Phase II Trial of SOM230 in Patients With Unresectable Hepatocellular Carcinoma

Phase II Trial of SOM230 (Pasireotide LAR) in Patients With Unresectable Hepatocellular Carcinoma (HCC)

The hypothesis of this clinical trial is that hepatocellular carcinomas contain somatostatin receptors which make them sensitive to the inhibitory effects of a new somatostatin analog, SOM230. This analog has greater and broader binding affinity to somatostatin receptors compared to the current drug in use, sandostatin LAR. Thus, SOM230 has the potential to be more effective in the treatment of patients with hepatocellular carcinoma.

Study Overview

• Status: Completed
• Conditions: Hepatocellular Carcinoma
• Intervention / Treatment: Biological: SOM230

Detailed Description

For all patients, SOM230 will be given at a starting dose of 60 mg intramuscularly (IM) every 28 days. Dose reduction will be allowed for toxicities which are deemed to be therapy-related. Patients will receive SOM230C (IM) as an outpatient and will be observed for at least 30 minutes for any immediate adverse reactions. Toxicity checks will be done every 2 weeks and laboratory tests every 4 weeks during study therapy). Safety and efficacy will be assessed throughout the treatment period. Toxicities will be graded using the Common Terminology Criteria for Adverse Events, version 4.02.

Therapy will continue for maximum of two years if the patient shows no evidence of disease progression or intolerable toxicity. After completion of all study related therapy patients will complete a 30 day safety follow up visit. Patients who are still benefiting from therapy after two years may continue longer only after discussion between the Principal Investigator (PI) and the drug sponsor.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Diagnosis of unresectable HCC by either:

   • Histopathology or
   • Elevated serum Alpha-fetoprotein (AFP) >400 ng/ml and findings on magnetic resonance imaging (MRI) or CT scans characteristic of a primary liver tumor.
   • Findings on MRI or CT scans characteristic of a primary liver tumor in patients with cirrhosis
   • Tumors at least 1 cm or greater
2. Age ≥ 18 years.
3. Minimum of four weeks since any major surgery, completion of radiation,or completion of all prior systemic anticancer therapy (adequately recovered from the acute toxicities of any prior therapy).
4. Patients may have progressed on sorafenib or refused or were intolerant of sorafenib. A maximum of 2 prior lines of systemic therapy (including chemotherapy or targeted therapy) will be allowed. Prior locoregional therapy such as surgery, radiofrequency ablation or transarterial chemoembolization are also allowed (these will not be counted as systemic therapy), provided that progression has been documented after these therapies, and at least 4 weeks have elapsed since the last therapy.
5. Karnofsky performance status (KPS) of 80 or Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Life expectancy 12 weeks or more.
7. Adequate bone marrow function as shown by: Absolute neutrophil count (ANC) ≥ 1.2 x 10^9/L, Platelets ≥ 50 x 10^9/L
8. Adequate liver function as shown by: serum bilirubin < 1.5x upper limit of normal (ULN) and serum transaminases activity ≤ 3 x ULN. Serum PT =< 16 seconds.
9. Adequate renal function as shown by serum creatinine ≤ 1.5 x ULN.
10. Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation (can start after one day of initiation of lipid lowering drug) of appropriate lipid lowering medication.
11. Women of childbearing potential must have a negative serum or urine pregnancy test within 14 days of the administration of the first study treatment. Women must not be lactating. Both men and women of childbearing potential must be advised of the importance of using effective birth control measures during the course of the study.
12. Signed informed consent to participate in the study must be obtained from patients after they have been fully informed of the nature and potential risks by the investigator (or his/her designee) with the aid of written information.
13. Child's A and early Child's B (no more than 7 points on the Child Pugh Classification).
14. Measurable disease by CT scan with contrast. If evaluable disease or measurable disease has been previously treated, this must show signs of tumor progression by CT. Measurable disease and evaluable disease will be defined by the RECISTguidelines (see section 9.0).
15. Patients with cirrhosis either radiologically or pathology with findings either by CT scan or MRI characteristic of primary liver cancer are eligible.

Exclusion Criteria:

1. Prior octreotide therapy or any somatostatin analog.
2. Chronic treatment with systemic steroids or another immunosuppressive agent.
3. Patients should not receive immunization with attenuated live vaccines during study period or within 1 week of study entry (ie. within 1 week of signing the informed consent).
4. Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases.
5. Patients with prior or concurrent malignancy except for the following: adequately treated basal cell or squamous cell skin cancer, or other adequately treated in situ cancer, or any other cancer from which the patient has been disease free for five years.
6. Patients with uncontrolled diabetes mellitus (defined as HgA1c > 7% or =8% despite therapy) or a fasting plasma glucose > 1.5 ULN. Note: At the principle investigator's discretion, non-eligible patients can be re-screened after adequate medical therapy has been instituted.
7. Patients with symptomatic cholelithiasis
8. Patients who have congestive heart failure (NYHA Class III or IV), unstable angina,sustained ventricular tachycardia, ventricular fibrillation, clinically significant bradycardia, advanced heart block or a history of acute myocardial infarction within the six months preceding enrollment.

