Clinical Trials /

Safety and Efficacy of Ad-p53 in Head and Neck Cancer

NCT03544723

Description:

This is a Phase 2 study of the combination of Ad-p53 administered intra-tumorally with Nivolumab in patients with recurrent head and neck squamous cell cancer and favorable p53 status. There is one cohort consisting of Ad-p53 in combination with Opdivo. Comparison will be made to historical data. General safety and efficacy using RECIST 1.1 and Immune-Related Response Criteria as well as ECOG numbers will be followed.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Safety and Efficacy of Ad-p53 in Head and Neck Cancer
  • Official Title: A Phase 2, Multi-Center, Open Label, Randomized Study to Evaluate Efficacy and Safety of Adenoviral p53 (Ad-p53) in Combination With Nivolumab Versus Nivolumab Alone in Patients With Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC)

Clinical Trial IDs

  • ORG STUDY ID: Ad-p53-002
  • NCT ID: NCT03544723

Conditions

  • Recurrent Head and Neck Cancer

Interventions

DrugSynonymsArms
Ad-P53Opdivo, nivolumabAd-p53 with Nivolumab 50% of patients
OpdivonivolumabAd-p53 with Nivolumab 50% of patients

Purpose

This is a Phase 2 study of the combination of Ad-p53 administered intra-tumorally with Nivolumab in patients with recurrent head and neck squamous cell cancer and favorable p53 status. There are two cohorts, one with Ad-p53 in combination with Opdivo, one with Opdivo alone, in an unblinded design. General safety and efficacy using RECIST 1.1 and Immune-Related Response Criteria as well as ECOG numbers will be followed.

Detailed Description

      This is a Phase 2 study of the combination of Ad-p53 administered intra-tumorally in
      combination with Opdivo infusions in patients with recurrent head and neck squamous cell
      cancer and favorable p53 status. This safety and efficacy study has two unblinded cohorts,
      Arm A will be treated with the combination of Ad-p53 and Opdivo, while Arm B is treated
      solely with Opdivo. Randomization will be done to ensure equal numbers in each arm. Patients
      will be followed for adverse events, ECOG status and preliminary efficacy. General safety and
      preliminary efficacy will be determined using RECIST 1.1, ECOG status and, as indicated,
      Immune-Related Response Criteria. Biomarker testing of archival or fresh tissue is performed
      during the study. Patients will undergo a maximum of 3 28-day cycles, with scans every 8
      weeks. No additional biopsies will be required after Screening. Enrollment will be up to 40
      patients.
    

Trial Arms

NameTypeDescriptionInterventions
Ad-p53 with Nivolumab 50% of patientsExperimentalUp to 20 patients, in Arm A, all 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) 240 mg, every 2 weeks.
  • Ad-P53
  • Opdivo
Nivolumab 50% of patientsActive ComparatorUp to 20 patients in Arm B, all patients treated with comparator intervention consisting of IV nivolumab (Opdivo) 240 mg, every 2 weeks.
  • Opdivo

Eligibility Criteria

        Inclusion Criteria:

          1. Signed informed consent.

          2. Male or female ≥ 18 years of age (females of childbearing potential must be
             non-pregnant, non-lactating). Males and females must agree to use barrier
             contraception for the duration of the study.

          3. Recurrent head and neck squamous cell carcinoma (HNSCC), excluding endolaryngeal
             recurrence, meeting the following criteria:

               -  Tumor progression within 6 months of platinum-based chemotherapy

               -  HNSCC primary diagnosis must be histologically confirmed. .

          4. All lesions should be suitable for intra-tumoral injection and the total sum of Ad-p53
             Injection Doses (mL) should be less than or equal to 25 mL (see Table 1) as the MTD of
             Ad-p53 is 2.5x1013 vp/treatment day.

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

          6. No brain metastases

          7. ECOG Performance Status 0-1

          8. Life expectancy > 16 weeks.

          9. Adequate bone marrow and hepatic function as evidenced by the following:

               1. ANC ≥ 1500 cells/mm3

               2. AST/SGOT and/or ALT/SGPT ≤ 3.0 x ULN

               3. alkaline phosphatase ≤ 5 x ULN

         10. Favorable tumor p53 biomarker profile as defined by either wild-type p53 gene
             configuration by Foundation One CDx assay or <20% p53-positive cells by
             immunohistochemistry (Nemunaitis 2009). Tumor p53 biomarker evaluations may be
             performed with tumor tissue (paraffin block or frozen tissue) from either primary or
             recurrent tumor although samples from recurrence are preferred if both are available.
             If archival tissue is not available, a fresh tumor biopsy specimen must be evaluated.

         11. Normal troponin blood levels.

         12. Echo with normal ejection fractions.

         13. QTcb ≤ 470 ms

         14. Normal lung oxygen saturation by pulse oximeter.

        Exclusion Criteria:

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

          2. Prior radiation performed to areas of measurable disease ≤ four weeks of study entry
             unless there is documented evidence of disease progression.

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

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

          5. Participation in clinical studies of non-approved experimental agents ≤ four weeks of
             study entry.

          6. Prior autologous or allogenic organ or tissue transplantation.

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

             a. Active clinically serious infection requiring intravenous antibiotics at the time
             of study entry (CTCAE Grade 2) b. Hepatic insufficiency not due to tumor resulting in
             clinical jaundice or bilirubin >1.5 x ULN and/or coagulation defects c. Thrombotic or
             embolic event within the last 6 months including portal vein thrombosis d. Must not
             require concomitant treatment with anticoagulants or have an abnormal INR f. Bleeding
             or evidence or history of clinically significant bleeding diathesis or coagulopathy
             within the last 3 months g. Uncontrolled hypertension on anti-hypertensive medication
             (systolic blood pressure >150 mmHg or diastolic blood pressure >95 mmHg) h. Must not
             have been diagnosed with autoimmune disease or be immunosuppressed i. must not have
             acute or chronic hepatitis B or hepatitis C infection with signs of immunosuppression
             j. Known significant immunodeficiency due to underlying illness (e.g. HIV/AIDS) and/or
             immunosuppressive medication including high-dose corticosteroids.

             k. Severe bleeding, hemoptysis, gastrointestinal hemorrhage, CNS bleeding l.
             Clinically significant hemorrhage or vaginal bleeding during the last 6 months m.
             Active brain metastases or leptomeningeal metastases are not allowed n. Subjects with
             active, known or suspected autoimmune disease o. Subjects must not have evidence of
             pneumonitis or inflammatory lung disease on CT scan and chest x-ray.

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

          9. 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.

         10. Subjects may 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:Progression-Free Survival (PFS) of patients using RECIST 1.1
Time Frame:Day 1 to progression through end of study, approximately 18 months.
Safety Issue:
Description: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. Sites will review questionable findings on scans with Immune Related Response Criteria (irRC) [Wolchok 2009].

Secondary Outcome Measures

Measure:Safety assessed by CTCAE
Time Frame:Screening to 30-days following Final Treatment (approximately 20 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
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 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:MultiVir, Inc.

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