Everolimus and Pasireotide (SOM230) in Patients With Advanced or Metastatic Hepatocellular Carcinoma
Condition: Advanced Adult Hepatocellular Carcinoma
MeSH terms: Carcinoma; Carcinoma, Hepatocellular
Intervention: Everolimus; Pasireotide
Intervention description: Everolimus 7.5 mg administered daily for 28 days per cycle until disease progression or unacceptable toxicity.; 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.
Intervention MeSH terms: Everolimus; Pasireotide; Somatostatin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 24.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: HCC; Advanced Hepatocellular Carcinoma; Metastatic Hepatocellular Carcinoma; Liver Cancer

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.
    

Eligibility criteria:

        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 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 diffusing
                       capacity for carbon monoxide (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
                       Glycated hemoglobin (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. Hepatitis B viral deoxyribonucleic
                       acid (HBV DNA) and Hepatitis C viral ribonucleic acid (HCV RNA) polymerase
                       chain reaction (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 Corrected QT Interval (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), human immunodeficiency virus
                       (HIV), uncontrolled hypothyroidism, or cardiac failure

                    -  Concomitant medication(s) known to increase QT interval (See Appendix B)

                         -  University of North Carolina at Chapel Hill (UNC) uses GE
                            electrocardiogram (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, Bacillus Calmette-Guérin (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). Low-molecular-weight heparin
                  (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