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Safety and Efficacy of Intra-Arterial Ad-p53 in Liver Metastases of Solid Tumors

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ClinicalTrials.gov Identifier: NCT02842125
Recruitment Status : Recruiting
First Posted : July 22, 2016
Last Update Posted : April 4, 2017
Sponsor:
Information provided by (Responsible Party):
MultiVir, Inc.

Brief Summary:
This is a Phase 1 study of the combination of Ad-p53 administered intra-arterially in combination with oral metronomic capecitabine in patients with unresectable, refractory liver metastases of colorectal carcinoma (CRC) and other solid tumors, including primary hepatocellular carcinoma (HCC). This safety study has a standard 3+3 design. The Maximum Tolerated Dose (MTD) will be determined as well as the general safety and preliminary efficacy using RECIST 1.1 and Immune-Related Response Criteria. CEA levels will also be followed.

Condition or disease Intervention/treatment Phase
Metastatic Solid Tumor Cancer Drug: Ad-P53 Drug: Xeloda Phase 1

Detailed Description:
This is a Phase 1 study of the combination of Ad-p53 administered intra-arterially in combination with oral metronomic capecitabine in patients with unresectable, refractory liver metastases of colorectal carcinoma (CRC) and other solid tumors, including primary hepatocellular carcinoma (HCC). This safety study has a standard 3+3 design, with dosing following the initial cohort determined by MTD and DLT criteria as well as safety and tolerance. Patients will be followed for adverse events and preliminary efficacy. The Maximum Tolerated dose (MTD) will be determined as well as the general safety and preliminary efficacy using RECIST 1.1 and Immune-Related Response Criteria. CEA levels will also be followed. Biomarker testing of archival or fresh tissue is performed during the study. Patients will undergo a maximum of 2 8-week cycles, with scans every 8 weeks. No additional biopsies are planned following Screening. Enrollment will be up to 24 patients.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Evaluation of Intra-Arterial Ad-p53 Combined With Capecitabine in Patients With Unresectable Liver Metastases of Colorectal Carcinoma and Other Solid Tumors as Well as Primary Hepatocellular Carcinoma (HCC)
Study Start Date : June 2016
Estimated Primary Completion Date : July 2018
Estimated Study Completion Date : July 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: All Patients
Up to 24 patients, in 3+3 cohorts, all patients treated with Intra-arterial Ad-P53 twice weekly, dosing dependent on DLT and MTD findings, and daily metronomic Xeloda (capecetabine), at a dose of 625 mg/m2 BID continuously. No randomization.
Drug: Ad-P53
Adenoviral Investigational Product Ad-P53 to treat metastases using an intra-arterial catheter, with oral metronomic Xeloda

Drug: Xeloda
Oral metronomic chemotherapeutic agent
Other Name: capecitabine




Primary Outcome Measures :
  1. Safety assessed by CTCAE [ Time Frame: Screening to 30-days following Final Treatment (approximately 22 weeks) ]
    Incidence of treatment-emergent and treatment-related adverse events (all AEs, laboratory AEs, SAEs and Fatal AEs, in accordance with the CTCAE

  2. Incidence of dose-limiting toxicities (DLTs) [ Time Frame: Day 1 to 30-days Following Last Treatment (approximately 21 weeks) ]
    To evaluate the safety, as assessed by the incidence of dose limiting toxicities, of the combination of Ad-P53 and Xeloda

  3. Determination of maximum-tolerated dose (MTD) [ Time Frame: Day 1 to 30 days following Final Treatment (Approximately 21 Weeks) ]
    Determination of maximum tolerated dose (MTD) by review of DLTs


Secondary Outcome Measures :
  1. Progression-Free Survival (PFS) of patients using RECIST 1.1 [ Time Frame: Day 1 to progression through end of study, approximately 2 years ]
    PFS determined by review of scans every 8 weeks for disease progression in accordance with RECIST 1.1. Scans are read locally but kept for possible central review. Scans are done every 8 weeks.

  2. Efficacy determined by Immune Related Response Criteria (irRC) [Wolchok 2009] [ Time Frame: Day 1 of Treatment through 30-days following last treatment (20 weeks) ]
    Efficacy will be determined by review of the irRC (Immune-Related Response Criteria. Patients will undergo scanning every 8 weeks for the duration of the study, with evaluation of the scans in accordance with the Immune Related Response Criteria, including confirmation of disease progression with a scan 4 weeks after noted per RECIST criteria.

