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Tremelimumab With Chemoembolization or Ablation for Liver Cancer

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Completed
CT.gov ID
NCT01853618
Collaborator
(none)
61
Enrollment
1
Location
6
Arms
49.2
Actual Duration (Months)
1.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Background:
  • Tremelimumab is a cancer treatment drug that helps the immune system recognize and destroy cancer cells. Researchers want to see if it can be used to treat advanced liver cancer. The drug will be given with one of two types of treatment for liver cancer. The first type, transarterial catheter chemoembolization (TACE), injects chemotherapy drugs into the tumor through the main blood vessel that is feeding it. That blood vessel is then closed off to help keep the drugs in the tumor longer. The second type, radiofrequency ablation (RFA), uses a heated probe to destroy the tumor tissue. Researchers want to study how safe and effective these treatments are with the study drug.
Objectives:
  • To test the safety and effectiveness of Tremelimumab with TACE or RFA for advanced liver cancer.
Eligibility:
  • Individuals at least 18 years of age who have advanced liver cancer that has not responded to other treatments.
Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

Background:

Worldwide, hepatocellular carcinoma (HCC) is the fifth most common malignancy with a median survival of 6-9 months. For patients with advanced disease sorafenib is the only approved drug and this has limited benefit.

Tremelimumab is a monoclonal antibody against cytotoxic T-lymphocyte-associated protein 4 (CTLA4). Anti-CTLA4 therapy has been shown to enhance anti-tumor immunity by blocking tumor-induced immune suppression of cytotoxic T cells.

Various tumor ablative procedures and techniques have been shown to result in immunogenic cell death and induction of a peripheral immune response. Both transarterial catheter chemoembolization (TACE) and radiofrequency ablation (RFA) have been shown to do this, as well as cryoablation and external beam radiation.

The underlying hypothesis of this study is that the effect of anti-CTLA4 treatment can be enhanced by TACE or RFA in patients with advanced hepatocellular carcinoma. We will also evaluate this in the context of cryoablation and radiation in hepatocellular carcinoma (HCC) and RFA in cholangiocarcinoma.

Objective:

To assess the safety and feasibility of combining Tremelimumab with trans-arterial catheter chemoembolization (TACE) radiofrequency ablation (RFA), or cryoablation in patients with advanced HCC.

Eligibility:

Histologically or cytologically confirmed diagnosis of HCC.

Childs-Pugh A/B7 cirrhosis only is allowed. If patient does not have cirrhosis, this limitation does not apply.

Barcelona Clinic Liver Cancer (BCLC) Stage B and C patients.

Patients must have disease that is not amenable to potentially curative resection, radiofrequency ablation, or liver transplantation.

Study Design

Study Type:
Interventional
Actual Enrollment :
61 participants
Allocation:
Non-Randomized
Intervention Model:
Sequential Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Pilot Study of Tremelimumab - A Monoclonal Antibody Against CTLA-4 in Combination With Trans-Arterial Catheter Chemoembolization (TACE), Radiofrequency Ablation (RFA), or Cryoablation in Subjects With Hepatocellular Carcinoma (HCC) or Biliary Tract Carcinomas (BTC)
Actual Study Start Date :
May 2, 2013
Actual Primary Completion Date :
Jun 7, 2017
Actual Study Completion Date :
Jun 7, 2017

Arms and Interventions

Arm Intervention/Treatment
Experimental: Pilot 1/Arm A1-Tremelimumab + RFA or TACE

Escalating doses of Tremelimumab + Radiofrequency Ablation (RFA) or Transarterial Catheter Chemoembolization (TACE)

Drug: Tremelimumab
3.5 mg/kg or 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years
Other Names:
  • Ticilimumab

    • Procedure: RFA
    Performed on Day 36
    Other Names:
  • Radiofrequency Ablation

    • Procedure: TACE
    Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated)
    Other Names:
  • Transarterial Catheter Chemoembolization

    		•
    Experimental: 2/Arm A2 - Tremelimumab + RFA or TACE

    Tremelimumab + Radiofrequency Ablation (RFA) or Transarterial Catheter Chemoembolization (TACE)

    Drug: Tremelimumab
    3.5 mg/kg or 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years
    Other Names:
  • Ticilimumab

    • Procedure: RFA
    Performed on Day 36
    Other Names:
  • Radiofrequency Ablation

    • Procedure: TACE
    Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated)
    Other Names:
  • Transarterial Catheter Chemoembolization

    		•
    Experimental: 3/Arm B - Tremelimumab + TACE

    Tremelimumab + Transarterial Catheter Chemoembolization (TACE)

    Drug: Tremelimumab
    3.5 mg/kg or 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years
    Other Names:
  • Ticilimumab

    • Procedure: TACE
    Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated)
    Other Names:
  • Transarterial Catheter Chemoembolization

    		•
    Experimental: 4/Arm C (never opened)

    Tremelimumab + Radiofrequency Ablation (RFA) or Transarterial Catheter Chemoembolization (TACE)

    Drug: Tremelimumab
    3.5 mg/kg or 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years
    Other Names:
  • Ticilimumab

    • Procedure: TACE
    Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated)
    Other Names:
  • Transarterial Catheter Chemoembolization

    • Procedure: Cryoablation
    Performed on Day 36
    Experimental: 5/Arm D - Tremelimumab + Cryoablation

    Tremelimumab + Cryoablation

    Drug: Tremelimumab
    3.5 mg/kg or 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years
    Other Names:
  • Ticilimumab

    • Procedure: Cryoablation
    Performed on Day 36
    Experimental: 6/Arm E - Tremelimumab + RFA

    Tremelimumab + Radiofrequency Ablation (RFA)

    Drug: Tremelimumab
    3.5 mg/kg or 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years
    Other Names:
  • Ticilimumab

    • Procedure: RFA
    Performed on Day 36
    Other Names:
  • Radiofrequency Ablation

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With Serious and Non-Serious Adverse Events Regardless of Attribution [Date treatment consent signed to date off study, approximately 44 months and 5 days for 1/Arm A1; 49 months and 26 days for 2/Arm A2; 1 month and 26 days for 3/Arm B; 30 months and 20 days for 5/Arm D; and 34 months and 25 days for 6/Arm E.]

      Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

    Secondary Outcome Measures

    1. Number of Participants With Best Response [Start of study, baseline target lesions until disease progression occurs with 20% increase of target lesions or appearance of new lesions, up to 13.1 months]

      Best response was assessed by the combined Response Evaluation Criteria in Solid Tumors (RECIST and the Modified Immune-Related Response Criteria (irRC). Complete Response (CR) is disappearance of all target lesions. Any patjhological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. Progressive Disease (PD) is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if it is the smallest on study). The appearance of one or more lesions is also considered progressions.

    2. Progression Free Survival (PFS) [Progression free survival is time patients were off treatment until death. For all cohorts progression free survival ranged from 3.4 months to 8.6 months]

      Progression free survival is defined as the amount of time a subject survives without disease progression after treatment. Progression is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if it is the smallest on study). The appearance of one or more lesions is also considered progressions.

    3. Overall Survival [From the time of initial treatment consent until date of death for each patient. Overall survival ranged from 6 months to 13.1 months.]

      Overall survival is defined as the amount of time a subject survives after therapy.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 99 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No

    -INCLUSION CRITERIA:

    1. Patients must have histopathological confirmation of hepatocellular carcinoma (HCC) or (Cohort E only) biliary tract carcinoma (BTC) by the Laboratory of Pathology of the National Cancer Institute (NCI) prior to entering this study OR histopathological confirmation of carcinoma in the setting of clinical and radiological characteristics which, together with the pathology, are highly suggestive of a diagnosis of HCC (or biliary tract carcinoma in Cohort E). Fibrolammelar variant is also allowed. For cohort E, the term BTC includes intraor extrahepatic cholangiocarcinoma, gallbladder cancer or ampullary cancer, as long as there is an intrahepatic component amenable to radiofrequency ablation (RFA).

    2. Patients must have disease that is not amenable to potentially curative resection, transplantation or ablation. For Cohorts A, C and D patients must have progressed on, been intolerant to, or refused prior sorafenib therapy. Cohort E patients must have received at least one line of chemotherapy for BTC.

    3. Disease must be technically amenable to transhepatic arterial chemoembolization (TACE), radiofrequency ablation (RFA) or cryoablation. Each case will be discussed at gastrointestinal (GI) tumor board with interventional radiology. Patients must have evaluable disease.

    4. If liver cirrhosis is present, patient must have a Child-Pugh A/B7 classification.

    5. Age greater than or equal to 18 years

    6. Life expectancy of greater than 3 months.

    7. Eastern Cooperative Oncology Group (ECOG) performance status 0-2.

    8. Patients must have normal organ and marrow function as defined below:

    • leukocytes greater than or equal to 3,000/mcL

    • absolute neutrophil count greater than or equal to 1,000/mcL

    • platelets greater than or equal to 60,000/mcL

    • total bilirubin, If cirrhosis present: Part of Child Pugh requirement. If no cirrhosis: Bili should be less than or equal to 2 times upper limit of normal (ULN)

    • Serum albumin, If cirrhosis present: Part of Child Pugh requirement. If no cirrhosis: albumin should be greater than or equal to 2.5g/dl

    • Patients are eligible with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) up to 5 times ULN.

    • creatinine, less than 1.5 times institution upper limit of normal OR

    • creatinine clearance greater than or equal to 45 mL/min/1.73 m(2), as calculated below, for patients with creatinine levels above institutional normal

    1. Patients must have recovered from any acute toxicity related to prior therapy, including surgery. Toxicity should be less than or equal to grade 1 or returned to baseline.

    2. Patients must not have other invasive malignancies within the past 5 years (with the exception of non-melanoma skin cancers, non-invasive bladder cancer or localized prostate cancer for whom systemic therapy is not required).

    3. Patient must be able to understand and willing to sign a written informed consent document.

    EXCLUSION CRITERIA:

    1. Patients who have had standard of care chemotherapy, large field radiotherapy, or major surgery must wait 2 weeks prior to entering the study. For recent experimental therapies a 28 day period of time must elapse before treatment.

    2. Patients who have undergone prior liver transplantation are ineligible.

    3. Patients with known brain metastases will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.

    4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active systemic infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (excluding insignificant sinus bradycardia and sinus tachycardia) or psychiatric illness/social situations that would limit compliance with study requirements.

    5. History of chronic autoimmune disease (e.g., Addison's disease, multiple sclerosis, Graves disease, Hashimoto's thyroiditis, rheumatoid arthritis, hypophysitis, etc.) with symptomatic disease within the 3 years before randomization. Note: Active vitiligo or a history of vitiligo will not be a basis for exclusion.

    6. Dementia or significantly altered mental status that would prohibit the understanding or rendering of Information and Consent and compliance with the requirements of the protocol.

    7. Diverticulitis (either active or history of) within the past 2 years. Note that diverticulosis is permitted.

    8. Active or history of inflammatory bowel disease (colitis, Crohn's), irritable bowel disease, celiac disease, or other serious, chronic, gastrointestinal conditions associated with diarrhea. Active or history of systemic lupus erythematosus or Wegener's granulomatosis.

    9. Currently receiving immunosuppressive doses of steroids or other immunosuppressive medications (inhaled and topical steroids are permitted)

    10. History of sarcoidosis syndrome

    11. Patients should not be vaccinated with live attenuated vaccines within 1 month of starting Tremelimumab treatment.

    12 Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)

    1. HIV-positive patients receiving anti-retroviral therapy are excluded from this study due to the possibility of pharmacokinetic interactions between antiretroviral medications and Tremelimumab. HIV positive patients not receiving antiretroviral therapy are excluded due to the possibility that Tremelimumab may worsen their condition and the likelihood that the underlying condition may obscure the attribution of adverse events.

