Advanced Adult Hepatocellular Carcinoma, Hepatocellular Carcinoma Metastatic
Conditions
Keywords
Child-Pugh A to B7,, Advanced/Metastatic Hepatocellular Carcinoma,, AZD9150,, Antisense Oligonucleotide Inhibitor of STAT3
Brief summary
This is a phase I/Ib open-label, multicentre study to assess the safety, tolerability, pharmacokinetics and preliminary anti-tumour activity of AZD9150 in patients with advanced/metastatic hepatocellular carcinoma.
Detailed description
A Phase I/Ib, Open-Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of AZD9150 in Patients with Advanced/Metastatic Hepatocellular Carcinoma.
Interventions
DRUGAZD9150
Intravenous infusion over 3 hours.
Sponsors
Ionis Pharmaceuticals, Inc.
AstraZeneca
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* Aged at least 18 years. Patient from Japan and Taiwan aged at least 20 years * Histologically or cytologically confirmed HCC (with the exception of fibrolamellar carcinoma or mixed variants of HCC with fibrolamellar histology OR clinically diagnosed HCC for patients with difficulty in obtaining histological diagnosis) * Relapsed, refractory, intolerant or unlikely to benefit from sorafenib (for example due to comorbidity) * Metastatic or locally advanced meeting ANY of the criteria below: * HCC not suitable to receive local therapy * Disease recurred or was refractory to last therapy (local or systemic) * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no deterioration over the previous 2 weeks and minimum life expectancy of 8 weeks
Exclusion criteria
* More than 2 prior systemic treatments for HCC * Prior grade 3 hematologic toxicity related to treatment with a JAK or STAT3 inhibitor * Presence of hepatic encephalopathy within 4 weeks of 1st dose * Uncontrolled massive ascites * High likelihood of bleeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities During Cycle 1 | DLT assessment window - Cycle 1 (22 days) | Cycle 1 was defined as 3 loading doses given on Days 1, 3, and 5 followed by 3 weekly doses given on Days 8, 15, and 22. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of Pharmacokinetics (PK) of AZD9150 (Following Single Administrations in Patients With HCC) by Determining Cmax, Using the Plasma Concentration Data. | 8 times of PK sampling on Day1 of Cycle1. Additional 6 patients in Japan; 8 times of PK sampling on Day1 of Cycle1. | 8 times (pre-dose, 1.5, 3, 3.5, 4, 6, 8, 24 hours post-dose) on Day1 of Cycle1. For additional 6 patients in Japan, 8 times (pre-dose, 1.5, 3, 3.5, 4, 6, 8, 24 hours post-dose) on Day1 of Cycle1. From the multiple samples a timecourse is obtained of treatment conc in the plasma over time. From this curve the associated PK parameters e.g. Cmax are obtained. For n patients we obtain up to n parameters which can then be averaged. |
| Preliminary Assessment of the Anti-tumour Activity of AZD9150 by Evaluation of Tumour Response. | Every 6 weeks, assessed up to 12 months. | Tumour response assessment by modified Response Evaluation Criteria in Solid Tumours (RECIST). Overall tumour response: assessed by mRECIST for HCC overall visit response of CR (disappearance of baseline TLs and NTLs), PR (\>=30% decrease in sum of TLs), SD (neither PR nor PD), PD (sum TLs increased \>20%), or NE . |
| Evaluation of Pharmacokinetics (PK) of AZD9150 (Following Single Administrations in Patients With HCC) by Determining Tmax, Using the Plasma Concentration Data. | 8 times of PK sampling on Day1 of Cycle1. Additional 6 patients in Japan; 8 times of PK sampling on Day 1 of Cycle 1. | 8 times (pre-dose, 1.5, 3, 3.5, 4, 6, 8, 24 hours post-dose) on Day1 of Cycle1. For additional 6 patients in Japan, 8 times (pre-dose, 1.5, 3, 3.5, 4, 6, 8, 24 hours post-dose) on Day1 of Cycle1. |
Countries
Hong Kong, Japan, South Korea, Taiwan
Participant flow
Recruitment details
The first patient entered the study on 03 May 2013, and the last patient last visit before the DCO was 31 December 2014. The DCO date was 05 January 2015.
Pre-assignment details
Note that 39 patients is the number of patients who were actually assigned to treatment out of the total enrolled. The ecpansion phase consisted of the 3mg/kg group only.
Participants by arm
| Arm | Count |
|---|---|
| AZD9150 1mg/kg Intravenous. Part A. | 6 |
| 1.5 mg/kg given intravenously. Part A | 6 |
| 2 mg/kg given intravenously Part A | 7 |
| 2.5 mg/kg given intravenously Part A | 5 |
| 3 mg/kg given intravenously (Part A & B pooled) | 15 |
| Total | 39 |
Baseline characteristics
| Characteristic | AZD9150 1mg/kg | 1.5 mg/kg | 2 mg/kg | 2.5 mg/kg | 3 mg/kg | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 59.3 years STANDARD_DEVIATION 13 | 58.3 years STANDARD_DEVIATION 12.9 | 64.1 years STANDARD_DEVIATION 10.4 | 58.0 years STANDARD_DEVIATION 11 | 57.5 years STANDARD_DEVIATION 8.9 | 59.2 years STANDARD_DEVIATION 10.4 |
| Gender Female | 0 Participants | 1 Participants | 2 Participants | 2 Participants | 0 Participants | 5 Participants |
| Gender Male | 6 Participants | 5 Participants | 5 Participants | 3 Participants | 15 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 7 / 7 | 5 / 5 | 15 / 15 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 2 / 7 | 2 / 5 | 4 / 15 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicities During Cycle 1
Cycle 1 was defined as 3 loading doses given on Days 1, 3, and 5 followed by 3 weekly doses given on Days 8, 15, and 22.
Time frame: DLT assessment window - Cycle 1 (22 days)
Population: Safety: All patients who received at least 1 dose of AZD9150
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD9150 1mg/kg | Number of Participants With Dose Limiting Toxicities During Cycle 1 | 0 participants with DLT |
| 1.5 mg/kg | Number of Participants With Dose Limiting Toxicities During Cycle 1 | 1 participants with DLT |
| 2 mg/kg | Number of Participants With Dose Limiting Toxicities During Cycle 1 | 1 participants with DLT |
| 2.5 mg/kg | Number of Participants With Dose Limiting Toxicities During Cycle 1 | 2 participants with DLT |
| 3 mg/kg | Number of Participants With Dose Limiting Toxicities During Cycle 1 | 3 participants with DLT |
Secondary
Evaluation of Pharmacokinetics (PK) of AZD9150 (Following Single Administrations in Patients With HCC) by Determining Cmax, Using the Plasma Concentration Data.
8 times (pre-dose, 1.5, 3, 3.5, 4, 6, 8, 24 hours post-dose) on Day1 of Cycle1. For additional 6 patients in Japan, 8 times (pre-dose, 1.5, 3, 3.5, 4, 6, 8, 24 hours post-dose) on Day1 of Cycle1. From the multiple samples a timecourse is obtained of treatment conc in the plasma over time. From this curve the associated PK parameters e.g. Cmax are obtained. For n patients we obtain up to n parameters which can then be averaged.
Time frame: 8 times of PK sampling on Day1 of Cycle1. Additional 6 patients in Japan; 8 times of PK sampling on Day1 of Cycle1.
Population: PK: All dosed patients with reportable AZD9150 plasma concentrations and no important adverse events or protocol deviations that may impact PK
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| AZD9150 1mg/kg | Evaluation of Pharmacokinetics (PK) of AZD9150 (Following Single Administrations in Patients With HCC) by Determining Cmax, Using the Plasma Concentration Data. | 5833 ng/mL | Geometric Coefficient of Variation 28.02 |
| 1.5 mg/kg | Evaluation of Pharmacokinetics (PK) of AZD9150 (Following Single Administrations in Patients With HCC) by Determining Cmax, Using the Plasma Concentration Data. | 5575 ng/mL | Geometric Coefficient of Variation 21.63 |
| 2 mg/kg | Evaluation of Pharmacokinetics (PK) of AZD9150 (Following Single Administrations in Patients With HCC) by Determining Cmax, Using the Plasma Concentration Data. | 8984 ng/mL | Geometric Coefficient of Variation 20.28 |
| 2.5 mg/kg | Evaluation of Pharmacokinetics (PK) of AZD9150 (Following Single Administrations in Patients With HCC) by Determining Cmax, Using the Plasma Concentration Data. | 11560 ng/mL | Geometric Coefficient of Variation 15.16 |
| 3 mg/kg | Evaluation of Pharmacokinetics (PK) of AZD9150 (Following Single Administrations in Patients With HCC) by Determining Cmax, Using the Plasma Concentration Data. | 16110 ng/mL | Geometric Coefficient of Variation 30.7 |
Secondary
Evaluation of Pharmacokinetics (PK) of AZD9150 (Following Single Administrations in Patients With HCC) by Determining Tmax, Using the Plasma Concentration Data.
8 times (pre-dose, 1.5, 3, 3.5, 4, 6, 8, 24 hours post-dose) on Day1 of Cycle1. For additional 6 patients in Japan, 8 times (pre-dose, 1.5, 3, 3.5, 4, 6, 8, 24 hours post-dose) on Day1 of Cycle1.
Time frame: 8 times of PK sampling on Day1 of Cycle1. Additional 6 patients in Japan; 8 times of PK sampling on Day 1 of Cycle 1.
Population: PK: All dosed patients with reportable AZD9150 plasma concentrations and no important adverse events or protocol deviations that may impact PK
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AZD9150 1mg/kg | Evaluation of Pharmacokinetics (PK) of AZD9150 (Following Single Administrations in Patients With HCC) by Determining Tmax, Using the Plasma Concentration Data. | 3.0 h |
| 1.5 mg/kg | Evaluation of Pharmacokinetics (PK) of AZD9150 (Following Single Administrations in Patients With HCC) by Determining Tmax, Using the Plasma Concentration Data. | 3.4 h |
| 2 mg/kg | Evaluation of Pharmacokinetics (PK) of AZD9150 (Following Single Administrations in Patients With HCC) by Determining Tmax, Using the Plasma Concentration Data. | 2.8 h |
| 2.5 mg/kg | Evaluation of Pharmacokinetics (PK) of AZD9150 (Following Single Administrations in Patients With HCC) by Determining Tmax, Using the Plasma Concentration Data. | 3.0 h |
| 3 mg/kg | Evaluation of Pharmacokinetics (PK) of AZD9150 (Following Single Administrations in Patients With HCC) by Determining Tmax, Using the Plasma Concentration Data. | 3.0 h |
Secondary
Preliminary Assessment of the Anti-tumour Activity of AZD9150 by Evaluation of Tumour Response.
Tumour response assessment by modified Response Evaluation Criteria in Solid Tumours (RECIST). Overall tumour response: assessed by mRECIST for HCC overall visit response of CR (disappearance of baseline TLs and NTLs), PR (\>=30% decrease in sum of TLs), SD (neither PR nor PD), PD (sum TLs increased \>20%), or NE .
Time frame: Every 6 weeks, assessed up to 12 months.
Population: Evaluable for response: Dosed patients with measurable disease at baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AZD9150 1mg/kg | Preliminary Assessment of the Anti-tumour Activity of AZD9150 by Evaluation of Tumour Response. | 0 participants with Partial Response |
| 1.5 mg/kg | Preliminary Assessment of the Anti-tumour Activity of AZD9150 by Evaluation of Tumour Response. | 0 participants with Partial Response |
| 2 mg/kg | Preliminary Assessment of the Anti-tumour Activity of AZD9150 by Evaluation of Tumour Response. | 1 participants with Partial Response |
| 2.5 mg/kg | Preliminary Assessment of the Anti-tumour Activity of AZD9150 by Evaluation of Tumour Response. | 0 participants with Partial Response |
| 3 mg/kg | Preliminary Assessment of the Anti-tumour Activity of AZD9150 by Evaluation of Tumour Response. | 0 participants with Partial Response |