Clinical Trials /

Safety and Efficacy of Intra-Arterial and Intra-Tumoral Ad-p53 With Capecitabine (Xeloda) or Anti-PD-1 in Liver Metastases of Solid Tumors and Recurrent Head and Neck Squamous Cell Cancer

NCT02842125

Description:

This is a Phase 1/2 study of the combination of Ad-p53 administered intra-arterially in combination with oral metronomic capecitabine or pembrolizumab in patients with unresectable, refractory liver metastases of colorectal carcinoma (CRC) and other solid tumors, including primary hepatocellular carcinoma (HCC). A third arm will study the intra-tumoral injection of Ad-p53 combined with nivolumab infusions in recurrent head and neck squamous cell cancer (HNSCC). This safety study has a standard 3+3 design for arms A and B; .HNSCC will be placed in a single dosing cohort. The Maximum Tolerated Dose (MTD) will be determined as well for intra-arterial infusions, and the entire study will determine the general efficacy using RECIST 1.1 and Immune-Related Response Criteria. Safety will be followed using the CTCAE listings for adverse events.

Related Conditions:
  • Colorectal Carcinoma
  • Head and Neck Squamous Cell Carcinoma
  • Hepatocellular Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Safety and Efficacy of Intra-Arterial and Intra-Tumoral Ad-p53 With Capecitabine (Xeloda) or Anti-PD-1 in Liver Metastases of Solid Tumors and Recurrent Head and Neck Squamous Cell Cancer
  • Official Title: Phase 1/2 Evaluation of Adenoviral p53 (Ad-p53) in Combination With Capecitabine (Xeloda) or Anti-PD-1 in Patients With Unresectable Liver Metastases of Colorectal Carcinoma(CRC) and Other Solid Tumors, Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC) and Primary Hepatic Cancers With Known Disease Progression on Standard Therapy

Clinical Trial IDs

  • ORG STUDY ID: MultiVir Ad-p53-001
  • NCT ID: NCT02842125

Conditions

  • Metastatic Solid Tumor Cancer
  • Recurrent Head and Neck Cancer

Interventions

DrugSynonymsArms
Ad-P53Ad-p53 with Xeloda 33.3% of patients
XelodacapecitabineAd-p53 with Xeloda 33.3% of patients
KeytrudaPembrolizumabAd-p53 with Keytruda 33.3% of patients
OpdivoNivolumabAd-p53 with Opdivo 33.3% of patients

Purpose

This is a Phase 1/2 study of the combination of Ad-p53 administered intra-arterially in combination with oral metronomic capecitabine or pembrolizumab in patients with unresectable, refractory liver metastases of colorectal carcinoma (CRC) and other solid tumors, including primary hepatocellular carcinoma (HCC). A third arm will study the intra-tumoral injection of Ad-p53 combined with nivolumab infusions in recurrent head and neck squamous cell cancer (HNSCC). This safety study has a standard 3+3 design for arms A and B; .HNSCC will be placed in a single dosing cohort. The Maximum Tolerated Dose (MTD) will be determined as well for intra-arterial infusions, and the entire study will determine the general efficacy using RECIST 1.1 and Immune-Related Response Criteria. Safety will be followed using the CTCAE listings for adverse events.

Detailed Description

      This is a Phase 1/2 study split into 3 arms. Arm A will follow the combination of Ad-p53
      administered intra-arterially in combination with oral metronomic capecitabine while Arm B
      follows the intra-arterial administration of Ad-p53 combined with pembrolizumab, both in
      patients with unresectable, refractory liver metastases of colorectal carcinoma (CRC) and
      other solid tumors, including primary hepatocellular carcinoma (HCC). Arm C will follow the
      combination of intra-tumoral injections of Ad-p53 and nivolumab infusions. Arms A and B have
      a standard 3+3 design, with dosing following the initial cohort determined by MTD and DLT
      criteria as well as safety and tolerance. Arm C will be a single dosing cohort followed for
      safety and efficacy. All patients will be followed for adverse events and preliminary
      efficacy. In Arms A and B, the Maximum Tolerated dose (MTD) will be determined. All patients
      will be followed for general safety and preliminary efficacy using RECIST 1.1 and
      Immune-Related Response Criteria. CEA levels will also be followed for patients with
      metastatic colo-rectal cancer. Biomarker testing of archival or fresh tissue is performed
      during the study. In Arms A and B, patients will undergo a maximum of 2 8-week cycles, with
      scans every 8 weeks. For Arm B, patients will undergo a maximum of 3 28-day Cycles. All
      patients will continue on the background therapy for any additional cycles. No additional
      biopsies are planned following Screening. Enrollment will be up to 24 patients.
    

