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Trial record 1 of 1 for:    NCT03289533
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A Study Of Avelumab In Combination With Axitinib In Advanced HCC (VEGF Liver 100)

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ClinicalTrials.gov Identifier: NCT03289533
Recruitment Status : Completed
First Posted : September 21, 2017
Results First Posted : September 4, 2020
Last Update Posted : September 4, 2020
Sponsor:
Information provided by (Responsible Party):
Pfizer

Tracking Information
First Submitted Date  ICMJE August 28, 2017
First Posted Date  ICMJE September 21, 2017
Results First Submitted Date  ICMJE August 13, 2020
Results First Posted Date  ICMJE September 4, 2020
Last Update Posted Date September 4, 2020
Actual Study Start Date  ICMJE September 8, 2017
Actual Primary Completion Date August 27, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 1, 2020)
  • Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version (v.) 4.03 [ Time Frame: From first dose of study drug up to 30 days after last dose of study drug or initiation of new anti-cancer drug therapy, whichever occurred first (maximum up to 21 months) ]
    An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. AEs were graded by investigator according to NCI CTCAE v.4.03 as follows: Grade 1: mild AE, Grade 2: moderate AE, Grade 3: severe AE, Grade 4: life-threatening consequences and urgent intervention indicated, Grade 5: death related to AE.
  • Number of Participants With Abnormal Laboratory Parameter Values (Hematology) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version 4.03 [ Time Frame: From first dose of study drug up to 30 days after last dose of study drug or initiation of new anti-cancer drug therapy, whichever occurred first (maximum up to 21 months) ]
    As per NCI-CTCAE v 4.03, anemia Grade 1= Less than (<) lower limit of normal (LLN) to 100 gram per liter (g/L),Grade 2= <100 to 80 g/L; hemoglobin increased: Grade 1= increase of greater than (>) 0 to 2 gram per deciliter(g/dL) above upper limit of normal [ULN]; lymphocyte count decreased: Grade 1= <LLN to 0.8*10^9/L, Grade 2= <0.8*10^9/L to 0.5*10^9/L, Grade 3= <0.5*10^9/L to 0.2*10^9/L ; lymphocyte count increased: Grade 2= >4*10^9/L to 20*10^9/L; neutrophil count decreased: Grade 1= <LLN to 1.5*10^9/L ,Grade 2= <1.5*10^9/L to 1.0*10^9/L; platelet count decreased: Grade 1= <LLN to 75.0*10^9/L, Grade 2= <75.0*10^9/L to 50.0*10^9/L; white blood cell decreased: Grade 1= <LLN to 3*10^9/L, Grade 2= <3*10^9/L to 2*10^9/L.
  • Number of Participants With Abnormal Laboratory Parameter Values (Chemistry) as Graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) Version (v) 4.03 [ Time Frame: From first dose of study drug up to 30 days after last dose of study drug or initiation of new anti-cancer drug therapy, whichever occurred first (maximum up to 21 months) ]
    ALT,ALP,AST increased grades(g):g1>ULN-3.0*ULN,g2>3.0-5.0*ULN,g3>5.0-20.0*ULN; blood bilirubin increased:g1>ULN-1.5*ULN, g2>1.5-3.0*ULN, g3>3.0-10.0*ULN; [cholesterol high:g1>ULN-7.75, g2 >7.75-10.34,g4 >12.92]millimoles per liter(mmol/L);creatine phosphokinase, gamma-glutamyl transferase(ggt) increased g1>ULN-2.5*ULN, g2>2.5*ULN-5*ULN; Ggt increased g3 >5.0-20.0*ULN; Creatinine increased: g1>ULN-1.5*ULN; [hypoalbuminemia:g1<LLN-30,g2<30-20] grams per liter(g/L);[hyperglycemia:g1> ULN-8.9,g2> 8.9-13.9,g3> 13.9-27.8;hypermagnesemia:g1>ULN-1.23;hypercalcemia:g1>ULN -2.9;hyperkalemia:g1>ULN-5.5,hypernatremia:g1>ULN-150;hypertriglyceridemia g1:1.71-3.42,g2 >3.42-5.7;hypocalcemia:g1<LLN-2.0,hypoglycemia:g1<LLN-3.0, g2<3.0-2.2;hypokalemia:g2<LLN-3.0,g4<2.5,hypomagnesemia:g1<LLN-0.5,hyponatremia:g1<LLN-130, g3<130-120,hypophosphatemia:g1<LLN-0.8,g2<0.8-0.6]mmol/L;lipase increased:g1>ULN-1.5*ULN,g3 >2.0-5.0*ULN;serum amylase increased:g1>ULN-1.5*ULN, g2>1.5-2.0*ULN,g3>2.0-5.0*ULN.