    2. History of hypersensitivity reaction to human or mouse antibody products.

    3. Pregnancy and breast feeding are exclusion factors. The effects of Tremelimumab on the developing human fetus are unknown. Enrolled patients must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, the duration of study participation and 3 months after the end of the treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

    4. Patients with unhealed surgical wounds for more than 30 days.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda Maryland United States 20892

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Tim F Greten, M.D., National Cancer Institute (NCI)

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    Responsible Party:
    Tim Greten, M.D., Principal Investigator, National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT01853618
    Other Study ID Numbers:
    • 130120
    • 13-C-0120
    First Posted:
    May 15, 2013
    Last Update Posted:
    Dec 10, 2019
    Last Verified:
    Nov 1, 2019
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Tim Greten, M.D., Principal Investigator, National Cancer Institute (NCI)
    Blocking of Immune Suppression
    Monoclonal Antibody
    Immunotherapy
    Ablative Therapy
    Additional relevant MeSH terms:
    Carcinoma
    Carcinoma, Hepatocellular
    Liver Neoplasms
    Biliary Tract Neoplasms
    Tremelimumab

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail 4/Arm C never opened, thus no participants were enrolled in this group.
    Arm/Group Title Pilot 1/Arm A1-Tremelimumab + RFA or TACE 2/Arm A2 - Tremelimumab + RFA or TACE 3/Arm B - Tremelimumab + TACE 5/Arm D - Tremelimumab + Cryoablation 6/Arm E - Tremelimumab + RFA
    Arm/Group Description Escalating doses of Tremelimumab + Radiofrequency Ablation (RFA) or Transarterial Catheter Chemoembolization (TACE) Tremelimumab: 3.5 mg/kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years RFA: Performed on Day 36 TACE: Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated) Tremelimumab + Radiofrequency Ablation (RFA) or Transarterial Catheter Chemoembolization (TACE) Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years RFA: Performed on Day 36 TACE: Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated) Tremelimumab + Transarterial Catheter Chemoembolization (TACE) Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years TACE: Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated) Tremelimumab + Cryoablation Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years Cryoablation: Performed on Day 36 Tremelimumab + Radiofrequency Ablation (RFA) Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years RFA: Performed on Day 36
    Period Title: Overall Study
    STARTED 8 12 12 9 20
    COMPLETED 6 10 10 8 17
    NOT COMPLETED 2 2 2 1 3