Trial Arms

NameTypeDescriptionInterventions
Ad-p53 with Xeloda 33.3% of patientsExperimentalUp to 12 patients, in 3+3 cohorts, all patients treated with Intra-arterial Ad-P53 once weekly, dosing dependent on DLT and MTD findings, and daily metronomic Xeloda (capecetabine), at a dose of 625 mg/m2 BID continuously.
  • Ad-P53
  • Xeloda
Ad-p53 with Keytruda 33.3% of patientsExperimentalUp to 12 patients, in 3+3 cohorts, all patients treated with Intra-arterial Ad-P53 once weekly, dosing dependent on DLT and MTD findings, and infusions of pembrolizumab every 3 weeks.
  • Ad-P53
  • Keytruda
Ad-p53 with Opdivo 33.3% of patientsExperimentalUp to 12 patients treated with intra-tumoral Ad-P53 3 times week 1 of each cycle, dose determined by tumor size, in combination with IV nivolumab (Opdivo) 480 mg, every 4 weeks.
  • Ad-P53
  • Opdivo

Eligibility Criteria

        Inclusion Criteria:

          1. Signed informed consent

          2. Male or female, age 18 or above, who agree to use barrier contraception throughout the
             study. Females of child-bearing potential must be non-pregnant and non-lactating
             throughout the study.

          3. Histologically or cytologically confirmed solid tumors or hepatocellular carcinoma
             with known disease progression.

          4. Each patient entered on the study must have disease that is evaluable for response
             using RECIST 1.1 criteria with a minimum size of 1 cm by CT/MRI or physical
             examination

          5. Carcinoma patients in Arm A or Arm B must have received at least 1 prior regimen of
             standard of care systemic antitumor therapy for their metastatic disease and
             experienced tumor progression within 3 months after the last prior administration of
             the therapy or experienced unacceptable toxicity to these treatments.

          6. Subjects in Arm A and Arm B 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.

          7. The maximum tumor diameters for each Cohort for both Arm A and Arm B should achieve a
             dose of approximately 1x1011 viral particles (vp)/cm3 of tumor volume. (see Table 1).
             Please refer to Table for calculating tumor volume.

          8. ECOG Performance Status 0 - 1

          9. Either no brain metastases or irradiated stable brain metastases

         10. Life expectancy at least 3 months

         11. No prior autologous or allogeneic organ or tissue transplantation

         12. PT/international normalized ratio (INR) ≤ULN; aPTT ≤ULN.

         13. ANC ≥1500 cells/mm3

         14. Platelet count ≥100,000 cells/mm3

         15. Hemoglobin ≥9.0 g/dL

         16. Creatinine <2.0 mg/dL or creatinine clearance ≥50 mL/min

         17. Total bilirubin <1.5 x ULN

         18. AST and ALT <3.0 x ULN

         19. Alkaline phosphatase ≤5 x ULN

         20. Negative pregnancy test in women of childbearing potential

         21. Fertile patients must use effective contraception

         22. No non-approved investigational agents or procedures ≤4 weeks of study entry

         23. Patients with PRIMARY HEPATIC CANCER must have an undetectable viral load for
             Hepatitis B and C.

         24. Patients with Primary Hepatic Cancer have not recently been treated with antivirals.

         25. Troponin blood level within normal limits.

         26. Favorable biomarker profile defined by either wild type p53 gene sequence or less than
             20% p53 positive tumor cells by immunohistochemistry

         27. Echocardiogram with normal ejection fractions

         28. Normal lung oxygen saturation by pulse oximeter, as determined by the Principal
             Investigator based on patient history and status.