Original Primary Outcome Measures  ICMJE
 (submitted: September 19, 2017)
Adverse events (AEs) and laboratory abnormalities as graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v. 4.03. [ Time Frame: Until 90 calendar days after the last administration of study treatment ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 1, 2020)
  • Time to Disease Progression (TTP) [ Time Frame: From first dose of study drug until first documentation of progressive disease or data censoring date, whichever occurred first (maximum up to 20 months) ]
    TTP as assessed by investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, was define as time (in months) from date of first dose of study drug to date of first documentation of progressive disease (PD) or data censoring date, whichever occurred first. PD was defined as greater than or equal to (>=) 20 percent (%) increase in sum of diameters of target lesions, taking as a reference smallest sum on study treatment (this included baseline sum if that was smallest on study treatment), with a minimum absolute increase of at least 5 millimeter (mm), or appearance of >=1 new lesions. TTP was analyzed by Kaplan-Meier method. TTP data was censored on the date the last adequate tumor assessment for participants without PD, for participants who start new anti-cancer treatment prior to PD, for participants who died without PD, or for participants with PD after >=2 missing tumor assessments.
  • Progression Free Survival (PFS) [ Time Frame: From first dose of study drug until first documentation of PD or death due to any cause or data censoring date, whichever occurred first (maximum up to 20 months) ]
    PFS as assessed by investigator per RECIST v1.1, was defined as time (in months) from date of first dose of study drug to date of first documentation of PD or death due to any cause or data censoring date, whichever occurred first. PD: >= 20% increase in sum of diameters of target lesions, taking as a reference smallest sum on study treatment (this included baseline sum if that was smallest on study treatment). The sum must also demonstrate absolute increase of >=5 mm, or appearance of >=1 new lesions. PFS was analyzed by Kaplan-Meier method. PFS data was censored on the date the last adequate tumor assessment for participants without an event (PD or death), for participants who started new anti-cancer treatment prior to PFS event, for participants with a PFS event after >=2 missing tumor assessments.
  • Percentage of Participants With Objective Response (OR) [ Time Frame: From first dose of study drug until disease progression or death due to any cause (maximum up to 20 months) ]
    OR as assessed by investigator per RECIST v.1.1, was defined as participants with confirmed best overall response of complete response (CR) or partial response (PR), were recorded from first dose of study drug until disease progression or death due to any cause. CR was defined as disappearance of all target and non-target lesions, and sustained for at least 4 weeks. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (<) 10 mm. PR was defined as >=30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters.
  • Percentage of Participants With Disease Control (DC) [ Time Frame: From first dose of study drug until first documentation of CR or PR or SD or till non-CR/non-PD (maximum up to 20 months) ]
    Disease control as assessed by investigator according to RECIST v1.1, was defined as participants with CR, PR, stable disease (SD), or non-CR/non-PD. CR: disappearance of all target and non-target lesions and sustained for 4 weeks. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: >= 30% decrease in sum of diameters of target lesions taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. The sum must also demonstrate an absolute increase of at least 5 mm or appearance of >=1 new lesions. Non-CR/non-PD: Persistence of any non-target lesions and/or tumor marker level above the normal limit at >=8 weeks after date of first dose of study treatment.
  • Time to Tumor Response (TTR) [ Time Frame: From first dose of study drug until first documentation of CR or PR (maximum up to 20 months) ]
    TTR as assessed by investigator according to RECIST v1.1 was defined as the time (in months) from the date of first dose of study drug to the first documentation of objective response (CR or PR) that was subsequently confirmed. CR was defined as disappearance of all target and non-target lesions, and sustained for at least 4 weeks. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: >= 30% decrease in sum of diameter of target lesions taking as reference baseline sum diameters.
  • Duration of Response (DR) [ Time Frame: From first documentation of CR or PR until first documentation of tumor progression or death due to any cause or data censoring date, whichever occurred first (maximum up to 20 months) ]
    DR as assessed by investigator according to RECIST v1.1, was defined as the time from date of first documentation of objective response (CR or PR) to date of PD or death due to any cause, or data censoring date, whichever occurred first. CR: disappearance of all target and non-target lesions, and sustained for at least 4 weeks. Any pathological lymph nodes (target or non-target) reduced in short axis to <10 mm. PR: >= 30% decrease in sum of diameter of target lesions taking as reference baseline sum diameters. PD: at least a 20% increase in sum of diameters of target lesions, taking as reference the smallest sum on study treatment, with absolute increase of at least 5 mm or appearance of >=1 new lesions. DR data was censored on the date of last adequate tumor assessment for participants without an event (CR, PR, PD or death), for participants who start new anti-cancer treatment prior to DR assessment, for participants with DR assessment after >=2 missing tumor assessments.