    Baseline Characteristics

    Arm/Group Title Pilot 1/Arm A1-Tremelimumab + RFA or TACE 2/Arm A2 - Tremelimumab + RFA or TACE 3/Arm B - Tremelimumab + TACE 5/Arm D - Tremelimumab + Cryoablation 6/Arm E - Tremelimumab + RFA Total
    Arm/Group Description Escalating doses of Tremelimumab + Radiofrequency Ablation (RFA) or Transarterial Catheter Chemoembolization (TACE) Tremelimumab: 3.5 mg/kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years RFA: Performed on Day 36 TACE: Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated) Tremelimumab + Radiofrequency Ablation (RFA) or Transarterial Catheter Chemoembolization (TACE) Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years RFA: Performed on Day 36 TACE: Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated) Tremelimumab + Transarterial Catheter Chemoembolization (TACE) Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years TACE: Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated) Tremelimumab + Cryoablation Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years Cryoablation: Performed on Day 36 Tremelimumab + Radiofrequency Ablation (RFA) Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years RFA: Performed on Day 36 Total of all reporting groups
    Overall Participants 8 12 12 9 20 61
    Age (Count of Participants)
    <=18 years
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Between 18 and 65 years
    6
    75%
    12
    100%
    9
    75%
    3
    33.3%
    18
    90%
    48
    78.7%
    >=65 years
    2
    25%
    0
    0%
    3
    25%
    6
    66.7%
    2
    10%
    13
    21.3%
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    58.53
    (15.27)
    64.02
    (10.4)
    55.68
    (10.17)
    64.12
    (11.73)
    55.79
    (8.89)
    59.6
    (9.5)
    Sex: Female, Male (Count of Participants)
    Female
    2
    25%
    0
    0%
    2
    16.7%
    0
    0%
    10
    50%
    14
    23%
    Male
    6
    75%
    12
    100%
    10
    83.3%
    9
    100%
    10
    50%
    47
    77%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    1
    12.5%
    0
    0%
    1
    8.3%
    0
    0%
    0
    0%
    2
    3.3%
    Not Hispanic or Latino
    7
    87.5%
    12
    100%
    11
    91.7%
    9
    100%
    20
    100%
    59
    96.7%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    3
    37.5%
    0
    0%
    1
    8.3%
    1
    11.1%
    0
    0%
    5
    8.2%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    2
    25%
    0
    0%
    7
    58.3%
    5
    55.6%
    0
    0%
    14
    23%
    White
    2
    25%
    12
    100%
    4
    33.3%
    3
    33.3%
    20
    100%
    41
    67.2%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    1
    12.5%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    1.6%
    Region of Enrollment (participants) [Number]
    United States
    8
    100%
    12
    100%
    12
    100%
    9
    100%
    20
    100%
    61
    100%
    Previous Therapy (Count of Participants)
    Any surgical resection
    3
    37.5%
    1
    8.3%
    2
    16.7%
    3
    33.3%
    10
    50%
    19
    31.1%
    Any TACE
    2
    25%
    5
    41.7%
    0
    0%
    2
    22.2%
    0
    0%
    9
    14.8%
    Any chemotherapy
    8
    100%
    12
    100%
    11
    91.7%
    9
    100%
    20
    100%
    60
    98.4%
    Any radiation therapy
    3
    37.5%
    2
    16.7%
    0
    0%
    0
    0%
    4
    20%
    9
    14.8%
    Misc. therapy - Y90
    1
    12.5%
    2
    16.7%
    0
    0%
    0
    0%
    0
    0%
    3
    4.9%
    Misc. therapy - Hyperthermia
    0
    0%
    0
    0%
    1
    8.3%
    0
    0%
    0
    0%
    1
    1.6%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With Serious and Non-Serious Adverse Events Regardless of Attribution
    Description Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
    Time Frame Date treatment consent signed to date off study, approximately 44 months and 5 days for 1/Arm A1; 49 months and 26 days for 2/Arm A2; 1 month and 26 days for 3/Arm B; 30 months and 20 days for 5/Arm D; and 34 months and 25 days for 6/Arm E.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pilot 1/Arm A1-Tremelimumab + RFA or TACE 2/Arm A2 - Tremelimumab + RFA or TACE 3/Arm B - Tremelimumab + TACE 5/Arm D - Tremelimumab + Cryoablation 6/Arm E - Tremelimumab + RFA
    Arm/Group Description Escalating doses of Tremelimumab + Radiofrequency Ablation (RFA) or Transarterial Catheter Chemoembolization (TACE) Tremelimumab: 3.5 mg/kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years RFA: Performed on Day 36 TACE: Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated) Tremelimumab + Radiofrequency Ablation (RFA) or Transarterial Catheter Chemoembolization (TACE) Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years RFA: Performed on Day 36 TACE: Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated) Tremelimumab + Transarterial Catheter Chemoembolization (TACE) Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years TACE: Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated) Tremelimumab + Cryoablation Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years Cryoablation: Performed on Day 36 Tremelimumab + Radiofrequency Ablation (RFA) Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years RFA: Performed on Day 36
    Measure Participants 8 12 12 9 20
    Count of Participants [Participants]
    8
    100%
    12
    100%
    12
    100%
    9
    100%
    20
    100%
    2. Secondary Outcome
    Title Number of Participants With Best Response
    Description Best response was assessed by the combined Response Evaluation Criteria in Solid Tumors (RECIST and the Modified Immune-Related Response Criteria (irRC). Complete Response (CR) is disappearance of all target lesions. Any patjhological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study. Progressive Disease (PD) is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if it is the smallest on study). The appearance of one or more lesions is also considered progressions.
    Time Frame Start of study, baseline target lesions until disease progression occurs with 20% increase of target lesions or appearance of new lesions, up to 13.1 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pilot 1/Arm A1-Tremelimumab + RFA or TACE 2/Arm A2 - Tremelimumab + RFA or TACE 3/Arm B - Tremelimumab + TACE 5/Arm D - Tremelimumab + Cryoablation 6/Arm E - Tremelimumab + RFA
    Arm/Group Description Escalating doses of Tremelimumab + Radiofrequency Ablation (RFA) or Transarterial Catheter Chemoembolization (TACE) Tremelimumab: 3.5 mg/kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years RFA: Performed on Day 36 TACE: Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated) Tremelimumab + Radiofrequency Ablation (RFA) or Transarterial Catheter Chemoembolization (TACE) Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years RFA: Performed on Day 36 TACE: Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated) Tremelimumab + Transarterial Catheter Chemoembolization (TACE) Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years TACE: Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated) Tremelimumab + Cryoablation Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years Cryoablation: Performed on Day 36 Tremelimumab + Radiofrequency Ablation (RFA) Tremelimumab:10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years RFA: Performed on Day 36
    Measure Participants 8 12 12 9 20
    Complete Response
    0
    0%
    0
    0%
    1
    8.3%
    0
    0%
    0
    0%
    Partial Response
    1
    12.5%
    2
    16.7%
    2
    16.7%
    2
    22.2%
    2
    10%
    Stable Disease
    3
    37.5%
    5
    41.7%
    4
    33.3%
    3
    33.3%
    5
    25%
    Progressive Disease
    1
    12.5%
    3
    25%
    4
    33.3%
    3
    33.3%
    11
    55%
    Not Evaluable
    3
    37.5%
    2
    16.7%
    1
    8.3%
    1
    11.1%
    2
    10%
    3. Secondary Outcome
    Title Progression Free Survival (PFS)
    Description Progression free survival is defined as the amount of time a subject survives without disease progression after treatment. Progression is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if it is the smallest on study). The appearance of one or more lesions is also considered progressions.
    Time Frame Progression free survival is time patients were off treatment until death. For all cohorts progression free survival ranged from 3.4 months to 8.6 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pilot 1/Arm A1-Tremelimumab + RFA or TACE 2/Arm A2 - Tremelimumab + RFA or TACE 3/Arm B - Tremelimumab + TACE 5/Arm D - Tremelimumab + Cryoablation 6/Arm E - Tremelimumab + RFA
    Arm/Group Description Escalating doses of Tremelimumab + Radiofrequency Ablation (RFA) or Transarterial Catheter Chemoembolization (TACE) Tremelimumab: 3.5 mg/kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years RFA: Performed on Day 36 TACE: Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated) Tremelimumab + Radiofrequency Ablation (RFA) or Transarterial Catheter Chemoembolization (TACE) Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years RFA: Performed on Day 36 TACE: Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated) Tremelimumab + Transarterial Catheter Chemoembolization (TACE) Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years TACE: Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated) Tremelimumab + Cryoablation Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years Cryoablation: Performed on Day 36 Tremelimumab + Radiofrequency Ablation (RFA) Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years RFA: Performed on Day 36
    Measure Participants 8 12 12 9 20
    Median (95% Confidence Interval) [Months]
    6.4
    7.5
    7.7
    8.6
    3.4
    4. Secondary Outcome
    Title Overall Survival
    Description Overall survival is defined as the amount of time a subject survives after therapy.
    Time Frame From the time of initial treatment consent until date of death for each patient. Overall survival ranged from 6 months to 13.1 months.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Pilot 1/Arm A1-Tremelimumab + RFA or TACE 2/Arm A2 - Tremelimumab + RFA or TACE 3/Arm B - Tremelimumab + TACE 5/Arm D - Tremelimumab + Cryoablation 6/Arm E - Tremelimumab + RFA
    Arm/Group Description Escalating doses of Tremelimumab + Radiofrequency Ablation (RFA) or Transarterial Catheter Chemoembolization (TACE) Tremelimumab: 3.5 mg/kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years RFA: Performed on Day 36 TACE: Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated) Tremelimumab + Radiofrequency Ablation (RFA) or Transarterial Catheter Chemoembolization (TACE) Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years RFA: Performed on Day 36 TACE: Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated) Tremelimumab + Transarterial Catheter Chemoembolization (TACE) Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years TACE: Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated) Tremelimumab + Cryoablation Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years Cryoablation: Performed on Day 36 Tremelimumab + Radiofrequency Ablation (RFA) Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years RFA: Performed on Day 36
    Measure Participants 8 12 12 9 20
    Median (95% Confidence Interval) [Months]
    10.5
    8.4
    13.1
    13.1
    6