9. Patients who are at high risk for cardiac arrhythmias as defined by any of the following:

   • Baseline QTcF > 470 msec
   • History of syncope or family history of idiopathic sudden death or long QT syndrome
   • 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 atrioventricular block (AV) block
   • Concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused by uncontrolled diabetes, or Parkinson's disease), HIV, uncontrolled hypothyroidism or cardiac failure
   • Concomitant medication(s) known to increase the QT interval (see Appendix II)
10. Patients with the presence of active or suspected acute or chronic uncontrolled infection or with a history of immunocompromise, including a positive HIV test result (ELISA and Western blot).

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

    • Severely impaired lung function
    • Any active (acute or chronic) or uncontrolled infection/ disorders.
    • Nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy
12. Women who are pregnant or breast feeding, or women/men able to conceive and unwilling to practice an effective method of birth control. (Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to administration of pasireotide). Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study.
13. Known hypersensitivity to somatostatin analogues or any component of the pasireotide or octreotide LAR formulations
14. History of noncompliance to medical regimens
15. Patients unwilling to or unable to comply with the protocol or unable to give informed consent.
16. Patients with baseline Alanine transaminase (ALT) or Aspartate transaminase (AST) > 3x ULN.
17. Patients with baseline serum bilirubin > 1.5 x ULN.
18. Prothrombin time (PT) > 16 seconds and/or partial thromboplastin time (PTT) > 1.5 x ULN
19. History of or current alcohol misuse/abuse within the past 12 months.
20. Known gallbladder or bile duct disease, acute or chronic pancreatitis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SOM230; 60mg of SOM230 via injection intramuscularly every 28 days	Biological: SOM230; Patients will be given a starting of 60mg of SOM230 via injection, intramuscularly every 28 days.; Other Names: Pasireotide LAR; SOM230C

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Control Rate (DCR)	The disease-control rate (DCR) is defined as the proportion of participants achieving a best overall response of complete response (CR), partial response or stable disease (SD) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions assessed by MRI or CT Scan, and that is maintained for at least 8 weeks. CR is defined as disappearance of all target lesions; PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD; and SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started.	At least 2 cycles, about 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Progression-Free Survival (PFS):	Rate of Progression-Free Survival (PFS). PFS will be measured from the date of enrollment to the earliest date of documented disease progression or death from any cause, whichever is earlier. Progression is defined according to RECIST v 1.1 criteria as an at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. For patients who remain alive without progression, follow up time will be censored at the date of last disease assessment.	From Enrollment Until Study Completion, Approximately 3 Years
Rate of Overall Survival (OS)	Rate of Overall Survival (OS) in participants receiving protocol therapy. OS will be measured from the date of enrollment to the date of death or last contact.	From Enrollment Until Study Completion, Approximately 3 Years
Overall Response Rate (ORR)	Proportion of patients achieving Complete Response and Partial Response (CR+PR) to protocol therapy per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI or CT Scan. CR is defined as disappearance of all target lesions; PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.	Up to 2 Years
Duration of Overall Response	Duration of Overall Response in participants achieving complete response (CR) or partial response (PR) to SOM230 treatment. The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Overall response is assessed per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions assessed by MRI or CT Scan. CR is defined as disappearance of all target lesions; PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD.	Up to 2 Years
Toxicity Profile of Protocol Therapy	Number of patients experiencing adverse events and/or toxicities while receiving protocol therapy.	Up to 2 Years

Collaborators and Investigators

• Sponsor: Lynn Feun
• Investigators: Principal Investigator: Lynn Feun, MD, University of Miami Sylvester Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start: July 1, 2012
• Primary Completion (Actual): August 1, 2016
• Study Completion (Actual): February 1, 2017

Study Registration Dates

• First Submitted: July 9, 2012
• First Submitted That Met QC Criteria: July 11, 2012
• First Posted (Estimate): July 12, 2012

Study Record Updates

• Last Update Posted (Actual): July 12, 2017
• Last Update Submitted That Met QC Criteria: June 13, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: Hepatocellular Carcinoma; HCC; SOM230; Pasireotide LAR
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pasireotide
• Other Study ID Numbers: 20100650

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No