  3. Efficacy as determined by carcinoembryonic antigen (CEA) level testing [ Time Frame: Day 1 of Treatment to End of Study (approximately 2 years) ]
    Efficacy determined by Carcinoembryonic antigens (CEA) testing performed at screening and at the end of weeks 2-8 and at EOT (End of Treatment) and Follow-up (to end of study, at approximately 2 years)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed informed consent
  2. Male or female
  3. Histologically or cytologically confirmed solid tumors or hepatocellular carcinoma with known disease progression.
  4. Subjects should have measurable CT-evidence of liver metastases or liver lesions that are not treatable by surgical resection or local ablation in consultation with hepatobiliary specialist.
  5. Age ≥18
  6. ECOG Performance Status 0 - 1
  7. Either no brain metastases or irradiated stable brain metastases.
  8. Life expectancy ≥ 5 months
  9. No prior autologous or allogeneic organ or tissue transplantation
  10. PT/international normalized ratio(INR) ≤ ULN; aPTT ≤ ULN
  11. New York Heart Association classification <III
  12. ANC ≥ 1500 cells/mm3
  13. Platelet count ≥100,000 cells/mm3
  14. Hemoglobin ≥10.0 g/dL
  15. Creatinine < 2.0 mg/dL or creatinine clearance ≥ 60 mL/min
  16. Total bilirubin < 1.5 x ULN
  17. AST and ALT < 3.0 x ULN
  18. Negative pregnancy test in women of childbearing potential
  19. Fertile patients must use effective contraception
  20. No non-approved investigational agents or procedures £4 weeks of study entry
  21. Favorable tumor p53 biomarker profiles for Ad-p53 efficacy defined by either wild-type p53 gene configuration or £20% p53 positive cells by immunohistochemistry
  22. Child-Pugh score must be A to B7
  23. Patients with HCC must have an undetectable viral load for Hepatitis B and C.
  24. Patients with HCC must not recently have been treated with antivirals.

Exclusion Criteria:

  1. Subjects must not be candidates for hepatic surgery or locoregional therapy of liver tumors with curative intent.
  2. Liver tumors must not be estimated to invade approximately more than one-third of the liver.
  3. Liver tumor-directed therapy, hepatic surgery, antibody-based therapy, or immunotherapy must not have been performed < 28 days, chemotherapy < 21 days, and targeted small molecule therapy or hormonal therapy < 14 days prior to enrollment. Nor radiation to tumor sites during the last 4 weeks.
  4. No macroscopic intra-vascular invasion by tumors of the main portal vein, hepatic vein or vena cava.
  5. Chronic liver dysfunction prior to development of liver metastases (Child-Pugh C or greater)
  6. Active alcohol dependence
  7. Neuropathy ( ≥ grade 2 NCI-CTC)
  8. History of allergic reactions to any components of the treatments
  9. Prior malignancy within 2 years except for non-melanoma skin cancer, carcinoma in situ of the breast, oral cavity or cervix.
  10. Severe, active comorbidity

    • Active clinically serious infection requiring intravenous antibiotics at the time of study entry (CTCAE Grade 2)
    • Hepatic insufficiency not due to tumor resulting in clinical jaundice or bilirubin >1.5 x ULN and/or coagulation defects
    • Thrombotic or embolic event within the last 6 months including portal vein thrombosis
    • Must not require concomitant treatment with anticoagulants
    • QTcb >470 ms
    • Bleeding or evidence or history of clinically significant bleeding diathesis or coagulopathy within the last 3 months
    • Uncontrolled hypertension on anti-hypertensive medication (systolic blood pressure >150 mmHg or diastolic blood pressure >95 mmHg)
    • Must not have been diagnosed with autoimmune disease or be immunosuppressed
    • Patients with non-hepatocellular carcinoma must not have acute or chronic hepatitis B or hepatitis C infection
    • Known human immunodeficiency virus (HIV)
    • Severe bleeding, hemoptysis, gastrointestinal hemorrhage, CNS bleeding
    • Clinically significant hemorrhage or vaginal bleeding during the last 6 months
  11. Chronic treatment for more than 6 months with systemic corticosteroids at doses above 10 mg (prednisolone or equivalent) before study entry
  12. Psychological, familial, sociological or geographical or other condition which in the opinion of the investigator would not permit study follow-up or other compliance with the study protocol.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02842125


Contacts
Contact: Kerstin B Menander, MD/PhD 713-665-9058 kmenander@multivir.com
Contact: Beatha H Sellman, MA 713-668-5684 bsellman@multivir.com

Locations
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Vivek Subbiah, MD    713-563-0393    vsubbiah@mdanderson.org   
Principal Investigator: Vivek Subbiah, MD         
Sponsors and Collaborators
MultiVir, Inc.
Investigators
Principal Investigator: Vivek Subbiah, MD M.D. Anderson Cancer Center

Responsible Party: MultiVir, Inc.
ClinicalTrials.gov Identifier: NCT02842125     History of Changes
Other Study ID Numbers: MultiVir Ad-p53
First Posted: July 22, 2016    Key Record Dates
Last Update Posted: April 4, 2017
Last Verified: March 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by MultiVir, Inc.:
Colorectal
solid tumors
hepatocellular
Ad-P53
metastatic
capecitabine

Additional relevant MeSH terms:
Capecitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents