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A Study of Tivozanib in Combination With Durvalumab in Subjects With Advanced Hepatocellular Carcinoma (DEDUCTIVE)

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ClinicalTrials.gov Identifier: NCT03970616
Recruitment Status : Recruiting
First Posted : May 31, 2019
Last Update Posted : September 10, 2021
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
AVEO Pharmaceuticals, Inc.

Tracking Information
First Submitted Date  ICMJE May 28, 2019
First Posted Date  ICMJE May 31, 2019
Last Update Posted Date September 10, 2021
Actual Study Start Date  ICMJE September 30, 2019
Estimated Primary Completion Date August 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 2, 2021)
  • Incidence of Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Approximately 24 months; Through study completion ]
    To establish the safety of tivozanib in combination with durvalumab in subjects with untreated advanced hepatocellular carcinoma (HCC).
  • Incidence of Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Approximately 24 months; Through study completion ]
    To establish the safety of tivozanib in combination with durvalumab in subjects with advanced hepatocellular carcinoma (HCC) previously treated with both bevacizumab and atezolizumab.
Original Primary Outcome Measures  ICMJE
 (submitted: May 30, 2019)
Incidence of Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Approximately 24 months; Through study completion ]
To establish the safety of tivozanib in combination with durvalumab in subjects with untreated advanced hepatocellular carcinoma (HCC).
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 2, 2021)
  • Response Rate (Objective Response Rate) [ Time Frame: Approximately 24 months ]
    To estimate the response rate of tivozanib in combination with durvalumab in subjects with untreated advanced HCC.
  • Progression Free Survival (PFS) [ Time Frame: Approximately 24 months ]
    To estimate the progression free survival (PFS) of tivozanib in combination with durvalumab in subjects with untreated advanced HCC.
  • Overall Survival (OS) [ Time Frame: Approximately 24 months; Through study completion ]
    To estimate the overall survival (OS) of tivozanib in combination with durvalumab in subjects with untreated advanced HCC.
  • Response Rate (Objective Response Rate) [ Time Frame: Approximately 24 months ]
    To estimate the response rate of tivozanib in combination with durvalumab in subjects with advanced HCC previously treated with both bevacizumab and atezolizumab.
  • Progression Free Survival (PFS) [ Time Frame: Approximately 24 months; Through study completion ]
    To estimate the progression free survival (PFS) of tivozanib in combination with durvalumab in subjects with advanced HCC previously treated with both bevacizumab and atezolizumab.
  • Overall Survival (OS) [ Time Frame: Approximately 24 months; Through study completion ]
    To estimate the overall survival (OS) of tivozanib in combination with durvalumab in subjects with advanced HCC previously treated with both bevacizumab and atezolizumab.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 30, 2019)
  • Response Rate (Objective Response Rate) [ Time Frame: Approximately 24 months ]
    To estimate the response rate of tivozanib in combination with durvalumab in subjects with untreated advanced HCC.
  • Progression Free Survival (PFS) [ Time Frame: Approximately 24 months ]
    To estimate the progression free survival (PFS) of tivozanib in combination with durvalumab in subjects with untreated advanced HCC.
  • Overall Survival (OS) [ Time Frame: Approximately 24 months; Through study completion ]
    To estimate the overall survival (OS) of tivozanib in combination with durvalumab in subjects with untreated advanced HCC.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Tivozanib in Combination With Durvalumab in Subjects With Advanced Hepatocellular Carcinoma
Official Title  ICMJE A Phase 1b/2, Open-Label, Study of Tivozanib in Combination With Durvalumab in Subjects With Advanced Hepatocellular Carcinoma
Brief Summary This study will evaluate the safety, tolerability, DLTs, MTD, and preliminary anti tumor activity of tivozanib in combination with durvalumab in subjects with advanced HCC.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Sequential Assignment
Intervention Model Description:
Phase 1 followed by expansion cohort
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hepatocellular Carcinoma
Intervention  ICMJE
  • Drug: Tivozanib
    Dose level 1: 1.0mg for 21 days followed by 7 days rest; Dose level -1: 1.0mg every other day
    Other Name: Fotivda
  • Drug: Durvalumab
    1500mg every 28 days
    Other Name: Imfinzi
Study Arms  ICMJE Experimental: Tivozanib in Combination with Durvalumab
Tivozanib in Combination with Durvalumab
Interventions:
  • Drug: Tivozanib
  • Drug: Durvalumab
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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 30, 2019)
42
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 2022
Estimated Primary Completion Date August 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. ≥ 18 years old
  2. Signed and dated written informed consent
  3. Histologically or cytologically confirmed unresectable locally advanced or metastatic hepatocellular carcinoma. Measurable or evaluable disease by RECIST 1.1 criteria. Patients can be either untreated or have progressed on both bevacizumab and atezolizumab.
  4. Child-Pugh Class A.
  5. ECOG performance status ≤ 1 (see Appendix A) and life expectancy ≥ 3 months.
  6. Body weight > 30 kg.
  7. Measured creatinine clearance (crCL) >40 mL/min or calculated crCL >40 mL/min as determined by Cockcroft-Gault (using actual body weight).
  8. Sexually active pre-menopausal female subjects (and female partners of male subjects) must use highly effective contraceptive measures, while on study and for at least 90 days after the last dose of study drug. Sexually active male subjects must use adequate contraceptive measures, while on study and for at least 90 days after the last dose of study drug. All fertile male and female subjects and their partners must agree to use a highly effective method of contraception.

Exclusion Criteria:

  1. Subjects who have received prior systemic treatment for HCC except for both bevacizumab and atezolizumab.
  2. Female subjects who are pregnant or breastfeeding or male or female subjects of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of study drug.
  3. Brain metastases or spinal cord compression. Subjects with suspected brain metastases at screening should have an MRI (preferred) or CT scan each preferable with IV contrast of the brain prior to study entry. Brain metastases will not be recorded on RECIST Target Lesions at baseline.
  4. Any of the following hematologic abnormalities:

    • Hemoglobin < 9.0 g/dL
    • Absolute neutrophil count (ANC) < 1500 per mm3
    • Platelet count < 75,000 per mm3
  5. Any of the following serum chemistry or urinalysis abnormalities:

    • Total bilirubin > 2 × ULN (>2.5 mg/dL in subjects with Gilbert's syndrome)
    • AST or ALT > 5 × ULN
    • Alkaline phosphatase > 2.5 × ULN (or > 5 × ULN for subjects with liver or bone metastasis)
    • Serum creatinine > 1.5 × ULN •> 2+ proteinuria
  6. History of hepatic encephalopathy within past 12 months or requirement for medications to prevent or control encephalopathy (eg, no lactulose, rifaximin, etc if used for purposes of hepatic encephalopathy).
  7. GI Bleeding (eg, esophageal varices or ulcer bleeding) within 12 months. (Note: For patients with a history of GI bleeding for more than 12 months or assessed as high risk for esophageal variceal bleed by the Investigator, adequate endoscopic therapy according to institutional standards is required).
  8. Clinically meaningful ascites defined as ascites requiring non-pharmacologic intervention (eg, paracentesis) to maintain symptomatic control, within 6 months prior to the first scheduled dose. Subjects on stable doses of diuretics for ascites for ≥ 2 months are eligible.
  9. Main portal vein thrombosis (Vp4) as documented on imaging. (VP4 is defined as portal vein thrombosis in the main trunk of the portal vein or a portal vein branch contralateral to the primarily involved lobe (or both).
  10. For subjects who require ongoing therapeutic anti-coagulation or anti-platelet therapy; the subject must be off either therapy for at least 7 days prior to the first dose of investigational product. Low-dose aspirin for cardiac prophylaxis/protection is permitted per local institutional standards.
  11. Patients co-infected with HBV and HCVHBV positive [presence of hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibodies (anti-HBcAb) with detectable HBV DNA (≥10IU/ml)]; HCV positive (presence of anti-HCV antibodies).
  12. Major surgery (as defined by the investigator) within 28 days prior to first dose of IP or still recovering from prior surgery. Local procedures (eg, core needle biopsy, and prostate biopsy) are allowed if completed at least 3 days prior to the administration of the first dose of study treatment.
  13. Significant cardiovascular disease, including:

