Hepatocellular Carcinoma
Conditions
Brief summary
A Phase 2 open-label, single-arm, non-randomized study in the treatment of advanced hepatocellular carcinoma (HCC) patients who failed prior treatment with sorafenib using a Simon's 2-stage design. A set minimum number of patients must demonstrate disease control at 16 weeks to proceed to Stage 2. At Stage 2, a set number of patients must have disease control at 16 weeks to declare that SGI-110 is of interest in the treatment of advanced HCC after failure of prior sorafenib.
Interventions
DRUGSGI-110
SGI-110 will be administered by subcutaneously (SC) on Days 1 - 5 every 28 days until disease progression or unacceptable toxicity
Sponsors
Astex Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. 18 years of age or older 2. Histological or cytological confirmed hepatocellular carcinoma with advanced stage disease 3. Received prior sorafenib treatment, and showed evidence of disease progression, which is defined as Investigator verified radiologic progression, or intolerance of prior systemic therapy, which is defined as having had clinically significant adverse events that persisted despite one or more dose reductions or interruptions 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 5. Acceptable organ function 6. Signed an approved informed consent
Exclusion criteria
1. Known hypersensitivity to SGI-110 2. Adequate washout of prior radiation, chemotherapy or other locoregional therapy 3. Abnormal left ventricular ejection fraction 4. Uncontrolled ischemic heart disease or a history of congestive cardiac failure 5. Known brain metastases 6. Clinically evident ascites 7. Child-Pugh C cirrhosis or Child-Pugh B cirrhosis with more than 7 points 8. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, non-metastatic prostate cancer with normal prostate-specific antigen (PSA) or other cancer from which the subject has been disease free for at least three years 9. Known history of human immunodeficiency virus (HIV)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) at 16 Weeks for Patients Treated With Guadecitabine After Failure of Sorafenib | 16 weeks | Percentage of patients achieving a best overall response of complete response (CR) or partial response (PR) plus subjects with stable disease at 16 weeks after the start of treatment. Response was assessed based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for target and non-target lesions using computed tomography (CT) or magnetic resonance imaging (MRI) as follows: Complete Response (CR), disappearance of all target lesions, disappearance of all non-target lesions, and normalization of tumor marker level; Partial Response (PR), at least a 30% decrease in the sum of diameters of target lesions from baseline; Progressive Disease (PD), at least a 20% relative increase and 5 mm absolute increase in the sum of diameters of target lesions, and unequivocal progression of non-target lesions; Stable Disease, neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for PD (Eisenhauer et al. 2009, Eur. J. Cancer 45:228-247). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability of Guadecitabine | Varied by patient (median number of treatment cycles was 2.0 (range 2-8) in 60 mg/m^2 group, and 4.0 (range 1-13) in 45 mg/m^2 group | Number of patients with serious adverse events and adverse events |
| Alpha Fetoprotein Response as a Result of Guadecitabine Administration | Varied by patient (median number of treatment cycles was 2.0 (range 2-8) in 60 mg/m^2 group, and 4.0 (range 1-13) in 45 mg/m^2 group | Percentage of patients with best post baseline alpha fetoprotein reduction of 50% or more |
| Duration of Response | From time of first response until disease progression or date of death due to any cause, whichever occurred earlier; an average of 192 days. | Duration of response as measured in days. Included subjects with a complete response or partial response based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. |
| Progression-free Survival | Through completion of response assessments (i.e., until disease progression or treatment discontinuation), an average of 112 days. | Progression-free survival measured in days. Progression-free survival was defined as the time interval from the date of the first dose of study treatment to the earlier of 1) documented radiologic progression per RECIST v1.1 or clinical progression, or 2) death due to any cause. |
| Overall Survival | Through completion of study survival follow-up, an average of 270 days. | Overall survival measured in days. |
Countries
Canada, United Kingdom, United States
Participant flow
Recruitment details
A total of 68 patients were screened for enrollment in the study. Of these, 16 were screen failures. Reasons for screen failure included not meeting all eligibility criteria (14 patients) and withdrawal of consent (2 patients).
Pre-assignment details
Of the 52 patients enrolled in the study, 2 did not receive any treatment. Reasons for not receiving treatment included death for one patient and no longer meeting eligibility criteria for the second patient.
Participants by arm
| Arm | Count |
|---|---|
| Guadecitabine 60 mg/m^2 Guadecitabine (SGI-110) 60 mg/m\^2 SC on Days 1 - 5 of each 28-day cycle | 4 |
| Guadecitabine 45 mg/m^2 Guadecitabine (SGI-110) 45 mg/m\^2 SC on Days 1 - 5 of each 28-day cycle | 46 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study and Follow-up | Death | 4 | 34 |
| Overall Study and Follow-up | Lost to Follow-up | 0 | 2 |
| Overall Study and Follow-up | Sponsor terminated study/Database lock | 0 | 7 |
| Overall Study and Follow-up | Withdrawal by Subject | 0 | 3 |
| Treatment | Adverse Event | 1 | 4 |
| Treatment | Death | 0 | 2 |
| Treatment | Disease Progression | 3 | 29 |
| Treatment | Hepatocellular carcinoma not confirmed | 0 | 1 |
| Treatment | Patient noncompliant | 0 | 1 |
| Treatment | Patient unable to travel to appointments | 0 | 1 |
| Treatment | Physician Decision | 0 | 3 |
| Treatment | Withdrawal by Subject | 0 | 5 |
Baseline characteristics
| Characteristic | Guadecitabine 60 mg/m^2 | Guadecitabine 45 mg/m^2 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 13 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 33 Participants | 37 Participants |
| Region of Enrollment Canada | 0 participants | 7 participants | 7 participants |
| Region of Enrollment United States | 4 participants | 39 participants | 43 participants |
| Sex: Female, Male Female | 0 Participants | 7 Participants | 7 Participants |
| Sex: Female, Male Male | 4 Participants | 39 Participants | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 4 | 34 / 46 |
| other Total, other adverse events | 4 / 4 | 46 / 46 |
| serious Total, serious adverse events | 1 / 4 | 21 / 46 |
Outcome results
Primary
Disease Control Rate (DCR) at 16 Weeks for Patients Treated With Guadecitabine After Failure of Sorafenib
Percentage of patients achieving a best overall response of complete response (CR) or partial response (PR) plus subjects with stable disease at 16 weeks after the start of treatment. Response was assessed based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for target and non-target lesions using computed tomography (CT) or magnetic resonance imaging (MRI) as follows: Complete Response (CR), disappearance of all target lesions, disappearance of all non-target lesions, and normalization of tumor marker level; Partial Response (PR), at least a 30% decrease in the sum of diameters of target lesions from baseline; Progressive Disease (PD), at least a 20% relative increase and 5 mm absolute increase in the sum of diameters of target lesions, and unequivocal progression of non-target lesions; Stable Disease, neither sufficient shrinkage to quality for PR nor sufficient increase to qualify for PD (Eisenhauer et al. 2009, Eur. J. Cancer 45:228-247).
Time frame: 16 weeks
Population: Patients who met major inclusion/exclusion criteria and followed the study protocol without a significant deviation (1 patient excluded because did not have confirmed HCC; 4 patients excluded because did not have a Week 16 assessment).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Guadecitabine 60 mg/m^2 | Disease Control Rate (DCR) at 16 Weeks for Patients Treated With Guadecitabine After Failure of Sorafenib | 25.0 percentage of patients |
| Guadecitabine 45 mg/m^2 | Disease Control Rate (DCR) at 16 Weeks for Patients Treated With Guadecitabine After Failure of Sorafenib | 24.4 percentage of patients |
Secondary
Alpha Fetoprotein Response as a Result of Guadecitabine Administration
Percentage of patients with best post baseline alpha fetoprotein reduction of 50% or more
Time frame: Varied by patient (median number of treatment cycles was 2.0 (range 2-8) in 60 mg/m^2 group, and 4.0 (range 1-13) in 45 mg/m^2 group
Population: Includes all patients who received any guadecitabine
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Guadecitabine 60 mg/m^2 | Alpha Fetoprotein Response as a Result of Guadecitabine Administration | 0 Participants |
| Guadecitabine 45 mg/m^2 | Alpha Fetoprotein Response as a Result of Guadecitabine Administration | 2 Participants |
Secondary
Duration of Response
Duration of response as measured in days. Included subjects with a complete response or partial response based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Time frame: From time of first response until disease progression or date of death due to any cause, whichever occurred earlier; an average of 192 days.
Population: Assessed for patients who had a clinical response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Guadecitabine 60 mg/m^2 | Duration of Response | 262 days |
| Guadecitabine 45 mg/m^2 | Duration of Response | 144 days |
Secondary
Overall Survival
Overall survival measured in days.
Time frame: Through completion of study survival follow-up, an average of 270 days.
Population: Includes all patients who received any guadecitabine
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Guadecitabine 60 mg/m^2 | Overall Survival | 294 days |
| Guadecitabine 45 mg/m^2 | Overall Survival | 245 days |
Secondary
Progression-free Survival
Progression-free survival measured in days. Progression-free survival was defined as the time interval from the date of the first dose of study treatment to the earlier of 1) documented radiologic progression per RECIST v1.1 or clinical progression, or 2) death due to any cause.
Time frame: Through completion of response assessments (i.e., until disease progression or treatment discontinuation), an average of 112 days.
Population: Includes all patients who received any guadecitabine
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Guadecitabine 60 mg/m^2 | Progression-free Survival | 55 days |
| Guadecitabine 45 mg/m^2 | Progression-free Survival | 82.5 days |
Secondary
Safety and Tolerability of Guadecitabine
Number of patients with serious adverse events and adverse events
Time frame: Varied by patient (median number of treatment cycles was 2.0 (range 2-8) in 60 mg/m^2 group, and 4.0 (range 1-13) in 45 mg/m^2 group
Population: Includes all patients who received any guadecitabine
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Guadecitabine 60 mg/m^2 | Safety and Tolerability of Guadecitabine | Serious Adverse Event | 1 Participants |
| Guadecitabine 60 mg/m^2 | Safety and Tolerability of Guadecitabine | Adverse Event | 4 Participants |
| Guadecitabine 45 mg/m^2 | Safety and Tolerability of Guadecitabine | Serious Adverse Event | 21 Participants |
| Guadecitabine 45 mg/m^2 | Safety and Tolerability of Guadecitabine | Adverse Event | 46 Participants |