  • Overall Survival (OS) [ Time Frame: From first dose of study drug to date of death from any cause or data censoring date, whichever occurred first (maximum up to 21 months) ]
    OS was defined as the time (in months) from the date of first dose of study drug to the date of death due to any cause or data censoring date, whichever occurred first. Participants last known to be alive were censored at the date of last contact. OS was analyzed by Kaplan-Meier method.
  • Maximum Observed Serum Concentration of Avelumab [ Time Frame: Pre-dose, at the end of avelumab infusion on Day 1 of Cycle 2, 3, 4 (Duration of each cycle=14 days) ]
  • Maximum Observed Plasma Concentration of Axitinib [ Time Frame: Pre-dose, 2 hours post dose Axitinib administration on Day 1 of Cycle 2, 3 (Duration of each cycle=14 days) ]
  • Pre-dose Serum Concentration of Avelumab [ Time Frame: Pre-dose on Day 1 of Cycle 2, 3, 4, 6, 8, 12, 16, 20, 24, 28 (Duration of each cycle=14 days) ]
  • Pre-dose Plasma Concentration of Axitinib [ Time Frame: Pre-dose on Day 1 of Cycle 2 and 3 (Duration of each cycle=14 days) ]
  • Number of Participants With Their Target Programmed Death-Ligand 1 (PD-L1) Status [ Time Frame: Baseline (Day 1) ]
    PD-L1 status was defined as positive when PD-L1 staining of any intensity was observed in tumor-associated immune cells covering >= 1% of the tumor area. PD-L1 status was defined as negative when PD-L1 staining of any intensity was observed in tumor-associated immune cells covering < 1% of the tumor area.
  • Mean Percentage of CD8+ Cells in Per Unit Area of Invasive Margin, Center of Tumor Cells and Total Area of Tumor Cells [ Time Frame: From first dose of study drug up to end of treatment (maximum up to 20 months) ]
    CD8+ cells are the type of T-lymphocytes. Invasive margin is defined as the region on each side of the border between tumor cells. Expression of CD8+ cells in invasive margin, center of tumor cells, total area of tumor cells has been reported as mean percentage of CD8+cells per unit area. Area was measured in millimeter square (mm^2).
  • Summary of Cluster of Differentiation 8 (CD8+) Cells Expression: Total Area Covered by CD8+ Cells in Center of Tumor Cells [ Time Frame: From first dose of study drug up to end of treatment (up to 20 months) ]
    CD8+ cells are the type of T-lymphocytes.
  • Number of Participants With Positive Anti-Drug Antibodies (ADAs) and Positive Neutralizing Antibodies (nAbs) [ Time Frame: From first dose of study drug until 30 days after the last dose of study drug (maximum up to 21 months) ]
    ADA positive was defined as presence of at least one positive ADA sample. nAb positive was defined as presence of at least one positive nAb sample.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 19, 2017)
  • Time to Progression (TTP) [ Time Frame: Every 8 weeks up to 16 months. ]
    TTP is the time from the start date to the date of the first documentation of objective progression of disease (PD).
  • Overall Survival (OS) [ Time Frame: Every 30 days (up to 90 days after the last administration) and then every 3 months up to 5 years ]
  • Maximum plasma concentration (Cmax) of avelumab [ Time Frame: 1 hour post-dose ]
  • Maximum plasma concentration (Cmax) of axitinib [ Time Frame: 2 hour post-dose ]
  • Tumor tissue biomarker status (ie, positive or negative based on, for example, PD-L1 expression and/or quantitation of tumor infiltrating CD8+ T lymphocytes as assessed by immunohistochemistry [IHC]). [ Time Frame: Pre-dose ]
  • Anti drug antibodies (ADAs, neutralizing antibodies [nAbs]) for avelumab when in combination with axitinib. [ Time Frame: Pre-dose ]
  • Progression Free Survival (PFS) [ Time Frame: Every 8 weeks up to 16 months. ]
    PFS is the time from the start date to the date of the first documentation of objective progression of disease (PD) or death due to any cause.