    Adverse Events

    Time Frame Date treatment consent signed to date off study, approximately 44 months and 5 days for 1/Arm A1-Tremelimumab + RFA or TACE; 49 months and 26 days for 2/Arm A2-MTD of Tremelimumab + RFA or TACE; 1 month and 26 days for 3/Arm B-MTD of Tremelimumab + TACE; 30 months and 20 days for 5/Arm D-MTD of Tremelimumab + Cryoablation; and 34 months and 25 days for 6/Arm E-MTD of Tremelimumab + RFA.
    Adverse Event Reporting Description All deaths in the mortality module are attributable to progressive disease (all deaths that occurred are reported).
    Arm/Group Title Pilot 1/Arm A1-Tremelimumab + RFA or TACE 2/Arm A2 -Tremelimumab + RFA or TACE 3/Arm B - Tremelimumab + TACE 5/Arm D - Tremelimumab + Cryoablation 6/Arm E - Tremelimumab + RFA
    Arm/Group Description Escalating doses of Tremelimumab + Radiofrequency Ablation (RFA) or Transarterial Catheter Chemoembolization (TACE) Tremelimumab: 3.5 mg/kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years RFA: Performed on Day 36 TACE: Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated) Tremelimumab + Radiofrequency Ablation (RFA) or Transarterial Catheter Chemoembolization (TACE) Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years RFA: Performed on Day 36 TACE: Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated) Tremelimumab + Transarterial Catheter Chemoembolization (TACE) Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years TACE: Performed on Day 36 and may be repeated (as per standard of care) on months 3, 7, and 13, and every (q)6 months thereafter (if indicated) Tremelimumab + Cryoablation Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years Cryoablation: Performed on Day 36 Tremelimumab + Radiofrequency Ablation (RFA) Tremelimumab: 10 mg /kg intravenous (IV) every 4 weeks times 6 doses and then every 12 weeks for 2 years RFA: Performed on Day 36
    All Cause Mortality
    Pilot 1/Arm A1-Tremelimumab + RFA or TACE 2/Arm A2 -Tremelimumab + RFA or TACE 3/Arm B - Tremelimumab + TACE 5/Arm D - Tremelimumab + Cryoablation 6/Arm E - Tremelimumab + RFA
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 8/8 (100%) 1/12 (8.3%) 8/12 (66.7%) 6/9 (66.7%) 17/20 (85%)
    Serious Adverse Events
    Pilot 1/Arm A1-Tremelimumab + RFA or TACE 2/Arm A2 -Tremelimumab + RFA or TACE 3/Arm B - Tremelimumab + TACE 5/Arm D - Tremelimumab + Cryoablation 6/Arm E - Tremelimumab + RFA
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 5/8 (62.5%) 1/12 (8.3%) 7/12 (58.3%) 3/9 (33.3%) 7/20 (35%)
    Blood and lymphatic system disorders
    Anemia 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 2
    Cardiac disorders
    Atrial fibrillation 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 2 0/9 (0%) 0 0/20 (0%) 0
    Endocrine disorders
    Adrenal insufficiency 0/8 (0%) 0 1/12 (8.3%) 1 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Gastrointestinal disorders
    Gastrointestinal disorders - Other, Gastroenteritis 1/8 (12.5%) 1 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Diarrhea 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 1/20 (5%) 3
    Gastrointestinal disorders - Other, Inguinal hernia 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Intra-abdominal hemorrhage 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Nausea 0/8 (0%) 0 0/12 (0%) 0 2/12 (16.7%) 2 0/9 (0%) 0 0/20 (0%) 0
    Abdominal pain 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Vomiting 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    General disorders
    Chills 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Fever 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 2/20 (10%) 2
    Immune system disorders
    Anaphylaxis 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Infections and infestations
    Lung infection 1/8 (12.5%) 1 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Infections and infestations - Other, C. Diff. 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 1 1/20 (5%) 1
    Meningitis 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Sepsis 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Soft tissue infection 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 2
    Urinary tract infection 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Infections and infestations - Other, C. Diff. 0/8 (0%) 0 1/12 (8.3%) 1 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Investigations
    Aspartate aminotransferase increased 1/8 (12.5%) 1 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Metabolism and nutrition disorders
    Dehydration 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Hypokalemia 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 2
    Hyponatremia 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Musculoskeletal and connective tissue disorders
    Back pain 1/8 (12.5%) 1 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Non-cardiac chest pain 1/8 (12.5%) 1 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Generalized muscle weakness 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 1/20 (5%) 1
    Muscle weakness left-sided 1/8 (12.5%) 1 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Muscle weakness lower limb 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 1 0/20 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, HCC 1/8 (12.5%) 1 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Nervous system disorders
    Seizure 1/8 (12.5%) 1 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Nervous system disorders - Other, Blackout 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 1 0/20 (0%) 0
    Stroke 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Pleural hemorrhage 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Skin and subcutaneous tissue disorders
    Rash maculo-papular 1/8 (12.5%) 1 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 2
