A Phase I/Ib Study of AZD9150 (ISIS-STAT3Rx) in Patients With Advanced/Metastatic Hepatocellular Carcinoma

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01839604
• Collaborator: Ionis Pharmaceuticals, Inc. (Industry)
• Enrollment: 58
• Locations: 7
• Arm: 1
• Duration (Months): 21.1
• Patients Per Site: 8.3
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Advanced Adult Hepatocellular Carcinoma; Hepatocellular Carcinoma Metastatic	Drug: AZD9150	Phase 1

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 58 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: May 1, 2013
• Actual Primary Completion Date: Feb 1, 2015
• Actual Study Completion Date: Feb 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AZD9150 There are two parts, dose escalation phase (Part A) and dose expansion phase (Part B).	Drug: AZD9150; Intravenous infusion over 3 hours.; Other Names: ISIS 481464

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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 .

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 130 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Hongkong		Hong Kong
2	Research Site	Chuo-ku		Japan
3	Research Site	Kashiwa-shi		Japan
4	Research Site	Matsuyama-shi		Japan
5	Research Site	Seoul		Korea, Republic of
6	Research Site	Tainan		Taiwan
7	Research Site	Taipei		Taiwan

Sponsors and Collaborators

• AstraZeneca
• Ionis Pharmaceuticals, Inc.

Investigators

• Study Director: Frank Neumann, MD, AstraZeneca

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01839604
• Other Study ID Numbers: D5660C00001; ISIS 481464
• First Posted: Apr 25, 2013
• Last Update Posted: Mar 6, 2017
• Last Verified: May 1, 2016

• Keywords provided by AstraZeneca: Child-Pugh A to B7,; Advanced/Metastatic Hepatocellular Carcinoma,; AZD9150,; Antisense Oligonucleotide Inhibitor of STAT3
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular

Study Results

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 Detail	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.

Arm/Group Title	AZD9150 1mg/kg	AZD9150 1.5 mg/kg	AZD9150 2mg/kg	AZD9150 2.5mg/kg	AZD9150 3mg/kg
Arm/Group Description	Intravenous. Part A.	Intravenous dosing Part A	Intravenous dosing Part A	Intravenous dosing Part A	Pooled over parts A & B
Period Title: Overall Study
STARTED	6	6	7	5	15
COMPLETED	6	6	7	5	15
NOT COMPLETED	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	AZD9150 1mg/kg	1.5 mg/kg	2 mg/kg	2.5 mg/kg	3 mg/kg	Total
Arm/Group Description	Intravenous. Part A.	given intravenously. Part A	given intravenously Part A	given intravenously Part A	given intravenously (Part A & B pooled)	Total of all reporting groups
Overall Participants	6	6	7	5	15	39
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.3 (13.0)	58.3 (12.9)	64.1 (10.4)	58.0 (11.0)	57.5 (8.9)	59.2 (10.4)
Gender (Count of Participants)
Female	0 0%	1 16.7%	2 28.6%	2 40%	0 0%	5 12.8%
Male	6 100%	5 83.3%	5 71.4%	3 60%	15 100%	34 87.2%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose Limiting Toxicities During Cycle 1
Description	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)

Outcome Measure Data

Analysis Population Description

Safety: All patients who received at least 1 dose of AZD9150

Arm/Group Title	AZD9150 1mg/kg	1.5 mg/kg	2 mg/kg	2.5 mg/kg	3 mg/kg
Arm/Group Description	Intravenous. Part A.	given intravenously. Part A	given intravenously Part A	given intravenously Part A	given intravenously (Part A & B pooled)
Measure Participants	6	6	6	5	14
Number [participants with DLT]	0 0%	1 16.7%	1 14.3%	2 40%	3 20%

2. Secondary Outcome

Title	Evaluation of Pharmacokinetics (PK) of AZD9150 (Following Single Administrations in Patients With HCC) by Determining Cmax, Using the Plasma Concentration Data.
Description	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.

