marrow is not mandatory at screening, however, blasts must be \<5% if the assessment is performed. * Has a life expectancy ≥3 months. * Has fully recovered from major surgery and from the acute toxic effects of prior chemotherapy and radiotherapy . * Hepatic function: 1. Is in Group 1 and is classified as having normal hepatic function based on NCI-ODWG criteria (i.e., total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) ≤ ULN); or 2. Is in Group 2 and has stable moderate or severe HI as defined by NCI ODWG criteria: * moderate HI: total bilirubin \>1.5 × to 3 × ULN, and any AST value * severe HI: total bilirubin \> 3 × ULN, and any AST value Key
Exclusion criteria
* Has a history of hypersensitivity to the study treatment or its excipients or to drugs of similar chemical class. * Has any other medical condition which, in the investigator's opinion, makes the participant unsuitable for the study. * Is a female participant who is pregnant (confirmed by a pregnancy test at screening) or is breastfeeding. * Is a woman of childbearing potential (WOCBP) who does not agree to follow the contraceptive guidance during the treatment period and for at least 184 days after the last dose of study treatment, and who does not agree to refrain from donating eggs during this period. * Has esophageal variceal bleeding within the past 2 months prior to the first dose of pelabresib. * Has an active clinically significant infection. * Has impaired cardiac function or clinically significant cardiac diseases * Has a GI tumor, impaired GI function, GI disease, or significant resection of stomach or other portion of the GI tract that could alter the absorption of pelabresib, including any unresolved nausea, vomiting, or diarrhea. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve from 0 to 24 hours on Day 14 (AUC₀-24h,D14) of pelabresib at steady state per study group | Cycle 1 Day 14: 0, 0.5, 1, 2, 4, 6, 8, and 12 hours postdose (1 cycle = 21 days) | Venous whole blood samples will be collected for pharmacokinetics characterization. AUC₀-24h,D14 of pelabresib at steady state per study group will be listed and summarized using descriptive statistics. |
| Maximum Plasma Concentration on Day 14 (Cmax,D14) of pelabresib at steady state per study group | Cycle 1 Day 14 (1 cycle = 21 days) | Venous whole blood samples will be collected for pharmacokinetics characterization. Cmax,D14 of pelabresib at steady state per study group will be listed and summarized using descriptive statistics. |
| Apparent Clearance (CL/F) of pelabresib at steady state per study group | Cycle 1 Day 14 (1 cycle = 21 days) | Venous whole blood samples will be collected for pharmacokinetics characterization. CL/F of pelabresib at steady state per study group will be listed and summarized using descriptive statistics. |
| Apparent Volume of Distribution (V/F) of pelabresib at steady state per study group | Cycle 1 Day 14 (1 cycle = 21 days) | Venous whole blood samples will be collected for pharmacokinetics characterization. V/F of pelabresib at steady state per study group will be listed and summarized using descriptive statistics. |
| Terminal Half-Life (T½) of pelabresib at steady state per study group | Cycle 1 Day 14 (1 cycle = 21 days) | Venous whole blood samples will be collected for pharmacokinetics characterization. T½ of pelabresib at steady state per study group will be listed and summarized using descriptive statistics. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration on Day 1 (Cmax,D1) of pelabresib per study group | Cycle 1 Day 1 (1 cycle = 21 days) | Venous whole blood samples will be collected for pharmacokinetics characterization. Cmax,D1 of pelabresib per study group will be listed and summarized using descriptive statistics. |
| Area Under the Curve from 0 to 24 hours on Day 1 (AUC₀-24h,D1) of pelabresib per study group | Cycle 1 Day 1: 0, 0.5, 1, 2, 4, 6, 8, and 12 hours postdose (1 cycle = 21 days) | Venous whole blood samples will be collected for pharmacokinetics characterization. AUC₀-24h,D1 of pelabresib per study group will be listed and summarized using descriptive statistics. |
| Trough Concentration on Day 14 (Ctrough,D14) of pelabresib per study group | Cycle 1 Day 14: predose (1 cycle = 21 days) | Venous whole blood samples will be collected for pharmacokinetics characterization. Ctrough,D14 of pelabresib per study group will be listed and summarized using descriptive statistics. |
| Accumulation Ratio (Rac) of pelabresib per study group | Cycle 1: Day 14 compared to Day 1 (1 cycle = 21 days) | Venous whole blood samples will be collected for pharmacokinetics characterization. Rac of pelabresib per study group will be listed and summarized using descriptive statistics. |
| Time to Maximum Concentration (Tmax) of pelabresib per study group | Cycle 1: Day 1 and Day 14 (1 cycle = 21 days) | Venous whole blood samples will be collected for pharmacokinetics characterization. Tmax of pelabresib per study group will be listed and summarized using descriptive statistics. |
| Terminal Half-Life (T½) of pelabresib per study group | Cycle 1 Day 1 (1 cycle = 21 days) | Venous whole blood samples will be collected for pharmacokinetics characterization. T½ of pelabresib per study group will be listed and summarized using descriptive statistics. |
| Fraction Unbound (fu) of pelabresib per study group | Cycle 1 Day 14: 0, 2, and 8 hours postdose (1 cycle = 21 days) | Venous whole blood samples will be collected for pharmacokinetics characterization. fu of pelabresib per study group will be listed and summarized using descriptive statistics. |
| fu-adjusted AUC of pelabresib per study group | Cycle 1: Day 1 and Day 14 (1 cycle = 21 days) | Venous whole blood samples will be collected for pharmacokinetics characterization. fu-adjusted AUC of pelabresib per study group will be listed and summarized using descriptive statistics. |
| fu-adjusted Cmax of pelabresib per study group | Cycle 1: Day 1 and Day 14 (1 cycle = 21 days) | Venous whole blood samples will be collected for pharmacokinetics characterization. fu-adjusted Cmax of pelabresib per study group will be listed and summarized using descriptive statistics. |
| fu-adjusted Ctrough of pelabresib per study group | Cycle 1 Day 1 and Day 14: predose (1 cycle = 21 days) | Venous whole blood samples will be collected for pharmacokinetics characterization. fu-adjusted Ctrough of pelabresib per study group will be listed and summarized using descriptive statistics. |
| Number of Participants with adverse events (AEs), serious AEs (SAEs) | Through study completion, an average of 28 months | Incidence of adverse events by type, frequency, and severity, as graded by the NCI CTCAE version 5.0. |
Contacts
CONTACTNovartis Pharmaceuticals
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Outcome results
None listed