    Vascular disorders
    Hypotension 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Hematoma 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Hypertension 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Hematoma 0/8 (0%) 0 1/12 (8.3%) 1 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Hypotension 0/8 (0%) 0 1/12 (8.3%) 1 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Other (Not Including Serious) Adverse Events
    Pilot 1/Arm A1-Tremelimumab + RFA or TACE 2/Arm A2 -Tremelimumab + RFA or TACE 3/Arm B - Tremelimumab + TACE 5/Arm D - Tremelimumab + Cryoablation 6/Arm E - Tremelimumab + RFA
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 8/8 (100%) 12/12 (100%) 12/12 (100%) 9/9 (100%) 20/20 (100%)
    Blood and lymphatic system disorders
    Anemia 8/8 (100%) 31 12/12 (100%) 17 11/12 (91.7%) 68 9/9 (100%) 31 20/20 (100%) 73
    Lymph node pain 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Cardiac disorders
    Sinus tachycardia 1/8 (12.5%) 1 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Atrial fibrillation 0/8 (0%) 0 1/12 (8.3%) 5 1/12 (8.3%) 4 0/9 (0%) 0 0/20 (0%) 0
    Atrial flutter 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Palpitations 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 1/9 (11.1%) 1 0/20 (0%) 0
    Cardiac disorders - Other, atrial fib with bradycardia 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 1 0/20 (0%) 0
    Ear and labyrinth disorders
    Hearing impaired 1/8 (12.5%) 1 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Vertigo 0/8 (0%) 0 1/12 (8.3%) 2 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Endocrine disorders
    Adrenal insufficiency 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 3 1/9 (11.1%) 1 0/20 (0%) 0
    Hypothyroidism 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 1/20 (5%) 1
    Hyperthyroidism 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 1/9 (11.1%) 3 0/20 (0%) 0
    Eye disorders
    Eyelid function disorder 1/8 (12.5%) 1 1/12 (8.3%) 1 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Blurred vision 0/8 (0%) 0 0/12 (0%) 0 2/12 (16.7%) 2 1/9 (11.1%) 1 1/20 (5%) 1
    Dry eye 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Gastrointestinal disorders
    Abdominal distension 1/8 (12.5%) 1 0/12 (0%) 0 1/12 (8.3%) 1 2/9 (22.2%) 3 0/20 (0%) 0
    Abdominal pain 1/8 (12.5%) 1 0/12 (0%) 0 6/12 (50%) 19 4/9 (44.4%) 8 12/20 (60%) 21
    Ascites 1/8 (12.5%) 1 2/12 (16.7%) 3 3/12 (25%) 7 1/9 (11.1%) 2 7/20 (35%) 10
    Bloating 1/8 (12.5%) 1 0/12 (0%) 0 2/12 (16.7%) 2 2/9 (22.2%) 2 4/20 (20%) 4
    Constipation 3/8 (37.5%) 3 2/12 (16.7%) 9 8/12 (66.7%) 12 1/9 (11.1%) 1 4/20 (20%) 4
    Dental caries 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Diarrhea 1/8 (12.5%) 1 6/12 (50%) 6 6/12 (50%) 12 2/9 (22.2%) 4 9/20 (45%) 16
    Dyspepsia 1/8 (12.5%) 1 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Dysphagia 1/8 (12.5%) 1 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 2/20 (10%) 2
    Esophageal varices hemorrhage 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Gastrointestinal disorders - Other, Dry throat 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Mucositis oral 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Vomiting 3/8 (37.5%) 3 0/12 (0%) 0 3/12 (25%) 8 2/9 (22.2%) 2 4/20 (20%) 5
    Dry mouth 0/8 (0%) 0 1/12 (8.3%) 1 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Gastric ulcer 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Gastrointestinal disorders - Other, gastrointestinal disorders - Other, cramping 0/8 (0%) 0 0/12 (0%) 0 2/12 (16.7%) 2 0/9 (0%) 0 0/20 (0%) 0
    Hoarseness: voice changes 0/8 (0%) 0 1/12 (8.3%) 1 1/12 (8.3%) 1 1/9 (11.1%) 1 0/20 (0%) 0
    Ileus 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Colonic hemorrhage 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 1 1/20 (5%) 1
    Toothache 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 1 0/20 (0%) 0
    Colitis 0/8 (0%) 0 0/12 (0%) 0 2/12 (16.7%) 2 1/9 (11.1%) 2 1/20 (5%) 1
    Gastroesophageal reflux disease 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 1/20 (5%) 1
    Hemorrhoids 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 2/20 (10%) 2
    Nausea 3/8 (37.5%) 5 6/12 (50%) 16 8/12 (66.7%) 15 2/9 (22.2%) 3 4/20 (20%) 6
    Rectal hemorrhage 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Sore throat 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 1 2/20 (10%) 2
    General disorders
    Chills 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 1 1/20 (5%) 2
    Fatigue 3/8 (37.5%) 5 6/12 (50%) 12 8/12 (66.7%) 13 2/9 (22.2%) 5 12/20 (60%) 18
    Fever 3/8 (37.5%) 3 1/12 (8.3%) 2 7/12 (58.3%) 9 1/9 (11.1%) 1 11/20 (55%) 20
    Flu like symptoms 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Edema trunk 0/8 (0%) 0 1/12 (8.3%) 1 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Myalgia 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Infusion related reaction 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 2 2/20 (10%) 3
    Edema limbs 1/8 (12.5%) 1 1/12 (8.3%) 3 2/12 (16.7%) 5 3/9 (33.3%) 3 6/20 (30%) 7
    General disorders and administration site conditions - Other, neuro-gait abnormalities 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Malaise 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 2/20 (10%) 2
    Pain 5/8 (62.5%) 11 4/12 (33.3%) 17 8/12 (66.7%) 34 6/9 (66.7%) 10 13/20 (65%) 26
    Hepatobiliary disorders
    Bile duct stenosis 1/8 (12.5%) 1 0/12 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 1 1/20 (5%) 1
    Infections and infestations
    Infections and infestations - Other, Oral thrush 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 2/9 (22.2%) 3 0/20 (0%) 0
    Bronchial infection 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 1/9 (11.1%) 1 0/20 (0%) 0
