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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT01488487
First received: December 6, 2011
Last updated: March 27, 2014
Last verified: March 2014
  Purpose

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.


Condition Intervention Phase
Advanced Adult Hepatocellular Carcinoma
Drug: Everolimus
Drug: Pasireotide
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Single Arm Study of Everolimus and Pasireotide (SOM230) in Patients With Advanced or Metastatic Hepatocellular Carcinoma (HCC)

Resource links provided by NLM:


Further study details as provided by UNC Lineberger Comprehensive Cancer Center:

Primary Outcome Measures:
  • Time to Progression (TTP) [ Time Frame: 7 years ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Number of Individuals Experiencing Toxicity [ Time Frame: 7 years ] [ Designated as safety issue: Yes ]
    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).

  • Overall survival (OS) [ Time Frame: 7 years ] [ Designated as safety issue: No ]
    Overall survival is defined as the time from study enrollment until death.

  • Objective Response Rate (ORR) [ Time Frame: 7 years ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 30
Study Start Date: December 2011
Estimated Study Completion Date: June 2015
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.
Drug: Everolimus
Everolimus 7.5 mg administered daily for 28 days per cycle until disease progression or unacceptable toxicity.
Other Names:
  • Afinitor
  • RAD001
Drug: 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.
Other Names:
  • SOM230
  • Pasireotide LAR
  • Pasireotide s.c.

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01488487

Locations
United States, Florida
Moffitt Cancer Center
Tampa, Florida, United States, 33612
United States, North Carolina
University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center
Chapel Hill, North Carolina, United States, 27599
Comprehensive Cancer Center of Wake Forest University
Winston-Salem, North Carolina, United States, 27157
Sponsors and Collaborators
UNC Lineberger Comprehensive Cancer Center
Novartis Pharmaceuticals
Investigators
Principal Investigator: Bert H O'Neil, MD University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT01488487     History of Changes
Other Study ID Numbers: LCCC 1032
Study First Received: December 6, 2011
Last Updated: March 27, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by UNC Lineberger Comprehensive Cancer Center:
HCC
Advanced Hepatocellular Carcinoma
Metastatic Hepatocellular Carcinoma
Liver Cancer

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Hepatocellular
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Everolimus
Sirolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents

ClinicalTrials.gov processed this record on August 20, 2014