    • Clinically symptomatic heart failure. Subjects with a history of heart failure must have an ECHO or MUGA scan to document left ventricular ejection fraction (LVEF) > 45% prior to start of protocol therapy
    • Any New York Heart Association classification ≥ Class 2 (prefer Class 0 or 1)
    • Any stenting procedure within the last 3 months
    • Venous thromboembolism or arterial thromboembolism within the last 3 months
    • Any IVC tumor thrombosis
    • History of a hemorrhagic event (i.e., GI bleed within 6 months)
    • Uncontrolled hypertension: blood pressure >150/95 mmHg on more than 2 antihypertensive medications, on two consecutive measurements obtained at least 24 hours apart. Subjects with a history of hypertension must have been on stable doses of anti-hypertensive drugs for ≥ 2 weeks prior to start of protocol therapy.
    • Myocardial infarction within 3 months prior to start of protocol therapy
  14. Subjects with delayed healing of wounds, ulcers, and/or bone fractures
  15. Serious/active infection or infection requiring parenteral antibiotics
  16. Inadequate recovery from any prior surgical procedure; major surgical procedure within 4 weeks prior to start of protocol therapy.
  17. Inability to comply with protocol requirements
  18. History of another primary malignancy except for:

    • Malignancy treated with curative intent and with no known active disease ≥ 5 years before the first dose of study drug and low potential risk for recurrence
    • Adequately treated non-melanoma skin cancer of lentigo maligna without evidence of disease
  19. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Subjects positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
  20. Patients with a history or current HBV infection (detectable HBV DNA), should be placed on anti-viral treatment and tested at every cycle for HBV DNA viral load.
  21. Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field of radiation or to more than 30% of the bone marrow within 4 weeks before the first dose of study intervention.
  22. Treatment with systemic hormonal therapy within 3 weeks prior to start of protocol therapy, with the exception of:

    • Hormonal therapy for appetite stimulation or contraception
    • Nasal, ophthalmic, inhaled and topical steroid preparations
    • Oral replacement therapy for adrenal insufficiency
    • Low-dose maintenance steroid therapy (equivalent of prednisone 10mg/day) for other conditions
    • Hormone replacement therapy such as testosterone
  23. Strong CYP3A4 inducers (see Appendix B) within 2 weeks prior to start of, or during, protocol therapy.
  24. Prior exposure to tivozanib or durvalumab. For subjects who have received prior atezolizumab:

    • Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy.
    • All AEs while receiving prior immunotherapy must have completely resolved or resolved to baseline prior to screening for this study.
    • Must not have experienced a Grade ≥ 3 immune-related AE or an immune-related neurologic or ocular AE of any grade while receiving prior immunotherapy. Note: Participants with an endocrine AE of Grade ≤ 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic.
    • Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not currently require maintenance doses of > 10 mg prednisone or equivalent per day.
  25. History of allogeneic organ transplantation
  26. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this criterion:

    • Subjects with vitiligo or alopecia
    • Subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
    • Any chronic skin condition that does not require systemic therapy
    • Subjects without active disease in the last 5 years may be included but only after consultation with Medical Monitor
    • Subjects with celiac disease controlled by diet alone
  27. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the subject to give written informed consent
  28. History of leptomeningeal carcinomatosis
  29. History of active primary immunodeficiency
  30. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart)
  31. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
  32. Concurrent enrollment in another clinical study, unless it is an observational (non interventional) clinical study or during the follow-up period of an interventional study
  33. Receipt of live attenuated vaccine within 30 days prior to the first dose of study drug. Note: Subjects, if enrolled, should not receive live vaccine whilst receiving study drug and up to 30 days after the last dose of study drug.
  34. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:

    • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
    • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent
    • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
  35. Previous study drug assignment in the present study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Chief Medical Officer 857-400-0101 Clinical@aveooncology.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03970616
Other Study ID Numbers  ICMJE AV-951-18-121
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party AVEO Pharmaceuticals, Inc.
Study Sponsor  ICMJE AVEO Pharmaceuticals, Inc.
Collaborators  ICMJE AstraZeneca
Investigators  ICMJE Not Provided
PRS Account AVEO Pharmaceuticals, Inc.
Verification Date September 2021

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