Advanced Hepatocellular Carcinoma
Conditions
Keywords
MDV3100, advanced hepatocellular carcinoma, enzalutamide, Xtandi, ASP9785
Brief summary
The purpose of the study was to evaluate the efficacy of enzalutamide in participants with advanced hepatocellular carcinoma (HCC) as measured by overall survival (OS). This study also evaluated the safety of enzalutamide; pharmacokinetics of enzalutamide and the active metabolite N-desmethyl and Progression Free Survival (PFS) of enzalutamide as compared to placebo in participants with advanced HCC.
Interventions
DRUGEnzalutamide
Oral capsule
DRUGPlacebo
Oral capsule
Sponsors
Pfizer
Astellas Pharma Global Development, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subject is ≥ 18 years of age or is considered an adult according to local regulation at the time of signing informed consent. * Subject has a documented diagnosis of advanced HCC of any etiology. * Subject has BCLC stage B or C. * Subject's lesions are not amenable to local therapies which may be beneficial, such as transarterial chemoembolization (TACE), radiofrequency ablation, radiotherapy, etc., and the subject is not a candidate for any curative treatments such as resection or liver transplant. * Subject has hepatic function status of Child Pugh Class A at Screening. * Subject received prior systemic treatment for HCC with sorafenib or other anti-VEGF therapy and had confirmed disease progression or discontinued treatment due to a drug-related toxicity. Subject may have received 1 line of systemic therapy before or after sorafenib/anti-VEGF treatment. * Subject has adequately recovered from toxicities due to prior HCC therapy to ≤ grade 1. * Subject has an ECOG performance status ≤ 1 at Screening and on Day 1. * Subject has available formalin-fixed, paraffin-embedded tumor specimen with adequate viable tumor cells in a tissue block or unstained serial slides accompanied by an associated pathology report prior to enrollment. Archival or fresh biopsy tissue is required. * Subject has an estimated life expectancy of at least 3 months on Day 1, in the opinion of the investigator. * Female subject is either: * Not of childbearing potential: postmenopausal (defined as no spontaneous menses for at least 12 consecutive months prior to Screening with follicle-stimulating hormone \[FSH\] \> 40 IU/L for women \< 55 years of age at Screening), or documented to be surgically sterile or status posthysterectomy (at least 1 month prior to Screening). * Or, if of childbearing potential: must have a negative urine pregnancy test at Screening and on Day 1 before the first dose of study drug is administered, and must use 2 acceptable methods of birth control\* if sexually active from Screening through 3 months after the last dose of study drug. * Sexually active male subject and his female partner who is of childbearing potential must use 2 acceptable methods of birth control from Screening through 3 months after the last dose of study drug. \* Two acceptable methods of birth control are as follows: * Condom (barrier method of contraception); AND * One of the following is required: Placement of an intrauterine device (IUD) or intrauterine system (IUS) by the female subject or female partner of a male subject; Additional barrier method: contraceptive sponge or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository by the female subject or female partner of a male subject. For male subject or male partner of female subject, vasectomy or other procedure resulting in infertility (e.g., bilateral orchiectomy) performed at least 6 months before Screening. Tubal ligation in the female partner of a male subject performed at least 6 months before Screening. Established and ongoing use of oral, injected, or implanted hormonal contraceptive by female partner of a male subject. * Female subject must not be breastfeeding at Screening or during the study period and for 3 months after final study drug administration. * Subject must agree not to donate sperm or ova from first dose of study drug through 3 months after the last dose of study drug. * Throughout the study, male subject must use a condom if having sex with a pregnant woman. * Subject must be able to swallow study drug and comply with study requirements. * Subject agrees not to participate in another interventional study while on treatment. * Received double-blind enzalutamide study treatment during the main study.