Outcome Measure Data

Analysis Population Description

PK: All dosed patients with reportable AZD9150 plasma concentrations and no important adverse events or protocol deviations that may impact PK

Arm/Group Title	AZD9150 1mg/kg	1.5 mg/kg	2 mg/kg	2.5 mg/kg	3 mg/kg
Arm/Group Description	Intravenous. Part A.	given intravenously. Part A	given intravenously Part A	given intravenously Part A	given intravenously (Part A & B pooled)
Measure Participants	6	6	7	5	15
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	5833 (28.02)	5575 (21.63)	8984 (20.28)	11560 (15.16)	16110 (30.70)

3. Secondary Outcome

Title	Preliminary Assessment of the Anti-tumour Activity of AZD9150 by Evaluation of Tumour Response.
Description	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.

Outcome Measure Data

Analysis Population Description

Evaluable for response: Dosed patients with measurable disease at baseline

Arm/Group Title	AZD9150 1mg/kg	1.5 mg/kg	2 mg/kg	2.5 mg/kg	3 mg/kg
Arm/Group Description	Intravenous. Part A.	given intravenously. Part A	given intravenously Part A	given intravenously Part A	given intravenously (Part A & B pooled)
Measure Participants	6	6	7	5	15
Number [participants with Partial Response]	0 0%	0 0%	1 14.3%	0 0%	0 0%

4. Secondary Outcome

Title	Evaluation of Pharmacokinetics (PK) of AZD9150 (Following Single Administrations in Patients With HCC) by Determining Tmax, Using the Plasma Concentration Data.
Description	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.

Outcome Measure Data

Analysis Population Description

PK: All dosed patients with reportable AZD9150 plasma concentrations and no important adverse events or protocol deviations that may impact PK

Arm/Group Title	AZD9150 1mg/kg	1.5 mg/kg	2 mg/kg	2.5 mg/kg	3 mg/kg
Arm/Group Description	Intravenous. Part A.	given intravenously. Part A	given intravenously Part A	given intravenously Part A	given intravenously (Part A & B pooled)
Measure Participants	6	6	7	5	15
Median (Full Range) [h]	3.0	3.4	2.8	3.0	3.0

