Advanced Adult Hepatocellular Carcinoma
Conditions
Keywords
HCC, Advanced Hepatocellular Carcinoma, Metastatic Hepatocellular Carcinoma, Liver Cancer
Brief summary
The purpose of this study is to estimate the time to disease progression when everolimus and pasireotide are given together in patients with advanced or metastatic HCC who have not had any prior systemic therapy.
Detailed description
This open label, single-arm Phase II study will assess time to progression (TTP) and safety of everolimus and pasireotide in patients with advanced or metastatic hepatocellular carcinoma (HCC) and limited prior systemic therapy. Should this regimen demonstrate efficacy, this will support a Phase III randomized clinical trial of this combination therapy. At least 30 patients will be enrolled into this Phase II study. Additionally, given the potential importance of the RAS/RAF/MEK/ERK and RAS/pAKT pathways, we propose to correlate outcomes with baseline pAKT, p-S6, somatostatin receptor tumor expression, and serum VEGF expression. We anticipate these exploratory analyses will increase understanding of the molecular pathways and their inhibition in this disease. The study will be performed as a University of North Carolina-coordinated, multicenter study.
Interventions
DRUGEverolimus
Everolimus 7.5 mg administered daily for 28 days per cycle until disease progression or unacceptable toxicity.
DRUGPasireotide
Monthly (every 28 days) intramuscular injection of long-acting pasireotide (pasireotide LAR 60 mg) repeated on day 1 of every 28 day cycle until disease progression or unacceptable toxicity.
Sponsors
Novartis Pharmaceuticals
UNC Lineberger Comprehensive Cancer Center
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
* Each subject must meet all of the following inclusion criteria to participate in this study: 1. Advanced or metastatic hepatocellular carcinoma (stage C per the BCLC criteria, see Appendix A). HCC may be diagnosed by tissue diagnosis or Alpha-fetoprotein (AFP) \>400 ng/mL with compatible mass on Magnetic Resonance Imaging Scan (MRI). Cat Scan (CT) abdomen with 3-phase contrast with arterial phase enhancement is acceptable, although MRI is preferred (imaging should be done within 4 weeks of study initiation). Recurrences of previously resected HCC will not require tissue confirmation if there is clear radiographic recurrence in the judgment of the investigator. Disease must not otherwise be amenable to local therapy. 2. Maximum Childs-Pugh score 6 (see Appendix A) with no active encephalopathy 3. Prior systemic therapy limited to sorafenib that was discontinued due to intolerance. Patients must undergo at least a 4-week washout prior to enrollment. 4. Eastern Cooperative Oncology Group (ECOG) PS of 0-2 5. Life expectancy of \>12 weeks 6. Age ≥18 years 7. Patients who have received previous local therapy, such as surgery, radiotherapy, hepatic arterial embolization, chemoembolization, radiofrequency ablation, percutaneous injection, or cryoablation, will be eligible for enrollment in the study provided that there is documented progression and disease is not amenable to further local therapies. Therapy must be completed \>4 weeks prior to study initiation (Day 1 of everolimus and pasireotide administration). 8. Minimum of 4 weeks since any major surgery 9. No active serious infection or other comorbid illness which would impair ability to participate in the trial. 10. International Normalized Ratio (INR) ≤1.5. (Anticoagulation is allowed if target INR ≤2.0 on a stable dose of warfarin or on a stable dose of low molecular weight heparin (LMWH) for \>2 weeks at time of enrollment). 11. Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides (TGs) ≤2.5 x upper limit of normal (ULN). NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication. 12. Patients must have adequate organ function as evidenced by: * Absolute neutrophil count (ANC) ≥1.5 x 109/L * Platelet count ≥50 x 109/L * Hemoglobin (Hg) \>9 g/dL * Bilirubin ≤2 x ULN * Aspartate transaminase (AST) or Alanine transaminase (ALT) ≤5 x ULN * Serum creatinine ≤1.5 x ULN OR creatinine clearance ≥50 mL/min (estimated by Cockcroft Gault or measured) 13. Serum magnesium and serum potassium within institutional normal limits (patients may be on replacement) 14. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test performed within 7 days prior to Day 1 of everolimus and pasireotide administration. 15. WOCBP and men must agree to use adequate contraception (barrier method of birth control) prior to study entry and for the duration of study participation. Men and women should use adequate birth control for at least 8 weeks after the last administration of study drugs. (Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions and are therefore not considered effective for this study.) 16. Signed, Institutional Review Board (IRB) approved written informed consent
Exclusion criteria
* Patients meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression (TTP) | 3.5 years | Time to progression is defined as the time from study enrollment until radiological progression in a previously embolized lobe, development of new lesions in an untreated lobe, or evidence of extrahepatic progression (based on modified Hepatocellular Carcinoma (HCC) Response Evaluation Criteria In Solid Tumors (RECIST) criteria). Patients will be followed until death. Patients that die of causes unrelated to the study drug without evidence of progression will be censored. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Individuals Experiencing Toxicity | 3.5 years | Safety determinations are based on the rate of drug-related adverse events (AEs) reported based upon the toxicity as measured by the NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). |
| Overall Survival (OS) | 3.5 years | Overall survival is defined as the time from study enrollment until death. |
| Objective Response Rate (ORR) | 3.5 years | ORR is the rate of complete responses (CRs) + partial responses (PRs) as determined by RECIST (v1.1) and modified HCC RECIST criteria. Responses defined as follows: CR: disappearance of all clinical/radiological evidence of tumor including any intratumoral arterial enhancement in all target lesions. Partial Response (PR): at least a 30% decrease in the sum of diameters of viable (contrast enhancement in the arterial phase) target lesions, referencing the baseline sum. Stable Disease (SD): any cases that do not qualify for either partial response or progressive disease. Progressive Disease (PD): an increase of at least 20% in the sum of the diameters of viable target lesions, referencing the nadir sum, and/or the appearance of one or more new lesions. A new hepatic nodule signals PD when the longest diameter is at least 10 mm and the nodule shows the typical vascular pattern of HCC on dynamic imaging or if at least 1-cm interval growth is seen in subsequent scans. |
Countries
United States
Participant flow
Pre-assignment details
Of the 33 participants screened for eligibility, 24 were deemed eligible and went on to treatment, 8 were ineligible, and 1 participant withdrew consent prior to treatment assignment.