Exclusion criteria
* Subject has a severe concurrent disease, infection or comorbidity that, in the judgment of the investigator, would make the subject inappropriate for enrollment. * Subject has fibrolamellar variant of HCC. * Subject has status of Child-Pugh Class B or C at Screening. * Subject has a history of organ allograft including liver transplant. * Subject has uncontrolled symptomatic ascites. * Subject has known or suspected brain metastasis or active leptomeningeal disease. * Subject has a history of a non-HCC malignancy with the following exceptions: * The subject with a previous history of a noninvasive carcinoma is eligible if in the opinion of the investigator he/she has had successful curative treatment any time prior to Screening and requires no further therapy for the malignancy. * For all other malignancies, the subject is eligible if he/she has undergone potentially curative therapy and has been considered disease free for at least 3 years prior to Screening. * Subject has inadequate marrow, hepatic, and/or renal function at the Screening Visit defined as: * Absolute neutrophil count \< 1.5 x109/L (\< 1500 cells/mm3) * Platelet count \< 50 x109/L (\< 50,000 cells/mm3) * Hemoglobin \< 8.5 g/dL (\< 5.3 mmol/L) * International normalized ratio \> 1.7 * Albumin \< 2.8 g/dL (\< 28 g/L) * Total bilirubin (TBL) \> 2 x ULN * AST or ALT \> 5 x ULN * Creatinine \> 1.5 x ULN * Note: Transfusions/infusions to meet eligibility criteria are not allowed but if in the opinion of the Principal Investigator, it is beneficial, the patient may be rescreened after receiving one of these procedures. * Subject has a history of seizure or any condition that may predispose to seizure (e.g., prior cortical stroke, significant brain trauma, encephalopathy within 3 months of Day 1). * Subject has a history of bleeding esophageal varices within 3 months before the Day 1 visit. * Subject has a history of loss of consciousness or transient ischemic attack within 12 months before the Day 1 visit. * Subject has clinically significant cardiovascular disease including: * Myocardial infarction within 6 months before the Day 1 visit. * Uncontrolled angina within 6 months before the Day 1 visit. * Congestive heart failure New York Heart Association (NYHA) Class III or IV or history of congestive heart failure NYHA Class III or IV in the past, unless a Screening echocardiogram or multi-gated acquisition scan performed within 3 months before the Day 1 visit reveals a left ventricular ejection fraction that is ≥ 45%. * History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, Torsade de Pointes). * History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place. * Hypotension as indicated by systolic blood pressure \< 86 mmHg on 2 consecutive measurements at the Screening visit. * Bradycardia (in the presence of known cardiovascular disease) as indicated by a heart rate of \< 50 beats per minute on the Screening electrocardiogram (ECG) recording. * Uncontrolled hypertension as indicated by systolic blood pressure \> 170 mmHg or diastolic blood pressure \> 105 mmHg on 2 consecutive measurements at the Screening visit. * Subject has a gastrointestinal disorder affecting absorption. * Subject had previous local therapy (e.g., surgery, radiation therapy, hepatic arterial therapy, chemoembolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation) within 14 days prior to Day 1, has not recovered from toxicities from prior local therapy or may require major surgical procedure during the course of the study. * Subject has received chemotherapy, immunotherapy or any other systemic anticancer therapy (including sorafenib) or any other investigational drug within 14 days prior to the Day 1 visit. * Subject has received an agent that either blocks androgen synthesis or targets the AR (e.g., abiraterone acetate, bicalutamide, enzalutamide, ARN-509 or other investigational AR signaling inhibitors). The exception of spironolactone is allowed after Medical Monitor consultation. * Subject has used any of the following within 28 days before the Day 1 visit: * 5-α reductase inhibitors * Systemic androgens and estrogens (vaginal estrogen creams are allowed) * Herbal therapies, with an antitumor effect. * Subject has a known history of positive test for Human Immunodeficiency Virus. * Subject has shown a hypersensitivity reaction to the active pharmaceutical ingredient or any of the enzalutamide capsule components, including caprylocaproyl polyoxylglycerides (Labrasol), butylated hydroxyanisole and butylated hydroxytoluene. * Subject has addictive/substance abuse problems. * Subject has any other condition or reason that, in the opinion of the investigator, interferes with the ability of the subject to participate in the trial, places the subject at undue risk or complicates the interpretation of safety data. * Received double-blind placebo during the main study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From date of randomization up to data cut-off date 02 Oct 2017 (approximately 22 months); median follow-up time was 14.65 months for enzalutamide and 13.83 for placebo. | OS was defined as the time from the date of randomization until the documented date of death from any cause. Participants who were still alive at the time of the data cut-off date was censored on the last date known to be alive or at the data cutoff date, whichever occurs first. Results based on Kaplan-Meier estimates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) | From first dose of study drug up to 30 days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo | Safety was assessed by AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant. A treatment-emergent AE (TEAE) was defined as an AE observed after starting administration of the study drug up to 30 days after last dose of study drug or initiation of new treatment, whichever comes first. AEs were considered as serious if resulted in in death, was life-threatening resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, resulted in congenital anomaly or birth defect, required inpatient hospitalization or led to prolongation of hospitalization and other medically important events. |