    Lung infection 1/8 (12.5%) 2 0/12 (0%) 0 1/12 (8.3%) 2 0/9 (0%) 0 0/20 (0%) 0
    Skin infection 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Infections and infestations - Other, Infection - E.coli 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 2/9 (22.2%) 3 0/20 (0%) 0
    Eye infection 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Infections and infestations - Other, C. Diff infection 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 2/20 (10%) 2
    Infections and infestations - Other, Infection-GI other, liver infection 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Urinary tract infection 1/8 (12.5%) 1 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 2/20 (10%) 2
    Injury, poisoning and procedural complications
    Fall 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Wound complication 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Burn 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 1 0/20 (0%) 0
    Investigations
    Activated partial thromboplastin time prolonged 4/8 (50%) 15 10/12 (83.3%) 11 9/12 (75%) 20 4/9 (44.4%) 6 14/20 (70%) 26
    Alanine aminotransferase increased 7/8 (87.5%) 33 1/12 (8.3%) 5 10/12 (83.3%) 33 7/9 (77.8%) 16 8/20 (40%) 16
    Alkaline phosphatase increased 7/8 (87.5%) 27 1/12 (8.3%) 2 10/12 (83.3%) 43 5/9 (55.6%) 12 13/20 (65%) 25
    Aspartate aminotransferase increased 8/8 (100%) 46 1/12 (8.3%) 1 10/12 (83.3%) 55 8/9 (88.9%) 25 13/20 (65%) 39
    Blood bilirubin increased 6/8 (75%) 24 1/12 (8.3%) 2 8/12 (66.7%) 35 4/9 (44.4%) 14 7/20 (35%) 21
    CPK increased 1/8 (12.5%) 1 0/12 (0%) 0 1/12 (8.3%) 1 2/9 (22.2%) 2 0/20 (0%) 0
    Creatinine increased 3/8 (37.5%) 3 1/12 (8.3%) 7 6/12 (50%) 20 4/9 (44.4%) 17 7/20 (35%) 15
    Fibrinogen decreased 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Serum amylase increased 1/8 (12.5%) 1 0/12 (0%) 0 6/12 (50%) 27 3/9 (33.3%) 15 0/20 (0%) 0
    Weight loss 1/8 (12.5%) 1 0/12 (0%) 0 2/12 (16.7%) 2 0/9 (0%) 0 0/20 (0%) 0
    White blood cell decreased 4/8 (50%) 7 1/12 (8.3%) 1 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Lipase increased 0/8 (0%) 0 0/12 (0%) 0 2/12 (16.7%) 18 1/9 (11.1%) 1 1/20 (5%) 1
    Lymphocyte count decreased 7/8 (87.5%) 32 6/12 (50%) 31 11/12 (91.7%) 68 7/9 (77.8%) 23 17/20 (85%) 63
    Lymphocyte count increased 1/8 (12.5%) 2 0/12 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 1 1/20 (5%) 1
    Neutrophil count decreased 1/8 (12.5%) 2 0/12 (0%) 0 2/12 (16.7%) 4 1/9 (11.1%) 14 3/20 (15%) 7
    Platelet count decreased 5/8 (62.5%) 25 3/12 (25%) 12 5/12 (41.7%) 22 5/9 (55.6%) 15 9/20 (45%) 22
    Metabolism and nutrition disorders
    Anorexia 2/8 (25%) 2 6/12 (50%) 11 5/12 (41.7%) 9 2/9 (22.2%) 2 8/20 (40%) 11
    Dehydration 0/8 (0%) 0 0/12 (0%) 0 3/12 (25%) 7 4/9 (44.4%) 4 2/20 (10%) 3
    Hypernatremia 0/8 (0%) 0 0/12 (0%) 0 2/12 (16.7%) 2 0/9 (0%) 0 0/20 (0%) 0
    Hyperuricemia 2/8 (25%) 4 6/12 (50%) 8 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Hypoalbuminemia 7/8 (87.5%) 27 10/12 (83.3%) 44 11/12 (91.7%) 74 7/9 (77.8%) 29 16/20 (80%) 60
    Hypocalcemia 0/8 (0%) 0 1/12 (8.3%) 2 3/12 (25%) 5 3/9 (33.3%) 5 6/20 (30%) 10
    Hypokalemia 2/8 (25%) 3 0/12 (0%) 0 5/12 (41.7%) 14 6/9 (66.7%) 16 8/20 (40%) 15
    Hypomagnesemia 2/8 (25%) 7 2/12 (16.7%) 2 3/12 (25%) 17 2/9 (22.2%) 9 7/20 (35%) 11
    Hyponatremia 8/8 (100%) 19 12/12 (100%) 40 12/12 (100%) 44 6/9 (66.7%) 25 12/20 (60%) 31
    Hypophosphatemia 3/8 (37.5%) 6 1/12 (8.3%) 1 9/12 (75%) 38 5/9 (55.6%) 7 8/20 (40%) 21
    Hyperkalemia 1/8 (12.5%) 1 1/12 (8.3%) 2 5/12 (41.7%) 8 2/9 (22.2%) 4 2/20 (10%) 2
    Hypercalcemia 5/8 (62.5%) 6 1/12 (8.3%) 1 5/12 (41.7%) 7 3/9 (33.3%) 6 8/20 (40%) 32
    Hyperglycemia 2/8 (25%) 3 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 13
    Hypermagnesemia 2/8 (25%) 4 0/12 (0%) 0 2/12 (16.7%) 3 0/9 (0%) 0 2/20 (10%) 2
    Hypoglycemia 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 1 1/20 (5%) 3
    Weight loss 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 2/20 (10%) 3
    Musculoskeletal and connective tissue disorders
    Back pain 3/8 (37.5%) 4 0/12 (0%) 0 3/12 (25%) 3 1/9 (11.1%) 1 4/20 (20%) 6
    Bone pain 1/8 (12.5%) 1 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Generalized muscle weakness 2/8 (25%) 2 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 1/20 (5%) 1
    Muscle weakness upper limb 1/8 (12.5%) 1 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Pain in extremity 1/8 (12.5%) 1 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Chest wall pain 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 1 0/20 (0%) 0
    Muscle weakness lower limb 0/8 (0%) 0 1/12 (8.3%) 1 0/12 (0%) 0 2/9 (22.2%) 3 0/20 (0%) 0
    Neck pain 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 1 0/20 (0%) 0
    Flank pain 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 2
    Non-cardiac chest pain 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 1 1/20 (5%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, HCC 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Tumor pain 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 1 0/20 (0%) 0
    Nervous system disorders
    Dizziness 1/8 (12.5%) 1 0/12 (0%) 0 2/12 (16.7%) 5 5/9 (55.6%) 5 3/20 (15%) 6
    Dysgeusia 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 1/9 (11.1%) 1 0/20 (0%) 0
    Neuralgia 1/8 (12.5%) 1 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Paresthesia 1/8 (12.5%) 1 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Peripheral sensory neuropathy 1/8 (12.5%) 1 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Peripheral motor neuropathy 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Concentration impairment 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Dysphasia 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Headache 2/8 (25%) 2 0/12 (0%) 0 2/12 (16.7%) 5 2/9 (22.2%) 2 1/20 (5%) 2