Adverse Events

Time Frame	AEs will be collected throughout the study, from informed consent until the end of the follow up period. The follow-up period is defined as 28 +/-7 days after study treatment is discontinued.
Arm/Group Title	AZD9150 1mg/kg		1.5 mg/kg		2 mg/kg		2.5 mg/kg		3 mg/kg
Arm/Group Description	Intravenous. Part A.		given intravenously. Part A		given intravenously Part A		given intravenously Part A		given intravenously (Part A & B pooled)
All Cause Mortality
	AZD9150 1mg/kg		1.5 mg/kg		2 mg/kg		2.5 mg/kg		3 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	AZD9150 1mg/kg		1.5 mg/kg		2 mg/kg		2.5 mg/kg		3 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/6 (0%)		2/7 (28.6%)		2/5 (40%)		4/15 (26.7%)
Blood and lymphatic system disorders
Anaemia	0/6 (0%)		0/6 (0%)		0/7 (0%)		0/5 (0%)		1/15 (6.7%)	1
Gastrointestinal disorders
Abdominal pain	0/6 (0%)		0/6 (0%)		0/7 (0%)		1/5 (20%)	1	0/15 (0%)	1
Abdominal pain upper	0/6 (0%)		0/6 (0%)		0/7 (0%)		0/5 (0%)		1/15 (6.7%)	1
Peritoneal haemorrhage	0/6 (0%)		0/6 (0%)		1/7 (14.3%)	1	0/5 (0%)	1	0/15 (0%)	1
Hepatobiliary disorders
Hepatorenal failure	0/6 (0%)		0/6 (0%)		0/7 (0%)		1/5 (20%)	1	0/15 (0%)	0
Infections and infestations
Cellulitis	0/6 (0%)		0/6 (0%)		0/7 (0%)		0/5 (0%)		1/15 (6.7%)	1
Liver abscess	0/6 (0%)		0/6 (0%)		1/7 (14.3%)	1	0/5 (0%)	1	0/15 (0%)	1
Investigations
Alanine amonitransferase increased	0/6 (0%)		0/6 (0%)		1/7 (14.3%)	1	0/5 (0%)	1	0/15 (0%)	1
Aspartate aminotransferase increased	0/6 (0%)		0/6 (0%)		1/7 (14.3%)	1	1/5 (20%)	1	0/15 (0%)	1
Platelet count decreased	0/6 (0%)		0/6 (0%)		0/7 (0%)		0/5 (0%)		1/15 (6.7%)	1
Prothrombin time prolonged	0/6 (0%)		0/6 (0%)		0/7 (0%)		0/5 (0%)		1/15 (6.7%)	2
Other (Not Including Serious) Adverse Events
	AZD9150 1mg/kg		1.5 mg/kg		2 mg/kg		2.5 mg/kg		3 mg/kg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		6/6 (100%)		7/7 (100%)		5/5 (100%)		15/15 (100%)
Blood and lymphatic system disorders
Neutropenia	1/6 (16.7%)	1	0/6 (0%)	1	2/7 (28.6%)	2	0/5 (0%)	2	3/15 (20%)	3
Anaemia	0/6 (0%)		0/6 (0%)		1/7 (14.3%)	1	1/5 (20%)	1	3/15 (20%)	3
Thrombocytopenia	0/6 (0%)		0/6 (0%)		1/7 (14.3%)	1	0/5 (0%)	1	2/15 (13.3%)	2
Gastrointestinal disorders
Dyspepsia	0/6 (0%)		1/6 (16.7%)	1	0/7 (0%)	1	2/5 (40%)	2	4/15 (26.7%)	4
Abdominal pain	0/6 (0%)		0/6 (0%)		2/7 (28.6%)	2	1/5 (20%)	1	2/15 (13.3%)	2
Constipation	0/6 (0%)		1/6 (16.7%)	1	0/7 (0%)	1	2/5 (40%)	2	2/15 (13.3%)	2
Diarrhoea	0/6 (0%)		1/6 (16.7%)	1	1/7 (14.3%)	1	1/5 (20%)	1	1/15 (6.7%)	1
Abdominal distension	0/6 (0%)		0/6 (0%)		1/7 (14.3%)	1	1/5 (20%)	1	1/15 (6.7%)	1
General disorders
Fatigue	0/6 (0%)		0/6 (0%)		0/7 (0%)		1/5 (20%)	1	3/15 (20%)	3
Pyrexia	0/6 (0%)		1/6 (16.7%)	1	1/7 (14.3%)	1	1/5 (20%)	1	1/15 (6.7%)	1
Asthenia	1/6 (16.7%)	1	0/6 (0%)	1	1/7 (14.3%)	1	1/5 (20%)	1	0/15 (0%)	1
Malaise	0/6 (0%)		0/6 (0%)		0/7 (0%)		1/5 (20%)	1	1/15 (6.7%)	1
Hepatobiliary disorders
Hepatic function abnormal	0/6 (0%)	0	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	2/15 (13.3%)	2
Infections and infestations
Upper respiratory tract infection	0/6 (0%)	0	1/6 (16.7%)	1	2/7 (28.6%)	2	0/5 (0%)	0	1/15 (6.7%)	1
Investigations
Aspartate aminotransferase increased	3/6 (50%)	3	4/6 (66.7%)	4	5/7 (71.4%)	5	3/5 (60%)	3	9/15 (60%)	9
Platelet count decreased	3/6 (50%)	3	3/6 (50%)	3	5/7 (71.4%)	5	1/5 (20%)	1	10/15 (66.7%)	10
Alanine aminotransferase increased	2/6 (33.3%)	2	3/6 (50%)	3	4/7 (57.1%)	4	3/5 (60%)	3	9/15 (60%)	9
Neutrophil count decreased	0/6 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1	0/5 (0%)	0	4/15 (26.7%)	4
Blood bilirubin increased	0/6 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1	1/5 (20%)	1	2/15 (13.3%)	2
Gamma-glutamylytransferase increased	0/6 (0%)	0	2/6 (33.3%)	2	1/7 (14.3%)	1	0/5 (0%)	0	0/15 (0%)	0
White blod cell count decreased	0/6 (0%)	0	1/6 (16.7%)	1	1/7 (14.3%)	1	0/5 (0%)	0	1/15 (6.7%)	1
Prothrombin time prolonged	0/6 (0%)	0	0/6 (0%)	0	0/7 (0%)	0	1/5 (20%)	1	1/15 (6.7%)	1
Metabolism and nutrition disorders
Decreased apetite	1/6 (16.7%)	1	1/6 (16.7%)	1	1/7 (14.3%)	1	0/5 (0%)	1	4/15 (26.7%)	4
Hypoalbuminaemia	0/6 (0%)		1/6 (16.7%)	1	0/7 (0%)	1	1/5 (20%)	1	0/15 (0%)	1
Hypophosphataemia	2/6 (33.3%)	2	0/6 (0%)	2	0/7 (0%)	2	0/5 (0%)	2	0/15 (0%)	2
Musculoskeletal and connective tissue disorders
Flank Pain	0/6 (0%)	0	1/6 (16.7%)	1	1/7 (14.3%)	1	0/5 (0%)	0	0/15 (0%)	0
Musculoskeletal chest pain	0/6 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1	1/5 (20%)	1	0/15 (0%)	0
Nervous system disorders
Headache	0/6 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1	0/5 (0%)	0	2/15 (13.3%)	2
Dizziness	1/6 (16.7%)	1	0/6 (0%)	0	1/7 (14.3%)	1	0/5 (0%)	0	0/15 (0%)	0
Psychiatric disorders
Insomnia	0/6 (0%)	0	1/6 (16.7%)	1	0/7 (0%)	0	1/5 (20%)	1	0/15 (0%)	0
Renal and urinary disorders
Haematuria	1/6 (16.7%)	1	0/6 (0%)	0	0/7 (0%)	0	0/5 (0%)	0	1/15 (6.7%)	1
Respiratory, thoracic and mediastinal disorders
Haemoptysis	1/6 (16.7%)	1	1/6 (16.7%)	1	1/7 (14.3%)	1	1/5 (20%)	1	2/15 (13.3%)	2
Cough	2/6 (33.3%)	2	0/6 (0%)	0	0/7 (0%)	0	1/5 (20%)	1	2/15 (13.3%)	2
Productive cough	0/6 (0%)		1/6 (16.7%)	1	0/7 (0%)	1	1/5 (20%)	1	3/15 (20%)	3
Rhinorrhoea	0/6 (0%)		0/6 (0%)		1/7 (14.3%)	1	0/5 (0%)	1	2/15 (13.3%)	2
Dysphonia	0/6 (0%)		1/6 (16.7%)	1	0/7 (0%)	1	1/5 (20%)	1	0/15 (0%)	1
Dyspnoea	0/6 (0%)		1/6 (16.7%)	1	0/7 (0%)	1	1/5 (20%)	1	0/15 (0%)	1
Oropharyngeal pain	0/6 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1	0/5 (0%)	0	1/15 (6.7%)	1
Skin and subcutaneous tissue disorders
Pruritus	0/6 (0%)	0	0/6 (0%)	0	0/7 (0%)	0	3/5 (60%)	3	1/15 (6.7%)	1
Rash	1/6 (16.7%)	1	2/6 (33.3%)	2	0/7 (0%)	0	0/5 (0%)	0	1/15 (6.7%)	1
Alopecia	1/6 (16.7%)	1	0/6 (0%)	0	1/7 (14.3%)	1	0/5 (0%)	0	0/15 (0%)	0
Urticaria	0/6 (0%)	0	0/6 (0%)	0	1/7 (14.3%)	1	0/5 (0%)	0	1/15 (6.7%)	1
Vascular disorders
Hypertension	0/6 (0%)	0	2/6 (33.3%)	2	1/7 (14.3%)	1	0/5 (0%)	0	2/15 (13.3%)	2

Limitations/Caveats

The overall study objectives were achieved earlier than anticipated, so recruitment was stopped and the study was considered complete. In turn multiple dose PK profiles were not obtained during the study expansion phase.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.