Everolimus and Pasireotide (SOM230) in Patients With Advanced or Metastatic Hepatocellular Carcinoma

Advanced Adult Hepatocellular Carcinoma Clinical Trial

Official title:

Phase II Single Arm Study of Everolimus and Pasireotide (SOM230) in Patients With Advanced or Metastatic Hepatocellular Carcinoma (HCC)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01488487
• Other study ID #: LCCC 1032
• Status: Completed
• Phase: Phase 2
• First received: December 6, 2011
• Last updated: March 20, 2015
• Start date: December 2011
• Est. completion date: March 2015

Study information

• Verified date: March 2014
• Source: UNC Lineberger Comprehensive Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: March 2015
• Est. primary completion date: March 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 MRI. 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

• Hg >9 g/dL

• Bilirubin =2 x ULN

• AST or 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, IRB approved written informed consent

Exclusion Criteria:

• Patients meeting any of the following exclusion criteria at baseline will be excluded from study participation:

1. Patients who have received prior treatment with an mTOR inhibitor (e.g., sirolimus, temsirolimus, everolimus) or somatostatin analog (e.g. octeotride)

2. Chronic treatment with systemic steroids (except for intermittent topical, local injection, or eye drops) or another immunosuppressive agent. NOTE: This restriction regarding systemic steroids does not apply should patient need course of glucocorticoid for treatment of non-infectious pneumonitis during study (see Section 4.5.2).

3. Patients with a known hypersensitivity to everolimus or other rapamycins (e.g., sirolimus, temsirolimus) or to its excipients

4. Patients with a known hypersensitivity to somatostatin or to its excipients

5. Concurrent or planned radiation, hormonal, chemotherapeutic, experimental, or targeted biologic therapy

6. Prior treatment with any investigational drug within the preceding 4 weeks

7. Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:

• Symptomatic congestive heart failure (New York Heart Association [NYHA] Class III or IV)

• Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease

• Severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air

• Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN or HbA1c >8.0% (Note: at the principle investigator's discretion, ineligible patients can be re-screened after adequate medical therapy has been instituted.)

• Active (acute or chronic) or uncontrolled severe infections. NOTE: A detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening for all patients. HBV DNA and HCV RNA PCR testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection. See Section 4.2 for further information.

8. Clinically significant third space fluid accumulation (i.e., ascites requiring paracentesis despite use of diuretics) or pleural effusion that either requires thoracentesis or is associated with shortness of breath

9. Risk factors for prolongation of QTc* including:

• QTc at screening >450 msec

• History of syncope or family history of idiopathic sudden death

• Sustained or clinically significant cardiac arrhythmias

• Risk factors for Torsades de Pointes such as hypokalemia, hypomagnesemia, cardiac failure, clinically significant/symptomatic bradycardia, or high-grade AV block

• Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused by diabetes or Parkinson's disease), HIV, uncontrolled hypothyroidism, or cardiac failure

• Concomitant medication(s) known to increase QT interval (See Appendix B)

• UNC uses GE ECG carts which use the Bazett formula for QTc.

10. Patients should not receive immunization with attenuated live vaccines within 1 week of study entry or during study period. Close contact with those who have received attenuated live vaccines should be avoided during treatment with everolimus. Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.

11. Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases

12. Symptomatic cholelithiasis

13. Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin

14. A known history of HIV seropositivity (HIV testing is not mandatory)

15. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection.)

16. Patients with an active, bleeding diathesis or on oral anti-vitamin K medication (except warfarin as long as the goal INR is =1.5). LMWH is permitted (see Section 3.1.10.)

17. Unable or unwilling to discontinue use of prohibited fruit (or its juices) and/or prohibited medications listed in Appendix B for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study

18. Male patient whose sexual partner(s) are WOCBP who are not willing to use adequate contraception during the study and for 8 weeks after the end of treatment

19. Active alcohol intake of 80 grams or more per day. For reference, one portion of alcohol (one glass of wine, one can or bottle of beer, or one ounce of hard liquor) contains approximately 15 grams of ethanol.

20. Inability to comply with study and/or follow-up procedures

21. History of noncompliance to medical regimens

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Advanced Adult Hepatocellular Carcinoma
• Carcinoma
• Carcinoma, Hepatocellular

Intervention

Drug:
• 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.

Locations

Country	Name	City	State
United States	University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina
United States	Moffitt Cancer Center	Tampa	Florida
United States	Comprehensive Cancer Center of Wake Forest University	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
UNC Lineberger Comprehensive Cancer Center	Novartis Pharmaceuticals

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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 HCC 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.	7 years	No
Secondary	Number of Individuals Experiencing Toxicity	Safety determinations are based on the rate of drug-related AEs reported based upon the toxicity as measured by the NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0).	7 years	Yes
Secondary	Overall survival (OS)	Overall survival is defined as the time from study enrollment until death.	7 years	No
Secondary	Objective Response Rate (ORR)	Objective response rate (ORR) is defined as the rate of complete responses (CRs) + partial responses (PRs) as determined by RECIST and modified HCC RECIST criteria.	7 years	No

External Links

•   UNC Lineberger Website