    Memory impairment 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Psychiatric disorders
    Agitation 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Anxiety 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 1/9 (11.1%) 1 2/20 (10%) 2
    Confusion 0/8 (0%) 0 0/12 (0%) 0 2/12 (16.7%) 2 2/9 (22.2%) 2 2/20 (10%) 2
    Insomnia 2/8 (25%) 2 1/12 (8.3%) 1 7/12 (58.3%) 7 1/9 (11.1%) 1 3/20 (15%) 4
    Depression 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 1/20 (5%) 1
    Hypersomnia 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Restlessness 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 1 1/20 (5%) 1
    Delayed orgasm 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Renal and urinary disorders
    Hematuria 1/8 (12.5%) 1 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Hemoglobinuria 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Proteinuria 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Renal and urinary disorders - Other, Dysuria 1/8 (12.5%) 1 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Urinary frequency 1/8 (12.5%) 1 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 1/20 (5%) 1
    Urinary retention 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 1 1/20 (5%) 3
    Urinary incontinence 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Reproductive system and breast disorders
    Erectile dysfunction 0/8 (0%) 0 1/12 (8.3%) 1 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Allergic rhinitis 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Atelectasis 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Cough 2/8 (25%) 4 0/12 (0%) 0 5/12 (41.7%) 8 1/9 (11.1%) 1 5/20 (25%) 5
    Dyspnea 2/8 (25%) 2 0/12 (0%) 0 2/12 (16.7%) 2 3/9 (33.3%) 4 3/20 (15%) 3
    Hypoxia 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 1/9 (11.1%) 1 0/20 (0%) 0
    Nasal congestion 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 1 0/20 (0%) 0
    Postnasal drip 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Productive cough 1/8 (12.5%) 1 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Respiratory, thoracic and mediastinal disorders - Other, shortness of breath 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Respiratory, thoracic and mediastinal disorders - Other, upper respiratory infection 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Sore throat 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Epistaxis 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 1/9 (11.1%) 1 2/20 (10%) 2
    Hiccups 0/8 (0%) 0 1/12 (8.3%) 2 1/12 (8.3%) 4 1/9 (11.1%) 2 1/20 (5%) 1
    Pneumothorax 1/8 (12.5%) 1 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Respiratory, thoracic and mediastinal disorders - Other, Pneumonia 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Wheezing 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 1 0/20 (0%) 0
    Pleural effusion 2/8 (25%) 2 1/12 (8.3%) 1 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Upper respiratory infection 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 4/20 (20%) 4
    Skin and subcutaneous tissue disorders
    Alopecia 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Hyperhidrosis 1/8 (12.5%) 1 0/12 (0%) 0 2/12 (16.7%) 3 0/9 (0%) 0 0/20 (0%) 0
    Pruritus 4/8 (50%) 5 3/12 (25%) 5 0/12 (0%) 0 3/9 (33.3%) 3 8/20 (40%) 14
    Rash acneiform 1/8 (12.5%) 1 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 1/20 (5%) 2
    Rash maculo-papular 5/8 (62.5%) 11 0/12 (0%) 0 5/12 (41.7%) 8 1/9 (11.1%) 1 9/20 (45%) 11
    Skin and subcutaneous tissue disorders - Other, mouth ulcers 1/8 (12.5%) 1 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Skin hyperpigmentation 2/8 (25%) 2 0/12 (0%) 0 1/12 (8.3%) 1 1/9 (11.1%) 1 0/20 (0%) 0
    Palmar-plantar erythrodysesthesia syndrome 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Papulopustular rash 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Skin and subcutaneous tissue disorders - Other, skin discoloration 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Skin and subcutaneous tissue disorders - Other, skin peeling - bil. Hands 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0
    Skin and subcutaneous tissue disorders - Other, blisters on abdominal area 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 1 0/20 (0%) 0
    Skin and subcutaneous tissue disorders - Other, various scabs 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 1/9 (11.1%) 1 0/20 (0%) 0
    Dry skin 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 1/20 (5%) 1
    Skin and subcutaneous tissue disorders - Other, itching 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Skin and subcutaneous tissue disorders 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Skin and subcutaneous tissue disorders - Other, lymph node swelling 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Skin and subcutaneous tissue disorders - Other, night sweats 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Urticaria 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 1/20 (5%) 1
    Vascular disorders
    Hematoma 0/8 (0%) 0 0/12 (0%) 0 0/12 (0%) 0 0/9 (0%) 0 0/20 (0%) 0
    Hypertension 1/8 (12.5%) 1 1/12 (8.3%) 1 1/12 (8.3%) 2 0/9 (0%) 0 0/20 (0%) 0
    Hypotension 0/8 (0%) 0 1/12 (8.3%) 1 2/12 (16.7%) 3 0/9 (0%) 0 2/20 (10%) 2
    Flushing 0/8 (0%) 0 0/12 (0%) 0 1/12 (8.3%) 1 0/9 (0%) 0 0/20 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr. Tim F. Greten
    Organization National Cancer Institute
    Phone (301) 451-4723
    Email tim.greten@nih.gov
    Responsible Party:
    Tim Greten, M.D., Principal Investigator, National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT01853618
    Other Study ID Numbers:
    • 130120
    • 13-C-0120
    First Posted:
    May 15, 2013
    Last Update Posted:
    Dec 10, 2019
    Last Verified:
    Nov 1, 2019