| Plasma Trough Concentrations of Enzalutamide | Predose at weeks 5, 9 and 13 | Blood samples were collected for analysis. |
| Plasma Trough Concentrations N-desmethyl Enzalutamide (M2 Metabolite) | Predose at weeks 5, 9 and 13 | Blood samples were collected for analysis. |
| Plasma Trough Concentrations of MDPC0001 (M1 Metabolite) | Predose at weeks 5, 9 and 13 | Blood samples were collected for analysis. |
| Progression Free Survival (PFS) | From date of randomization up to data cut-off date 02 Oct 2017 (approximately 22 months); median follow-up time was 14.65 months for enzalutamide and 13.83 for placebo. | PFS was defined as the time from the date of randomization until the date of documented radiographic disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as determined by the investigator or death from any cause on study, whichever occurred first. The earliest of the censoring times was used: Participants with (1) no evaluable postbaseline imaging assessments or did not die were censored at the randomization date; (2) no radiographical progression or did not die before analysis cutoff date were censored at the last radiological assessment date before analysis cutoff date; (3) with no radiographical progression or did not die before new HCC treatment was censored at the last radiological assessment date before start of new HCC treatment. Based on Kaplan-Meier. |
Countries
Canada, Hong Kong, Italy, Puerto Rico, South Korea, Spain, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled from 37 sites in 9 countries in Europe, Asia, and North America. Participants with hepatocellular carcinoma (HCC) of any etiology whose disease had progressed on or who were intolerant to sorafenib or other antivascular endothelial growth factor (VEGF) therapy in the advanced setting were enrolled. Double blind treatment (DB) Open label (OL).
Pre-assignment details
Eligible participants were stratified by geographic region (Asia vs other) and Eastern Cooperative Oncology Group (ECOG) performance (0 vs 1) and randomized in a 2:1 ratio. Participants who discontinued treatment entered a follow-up period .
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received enzalutamide matching placebo orally, QD during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days. | 55 |
| Enzalutamide Participants received enzalutamide 160 mg capsules, orally QD during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days. | 110 |
| Total | 165 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| DB (Median Duration up to 14.65 Months) | Adverse Event | 5 | 8 |
| DB (Median Duration up to 14.65 Months) | Death | 1 | 6 |
| DB (Median Duration up to 14.65 Months) | Lost to Follow-up | 0 | 1 |
| DB (Median Duration up to 14.65 Months) | Miscellaneous | 3 | 5 |
| DB (Median Duration up to 14.65 Months) | Progressive Disease | 44 | 82 |
| DB (Median Duration up to 14.65 Months) | Withdrawal by Subject | 2 | 8 |
| OL (Median Duration up to 27.56 Months) | Progressive Disease | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Placebo | Enzalutamide |
|---|---|---|---|
| Age, Continuous | 63.3 Years STANDARD_DEVIATION 11.5 | 62.6 Years STANDARD_DEVIATION 12.5 | 63.7 Years STANDARD_DEVIATION 10.9 |
| Eastern Cooperative Oncology Group (ECOG) PS (0,1) ECOG PS = 0 | 66 Participants | 23 Participants | 43 Participants |
| Eastern Cooperative Oncology Group (ECOG) PS (0,1) ECOG PS = 1 | 99 Participants | 32 Participants | 67 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 162 Participants | 55 Participants | 107 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Geographic Region Asia | 72 Participants | 24 Participants | 48 Participants |
| Geographic Region Other | 93 Participants | 31 Participants | 62 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 77 Participants | 25 Participants | 52 Participants |
| Race/Ethnicity, Customized Black or African American | 8 Participants | 3 Participants | 5 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 78 Participants | 26 Participants | 52 Participants |
| Sex: Female, Male Female | 21 Participants | 6 Participants | 15 Participants |
| Sex: Female, Male Male | 144 Participants | 49 Participants | 95 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 45 / 55 | 82 / 107 |
| other Total, other adverse events | 46 / 55 | 96 / 107 |
| serious Total, serious adverse events | 22 / 55 | 47 / 107 |
Outcome results
Primary
Overall Survival (OS)
OS was defined as the time from the date of randomization until the documented date of death from any cause. Participants who were still alive at the time of the data cut-off date was censored on the last date known to be alive or at the data cutoff date, whichever occurs first. Results based on Kaplan-Meier estimates.
Time frame: From date of randomization up to data cut-off date 02 Oct 2017 (approximately 22 months); median follow-up time was 14.65 months for enzalutamide and 13.83 for placebo.
Population: The analysis population was the FAS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Overall Survival (OS) | 7.69 months |
| Enzalutamide | Overall Survival (OS) | 7.75 months |
Comparison: Stratified Analysis. The null hypothesis was stated as: OS distributions of the 2 arms are equivalent. The alternative hypothesis was stated as: OS is prolonged in enzalutamide arm. The null hypothesis was tested using a stratified one-sided log-rank test at the 0.10 level. Stratification factors were ECOG performance status and region from eCRF.p-value: 0.24895% CI: [0.774, 1.696]Log Rank
Comparison: Unstratified Analysis. The null hypothesis was stated as: OS distributions of the 2 arms are equivalent. The alternative hypothesis was stated as: OS is prolonged in enzalutamide arm. The null hypothesis was tested using a one-sided log-rank test at the 0.10 level.p-value: 0.25295% CI: [0.773, 1.688]Log Rank
Secondary
Number of Participants With Adverse Events (AEs)
Safety was assessed by AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant. A treatment-emergent AE (TEAE) was defined as an AE observed after starting administration of the study drug up to 30 days after last dose of study drug or initiation of new treatment, whichever comes first. AEs were considered as serious if resulted in in death, was life-threatening resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, resulted in congenital anomaly or birth defect, required inpatient hospitalization or led to prolongation of hospitalization and other medically important events.
Time frame: From first dose of study drug up to 30 days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo
Population: The analysis population was the safety analysis set (SAF), which consisted of all participants who have received at least 1 or partial capsule of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Events (AEs) | Drug-related TEAEs | 24 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Serious TEAEs | 22 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | TEAE Leading to Death | 6 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Drug-related Serious TEAEs | 3 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Deaths | 45 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | TEAEs Leading to Treatment Withdrawal | 14 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Drug-related TEAEs Leading to Death | 0 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Drug-related TEAEs Leading to Treatment Withdrawal | 4 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) | TEAE | 50 Participants |
| Enzalutamide | Number of Participants With Adverse Events (AEs) | Drug-related TEAEs Leading to Treatment Withdrawal | 7 Participants |
| Enzalutamide | Number of Participants With Adverse Events (AEs) | TEAE | 105 Participants |
| Enzalutamide | Number of Participants With Adverse Events (AEs) | Drug-related TEAEs | 69 Participants |
| Enzalutamide | Number of Participants With Adverse Events (AEs) | Deaths | 82 Participants |
| Enzalutamide | Number of Participants With Adverse Events (AEs) | TEAE Leading to Death | 12 Participants |
| Enzalutamide | Number of Participants With Adverse Events (AEs) | Drug-related TEAEs Leading to Death | 0 Participants |
| Enzalutamide | Number of Participants With Adverse Events (AEs) | Serious TEAEs | 47 Participants |
| Enzalutamide | Number of Participants With Adverse Events (AEs) | Drug-related Serious TEAEs | 7 Participants |
| Enzalutamide | Number of Participants With Adverse Events (AEs) | TEAEs Leading to Treatment Withdrawal | 34 Participants |
Secondary
Plasma Trough Concentrations N-desmethyl Enzalutamide (M2 Metabolite)
Blood samples were collected for analysis.
Time frame: Predose at weeks 5, 9 and 13
Population: The analysis population was the PKAS, with participants who had available concentration data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Plasma Trough Concentrations N-desmethyl Enzalutamide (M2 Metabolite) | Week 5 | 11.01 μg/mL | Standard Deviation 3.63 |
| Placebo | Plasma Trough Concentrations N-desmethyl Enzalutamide (M2 Metabolite) | Week 9 | 12.65 μg/mL | Standard Deviation 3.89 |
| Placebo | Plasma Trough Concentrations N-desmethyl Enzalutamide (M2 Metabolite) | Week 13 | 12.21 μg/mL | Standard Deviation 4.94 |
Secondary
Plasma Trough Concentrations of Enzalutamide
Blood samples were collected for analysis.
Time frame: Predose at weeks 5, 9 and 13
Population: The analysis population was the pharmacokinetics analysis set (PKAS), consisted of the subset of the SAF population for whom at least 1 quantifiable enzalutamide and N-desmethyl enzalutamide concentration value was available. Participants who had available concentration data were included in the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Plasma Trough Concentrations of Enzalutamide | Week 5 | 14.29 μg/mL | Standard Deviation 4.15 |
| Placebo | Plasma Trough Concentrations of Enzalutamide | Week 9 | 12.15 μg/mL | Standard Deviation 4.68 |
| Placebo | Plasma Trough Concentrations of Enzalutamide | Week 13 | 12.45 μg/mL | Standard Deviation 5.44 |
Secondary
Plasma Trough Concentrations of MDPC0001 (M1 Metabolite)
Blood samples were collected for analysis.
Time frame: Predose at weeks 5, 9 and 13
Population: The analysis population was the PKAS, with participants who had available concentration data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Plasma Trough Concentrations of MDPC0001 (M1 Metabolite) | Week 5 | 4.70 μg/mL | Standard Deviation 3.86 |
| Placebo | Plasma Trough Concentrations of MDPC0001 (M1 Metabolite) | Week 9 | 5.60 μg/mL | Standard Deviation 5.63 |
| Placebo | Plasma Trough Concentrations of MDPC0001 (M1 Metabolite) | Week 13 | 6.12 μg/mL | Standard Deviation 4.24 |
Secondary
Progression Free Survival (PFS)
PFS was defined as the time from the date of randomization until the date of documented radiographic disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as determined by the investigator or death from any cause on study, whichever occurred first. The earliest of the censoring times was used: Participants with (1) no evaluable postbaseline imaging assessments or did not die were censored at the randomization date; (2) no radiographical progression or did not die before analysis cutoff date were censored at the last radiological assessment date before analysis cutoff date; (3) with no radiographical progression or did not die before new HCC treatment was censored at the last radiological assessment date before start of new HCC treatment. Based on Kaplan-Meier.
Time frame: From date of randomization up to data cut-off date 02 Oct 2017 (approximately 22 months); median follow-up time was 14.65 months for enzalutamide and 13.83 for placebo.
Population: The analysis population was the FAS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Progression Free Survival (PFS) | 1.87 months |
| Enzalutamide | Progression Free Survival (PFS) | 2.23 months |
Comparison: Stratified Analysis. The null hypothesis was stated as: PFS distributions of the 2 arms are equivalent. The alternative hypothesis was stated as: PFS is prolonged in enzalutamide arm. The null hypothesis was tested using a stratified one-sided log-rank test at the 0.10 level. Stratification factors were ECOG performance status and region from eCRF.p-value: 0.39695% CI: [0.732, 1.474]Log Rank
Comparison: Unstratified Analysis. The null hypothesis was stated as: PFS distributions of the 2 arms are equivalent. The alternative hypothesis was stated as: PFS is prolonged in enzalutamide arm. The null hypothesis was tested using a one-sided log-rank test at the 0.10 level.p-value: 0.58695% CI: [0.684, 1.345]Log Rank