         29. Arm C patients must have loco-regional recurrent head and neck squamous cell carcinoma
             (HNSCC), excluding endolaryngeal recurrence, meeting the following criteria:

               -  Tumor progression within 6 months of platinum-based chemotherapy

               -  All HNSCC lesions should be in the head and neck region and suitable for
                  intra-tumoral injection

               -  The total sum of Ad-p53 Injection Doses (mL) based upon the tumor volumes shown
                  in Table 2 should be less than or equal to 25 mL as the MTD of Ad-p53 is 2.5
                  x1013 vp/treatment day.

        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. No
             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. Prior radiation performed to areas of measurable disease ≤ four weeks of study entry
             unless there is documented evidence of disease progression.

          8. Use of systemic anti-cancer therapy ≤ 4 weeks, or six weeks if the systemic therapy
             contains a nitrosourea or mitomycin C.

          9. Neuropathy (≥grade 2 CTCAE)

         10. History of allergic reactions to any components of the treatments

         11. Prior additional malignancy within 2 years except for non-melanoma skin cancer,
             carcinoma in situ of the breast, oral cavity or cervix.

         12. Severe, active comorbidity, including any of the following:

               1. Active clinically serious infection requiring intravenous antibiotics at the time
                  of study entry (CTCAE Grade 2)

               2. Hepatic insufficiency not due to tumor resulting in clinical jaundice or
                  bilirubin >1.5 x ULN and/or coagulation defects

               3. Thrombotic or embolic event within the last 6 months including portal vein
                  thrombosis

               4. Must not require concomitant treatment with anticoagulants

               5. QTcb >470 ms

               6. Bleeding or evidence or history of clinically significant bleeding diathesis or
                  coagulopathy within the last 3 months

               7. Uncontrolled hypertension on anti-hypertensive medication (systolic blood
                  pressure >150 mmHg or diastolic blood pressure >95 mmHg)

               8. Must not have been diagnosed with autoimmune disease or be immunosuppressed

               9. Patients with non-hepatocellular carcinoma must not have acute or chronic
                  hepatitis B or hepatitis C infection

              10. Known significant immunodeficiency due to underlying illness (e.g. HIV/AIDS)
                  and/or immunosuppressive medication including high-dose corticosteroids.

              11. Severe bleeding, hemoptysis, gastrointestinal hemorrhage, CNS bleeding,
                  clinically significant hemorrhage or vaginal bleeding during the last 6 months

              12. Subjects must not have evidence of pneumonitis or inflammatory lung disease on CT
                  scan and x-ray

         13. Chronic treatment for more than 6 months with systemic corticosteroids at doses above
             10 mg prednisolone or equivalent before study entry

         14. 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.

         15. Subjects must not have tumors adjacent to vital structures such as carotid arteries.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety assessed by CTCAE
Time Frame:Screening to 30-days following Final Treatment (approximately 22 weeks)
Safety Issue:
Description:Incidence of treatment-emergent and treatment-related adverse events (all AEs, laboratory AEs, SAEs and Fatal AEs, in accordance with the CTCAE

Secondary Outcome Measures

Measure:Progression-Free Survival (PFS) of patients using RECIST 1.1
Time Frame:Day 1 to progression through end of study, approximately 2 years
Safety Issue:
Description:PFS determined by review of scans every 8 weeks for disease progression in accordance with RECIST 1.1 in patients treated with Ad-p53 and either Xeloda or Keytruda. Scans are read locally but kept for possible central review. Scans are done every 8 weeks.
Measure:Efficacy determined by Immune Related Response Criteria (irRC) [Wolchok 2009]
Time Frame:Day 1 of Treatment through 30-days following last treatment (20 weeks)
Safety Issue:
Description: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.
Measure:Efficacy as determined by biomarker testing and immunohistochemistry testing
Time Frame:Day 1 of Treatment to End of Study (approximately 18 months)
Safety Issue:
Description:Efficacy endpoints will be correlated with central biomarker testing for PDL-1, PD-2, as well as central biomarker testing for immune cell infiltrates and tumor mutational burden biomarkers in exploratory analyses, through Cancer Genetics, Inc.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:MultiVir, Inc.

Trial Keywords

  • Head and Neck Squamous Cell Cancer
  • solid tumors
  • nivolumab
  • Ad-P53
  • metastatic
  • capecitabine
  • pembrolizumab

Last Updated

March 5, 2019