Participants by arm
| Arm | Count |
|---|---|
| Everolimus + Pasireotide Oral Everolimus 7.5 mg administered daily for 28 days per cycle, plus pasireotide LAR 60 mg administered by intramuscular injection once per 28 day cycle on day 1.
Everolimus: Everolimus 7.5 mg administered daily for 28 days per cycle until disease progression or unacceptable toxicity.
Pasireotide: Monthly (every 28 days) intramuscular injection of long-acting pasireotide (pasireotide LAR 60 mg) repeated on day 1 of every 28 day cycle until disease progression or unacceptable toxicity. | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 6 |
| Overall Study | Death | 1 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Everolimus + Pasireotide |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 9 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants |
| Age, Continuous | 59 years |
| BCLC (Barcelona Clinic Liver Cancer) Stage Missing | 1 participants |
| BCLC (Barcelona Clinic Liver Cancer) Stage Stage B | 2 participants |
| BCLC (Barcelona Clinic Liver Cancer) Stage Stage C | 21 participants |
| Child-Pugh Score (Stage) | 5 units on a scale |
| Chronic Hepatitis B Absent | 22 participants |
| Chronic Hepatitis B Present | 2 participants |
| Chronic Hepatitis C Absent | 17 participants |
| Chronic Hepatitis C Present | 7 participants |
| CLIP (Cancer of the Liver Italian Program) score | 1.5 units on a scale |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Extent of cancer Metastatic | 11 participants |
| Extent of cancer Multifocal | 11 participants |
| Extent of cancer Unifocal | 2 participants |
| Portal vein involvement Absent | 15 participants |
| Portal vein involvement Present | 9 participants |
| Prior therapy received for this cancer Ablation | 2 participants receiving this prior tx |
| Prior therapy received for this cancer Missing | 1 participants receiving this prior tx |
| Prior therapy received for this cancer None | 12 participants receiving this prior tx |
| Prior therapy received for this cancer Surgery | 8 participants receiving this prior tx |
| Prior therapy received for this cancer Transarterial chemoembolization (TACE) | 4 participants receiving this prior tx |
| Prior therapy received for this cancer Transarterial radioembolization (TARE) | 2 participants receiving this prior tx |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 21 Participants |
| Region of Enrollment United States | 24 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 16 Participants |
| Time from diagnosis to enrollment | 4 Months |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 24 / 24 |
| serious Total, serious adverse events | 6 / 24 |
Outcome results
Primary
Time to Progression (TTP)
Time to progression is defined as the time from study enrollment until radiological progression in a previously embolized lobe, development of new lesions in an untreated lobe, or evidence of extrahepatic progression (based on modified Hepatocellular Carcinoma (HCC) Response Evaluation Criteria In Solid Tumors (RECIST) criteria). Patients will be followed until death. Patients that die of causes unrelated to the study drug without evidence of progression will be censored.
Time frame: 3.5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus + Pasireotide | Time to Progression (TTP) | 3.5 months |
Secondary
Number of Individuals Experiencing Toxicity
Safety determinations are based on the rate of drug-related adverse events (AEs) reported based upon the toxicity as measured by the NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0).
Time frame: 3.5 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus + Pasireotide | Number of Individuals Experiencing Toxicity | Dose Limiting Toxicities (DLT) | 1 participants |
| Everolimus + Pasireotide | Number of Individuals Experiencing Toxicity | Any adverse event | 24 participants |
Secondary
Objective Response Rate (ORR)
ORR is the rate of complete responses (CRs) + partial responses (PRs) as determined by RECIST (v1.1) and modified HCC RECIST criteria. Responses defined as follows: CR: disappearance of all clinical/radiological evidence of tumor including any intratumoral arterial enhancement in all target lesions. Partial Response (PR): at least a 30% decrease in the sum of diameters of viable (contrast enhancement in the arterial phase) target lesions, referencing the baseline sum. Stable Disease (SD): any cases that do not qualify for either partial response or progressive disease. Progressive Disease (PD): an increase of at least 20% in the sum of the diameters of viable target lesions, referencing the nadir sum, and/or the appearance of one or more new lesions. A new hepatic nodule signals PD when the longest diameter is at least 10 mm and the nodule shows the typical vascular pattern of HCC on dynamic imaging or if at least 1-cm interval growth is seen in subsequent scans.
Time frame: 3.5 years
Population: Two patients were not evaluable; one due to death prior to radiographic evaluation (death clinically attributed to progressive disease) and the other due to early termination of treatment due to intolerance.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus + Pasireotide | Objective Response Rate (ORR) | Radiographic response (CR or PR) | 0 percentage of participants |
| Everolimus + Pasireotide | Objective Response Rate (ORR) | Stable disease | 45.5 percentage of participants |
Secondary
Overall Survival (OS)
Overall survival is defined as the time from study enrollment until death.
Time frame: 3.5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Everolimus + Pasireotide | Overall Survival (OS) | 6.7 months |