Clinical trial NCT02323906 (phase 1, status: terminated)
Conditions: carcinoma, hepatocellular
ICD codes: C22.0, C4A.9, C7B.1, C4A.0, C4A.31, C4A.51, C4A.8
Drugs: cc-122, sorafenib
SMILES: CNC(=O)C1=NC=CC(OC2=CC=C(NC(=O)NC3=CC(=C(Cl)C=C3)C(F)(F)F)C=C2)=C1
Reason stopped: 
    slow enrollment and business decision. no safety concerns were identified for the study drugs.
  
Eligibility criteria:

        Inclusion Criteria:

          1. Subject understands and voluntarily signs an informed consent document prior to
             conducting any study related assessments/procedures

          2. Subject is 18 years of age or more at the time of signing the Informed Consent Form

          3. Subject has a confirmed pathologic diagnosis of Hepatocellular carcinoma according to
             the American Association for the Study of Liver Diseases Guidelines.A biopsy performed
             at screening may serve as a diagnostic biopsy for subjects with radiographic
             diagnosis.

          4. Subject has unresectable stage B (intermediate), or C (advanced) Hepatocellular
             carcinoma according to the Barcelona Clinic Liver Cancer staging.Stage B subjects must
             have progressed after, or are not eligible for curative resection, transplantation,
             embolic, or ablative therapies

          5. Subject has at least one measurable lesion according to Response Evaluation Criteria
             in Solid Tumors version 1.1. Evaluable target lesions may not have been treated with
             local therapy; previously treated lesions may only be evaluated as target lesions if
             they are the only lesions available and have shown objective definite progression
             after prior treatment. Local therapy must have been completed at least four weeks
             prior to baseline tumor evaluation

          6. Satisfactory archival tumor biopsy tissue is retrieved, or new tumor biopsy is
             performed, prior to starting Cycle 1

          7. Subject has life expectancy of more than 12 weeks

          8. Subject has Eastern Cooperative Oncology Group Performance Status of 0 or 1

          9. Subject has Child-Pugh score of less than 7 (ie, class A or better) with neither
             encephalopathy nor clinically significant ascites (ascites requiring paracentesis
             within 3 months of signing the ICF is excluded). Child-Pugh status is calculated based
             on clinical findings and laboratory results during the screening period.

         10. Subject has the following laboratory parameters at screening:

             Adequate hematologic function including:

               1. Absolute Neutrophil Count of at least 1.5 x 109/L

               2. Platelets of at least 75,000 x 106/L

               3. Hemoglobin of at least 9 g/dL

               4. International Normalized Ratio of at least 1.7

             Adequate hepatic function including:

               1. Serum aspartate aminotransferase and alanine amino-transferase of at least 5
                  times the upper limit of normal

               2. Serum total bilirubin of at least 3 mg/dL

               3. Serum albumin of at least 2.8 g/dL Note: Laboratories in combination must still
                  be Child Pugh score less than 7

             Other laboratory parameters:

               1. Serum creatinine of at least 1.5 times the upper limit of normal

               2. Potassium within normal range or corrected with supplements

         11. For subjects with known or suspected cirrhosis, esophagogastroduodenoscopy ) within 12
             months of signing the informed consent form, showing no evidence of untreated varices
             or stigmata of active bleeding (such as active ulcer, visible vessel, or blood) is
             required.

             Subjects with history of upper GI bleeding must have an EGD of 3 months or less prior
             to signing the consent form confirming adequate prior endoscopic therapy (eg, no
             evidence of any untreated varices, recent or active bleeding, stigmata suggesting high
             risk for bleeding, active ulcer). Subjects with history/suspected esophageal varices
             must be on optimal medical management (eg, proton pump inhibitor and non-selective
             beta-blocker) per local institutional policy.

         12. Subject is able to adhere to the study visit schedule and other protocol requirements

         13. Pregnancy Prevention Risk Management Plan

               1. Females of childbearing potential must undergo pregnancy testing based on the
                  frequency outlined in Pregnancy Prevention Risk Minimization Plan and pregnancy
                  results must be negative.

               2. Unless practicing complete abstinence from heterosexual intercourse, sexually
                  active FCBP must agree to use adequate contraceptive methods as specified in
                  Pregnancy Prevention Risk Minimization Plan.

                    -  Complete abstinence is only acceptable in cases where this is the preferred
                       and usual lifestyle of the subject.

                    -  Periodic abstinence (calendar ovulation, symptothermal, post-ovulation
                       methods) and withdrawal are not acceptable.

               3. Males (including those who have had a vasectomy) must use barrier contraception
                  (condoms) when engaging in sexual activity with Female of Childbearing Potential
                  as specified in Pregnancy Prevention Risk Minimization Plan.

               4. Males must agree not to donate semen or sperm for 3 months after last dose of
                  CC-122.

               5. All subjects must:

                    -  Understand that CC-122 could have a potential teratogenic risk.

                    -  Agree to abstain from donating blood while taking CC-122 or sorafenib and
                       following discontinuation of their use.

                    -  Agree not to share either study drug with another person.

               6. Other than the subject, Female of Childbearing Potential and males able to father
                  a child should not handle CC-122 or touch the capsules, unless gloves are worn.

               7. Be counseled about pregnancy precautions and risks of fetal exposure

        Exclusion Criteria:

          -  1. Subject has received previous systemic therapy for Hepatocellular carcinoma
             including sorafenib, chemotherapy and investigational agents 2. Subject has received
             any local anticancer therapy ≤ 4 weeks prior to baseline tumor evaluation 3. Subject
             has undergone major surgery within the last 4 weeks or minor surgery within the last 2
             weeks prior to signing the Informed Consent Form or who have not recovered from
             surgery 4. Subject has received an investigational drug or therapy for disease other
             than Hepatocellular carcinoma within the last 4 weeks or 5 half-lives, whichever is
             shorter, prior to signing the Informed Consent Form 5. Subject has completed any
             radiation treatment less than 2 weeks prior to signing the Informed Consent Form 6.
             Subject has received the last dose of α-interferon, ribavirin, sofobuvir and/or other
             antiviral therapies for Hepatitis C Virus (HCV) less than 4 weeks prior to signing the
             Informed Consent Form 7. Subject has any clinically significant bleeding, including
             bleeding from esophageal/gastric varices within ≤ 3 months of signing the informed
             consent form, which required transfusion, surgical procedure or hospitalization.
             Esophageal varices should be treated according to local standard practice (eg,
             ligation or banding and procedure completed ≤ 3 months prior to signing the informed
             consent form). See Inclusion Criterion 10 8. Subjects requiring therapeutic
             anticoagulation with either warfarin or low molecular weight heparin. Low dose low
             molecular weight heparin for catheter maintenance are permitted 9. Subject has tumor
             invasion of stomach or duodenum 10. Subject has histologic proof of fibrolamellar
             carcinoma 11. Subjects with known symptomatic brain metastasis 12. Subject has
             persistent diarrhea due to a malabsorptive syndrome (such as celiac sprue or
             inflammatory bowel disease) malabsorption ≥ National Cancer Institute Common
             Terminology Criteria for Adverse Events (CTCAE, Version 4.03) Grade 2, despite medical
             management, or any other significant GI disorder that could affect the absorption of
             either study drug 13. Subject has history of concurrent second cancers requiring
             active, ongoing systemic treatment. 14. Subject has a known history of human
             immunodeficiency virus (HIV) seropositivity (HIV testing is not mandatory) 15. Subject
             has peripheral neuropathy of at least NCI CTCAE Grade 2 16. Subject has a history of
             persistent skin rash of at least NCI CTCAE Grade 2 17. Subject has impaired cardiac
             function or clinically significant cardiac disease including any of the following:

               1. LVEF (left ventricular ejection fraction) of 45% or less as determined by MUGA
                  (multi-gated acquisition) or ECHO (Echocardiogram)

               2. Complete left bundle branch or bifascicular block

               3. Congenital long QT syndrome

               4. Persistent or clinically meaningful ventricular arrhythmias

               5. QTcF greater than 460 msec on Screening ECG (mean of triplicate recordings)

               6. Unstable angina pectoris or myocardial infarction less than 6 months prior to
                  starting either study drug

               7. Uncontrolled hypertension (blood pressure greater than 140/90 mmHg on at least 2
                  measurements on sequential visits, despite blood pressure medication)

          -  Subjects with baseline blood pressure 140/90 mmHg are eligible but must have optimal
             medication for blood pressure management h. Troponin-T value more than the upper limit
             of normal or BNP greater than 100 pg/mL 18. Subject has acute or chronic active
             infectious disorders or uncontrolled nonmalignant illnesses whose control, in the
             opinion of the investigator, may be jeopardized by complications of this study
             therapy. Chronic hepatitis B and C virus (HBV and HCV) are excepted (ie, eligible for
             study); HBV requires antiviral therapy 19. Subject has undergone liver transplantation
             or other solid organ transplantation requiring immunosuppression 20. Subject is
             receiving chronic treatment with systemic corticosteroids or other potentially
             immunosuppressive agent. Intermittent topical or local injection of corticosteroids
             and oral/IV aldosterone or other mineralocorticoids is allowed 21. Subjects with
             history of non-healing wounds or ulcers, or bone fractures less than 3 months of a
             prior fracture 22. Subject is being treated with concomitant strong CYP3A4 inducers
             such as St. John's Wort, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin,
             phenobarbital. The use of concomitant strong CYP3A4 inducers may decrease sorafenib
             plasma concentrations and must be avoided.

             23. Subject is a female who is pregnant or is breast feeding 24. Subject is unwilling
             or unable to comply with the protocol, in the opinion of the investigator 25. Subject
             has any significant medical condition, laboratory abnormality, or psychiatric illness
             that would prevent the subject from participating in the study 26. Subject has any
             condition that confounds the ability to interpret data from the study