  • Objective Response (OR) [ Time Frame: Every 8 weeks up to 16 months. ]
    Number of participants with objective response (ie, confirmed complete or partial response according to RECIST Version 1.1) from the start date until disease progression or death due to any cause.
  • Time to Tumor Response (TTR) [ Time Frame: Every 8 weeks up to 16 months. ]
    TTR is the time from start date to the first documentation of objective tumor response (CR or PR) that is subsequently confirmed.
  • Duration of Response (DR) [ Time Frame: Every 8 weeks up to 16 months. ]
    DR is the time from the first documentation of objective tumor response (CR or PR) that is subsequently confirmed to the first documentation of objective tumor progression or to death due to any cause.
  • Trough plasma concentration (Ctrough) of avelumab [ Time Frame: Pre-dose ]
  • Trough plasma concentration (Ctrough) of axitinib [ Time Frame: Pre-dose ]
  • Disease Control (DC) [ Time Frame: Every 8 weeks up to 16 months. ]
    DR is the time from the first documentation of objective tumor response (CR or PR) that is subsequently confirmed to the first documentation of objective tumor progression or to death due to any cause.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study Of Avelumab In Combination With Axitinib In Advanced HCC (VEGF Liver 100)
Official Title  ICMJE AN OPEN LABEL, SINGLE ARM PHASE 1B STUDY OF AVELUMAB PLUS AXITINIB AS FIRST LINE TREATMENT IN PATIENTS WITH ADVANCED HEPATOCELLULAR CARCINOMA
Brief Summary To evaluate the safety, efficacy and PK of avelumab in combination with axitinib as first line treatment in patients with advanced HCC
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Carcinoma, Hepatocellular
Intervention  ICMJE
  • Drug: Avelumab (MSB0010718C)
    Patients will receive avelumab 10 mg/kg Q2W in combination with axitinib 5 mg BID.
  • Drug: Axitinib (AG-013736)
    Patients will receive avelumab 10 mg/kg Q2W in combination with axitinib 5 mg BID.
Study Arms  ICMJE Experimental: Experimental 1
Avelumab (MSB0010718C) in combination with axitinib (AG-013736)
Interventions:
  • Drug: Avelumab (MSB0010718C)
  • Drug: Axitinib (AG-013736)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 14, 2019)
22
Original Estimated Enrollment  ICMJE
 (submitted: September 19, 2017)
20
Actual Study Completion Date  ICMJE October 25, 2019
Actual Primary Completion Date August 27, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Diagnosis of locally advanced or metastatic HCC, obtained by histology/cytology (on a prior tumor biopsy) or by imaging with serum α-fetoprotein (AFP) ≥400 ng/mL.
  • All patients must provide at least 1 archival tumor specimen. If archival tumor specimen is no longer available, de novo tumor biopsy will be required during screening.
  • HCC not amenable to local therapy.
  • Measurable disease according to RECIST v. 1.1.
  • Child Pugh Class A disease.
  • BCLC stage B or C disease.
  • No evidence of uncontrolled hypertension as documented by 2 baseline blood pressure readings taken at least 1 hour apart.
  • ECOG performance status 0 or 1.
  • Adequate bone marrow function, renal and liver functions
  • Left ventricular ejection fraction (LVEF) ≥ lower limit of normal (LLN) as assessed by multigated acquisition (MUGA) scan or echocardiogram (ECHO).

Exclusion Criteria:

  • Prior systemic treatment for advanced HCC, including prior treatment with approved or investigational drugs.
  • Any prior locoregional therapy within 4 weeks and radiotherapy or surgical procedure within 2 weeks (4 weeks for major surgery) of enrollment.
  • Patients with known symptomatic brain metastases requiring steroids.
  • Presence of hepatic encephalopathy (ie, Child Pugh score of 2 or 3) and/or clinically relevant ascites (ie, Child Pugh score of 3).
  • Presence of main portal vein invasion by HCC.
  • Any of the following within the 12 months prior to enrollment: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, LVEF less than LLN, clinically significant pericardial effusion, cerebrovascular accident, transient ischemic attack.
  • Active infection requiring systemic therapy except for hepatitis C virus (HCV) and hepatitis B virus (HBV).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 20 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Japan
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03289533
Other Study ID Numbers  ICMJE B9991024
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
Responsible Party Pfizer
Study Sponsor  ICMJE Pfizer
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Pfizer CT.gov Call Center Pfizer
PRS Account Pfizer
Verification Date August 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP