Clinical Trials /

Safety and Efficacy of p53 Gene Therapy Combined With Immune Checkpoint Inhibitors in Solid Tumors.

NCT03544723

Description:

This is a single arm Phase 2 study of the combination of adenoviral p53 (Ad-p53) gene therapy administered intra-tumorally with approved immune checkpoint inhibitors in patients with recurrent or metastatic cancers. Comparison will be made to historical data. General safety and efficacy using RECIST 1.1 and Immune-Related Response Criteria as well as ECOG performance will be utilized.

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 Combined With Checkpoint Inhibitor in Head and Neck Cancer
  • Official Title: A Phase 2, Multi-Center, Open Label Study to Evaluate Efficacy and Safety of Adenoviral p53 (Ad-p53) in Combination With Immune Checkpoint Inhibitor Therapy in Patients With Progression or Recurrence of Head and Neck Squamous Cell Carcinoma (HNSCC)

Clinical Trial IDs

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

Conditions

  • Solid Tumor
  • Lymphoma

Interventions

DrugSynonymsArms
Ad-P53anti-PD-1/anti-PD-L1, nivolumab, pembrolizumab, atezolizumab, durvalumabAd-p53 with anti-PD-1/anti-PD-L1 100% of patients

Purpose

This is a Phase 2 study of the combination of Ad-p53 administered intra-tumorally with approved checkpoint inhibitors in patients with recurrent or metastatic solid and other tumors and favorable p53 status. There is a single cohort consisting of Ad-p53 in combination with checkpoint inhibitor. 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.

Detailed Description

      This is a Phase 2 study of the combination of Ad-p53 administered intra-tumorally in
      combination with physician's choice of FDA approved checkpoint inhibitor therapy in patients
      with recurrent or metastatic solid and other tumors and and favorable p53 status. This is a
      safety and efficacy study with a single cohort, consisting of the combination of Ad-p53 and
      infusions of checkpoint inhibitors at a schedule and dose in accordance with package inserts.
      Comparison will be made to historical data. 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, with a biopsy or
      archival tissue at Screening, followed by a second optional fresh biopsy during the Ad-p53
      treatment. Patients will undergo 3 planned 28-day cycles; however, with PI and physician
      approval additional cycles may be performed. Following these initial 3 Cycles, patients will
      be treated solely with the checkpoint inhibitor therapy until disease progression, death or
      withdrawal of consent. Scans are every 8 weeks. There is an additional optional biopsy.
      Enrollment will be up to 40 patients.
    

Trial Arms

NameTypeDescriptionInterventions
Ad-p53 with anti-PD-1/anti-PD-L1 100% of patientsExperimentalUp to 40 patients, all patients treated with intra-tumoral Ad-P53 3 times week 1 of 3 cycles, dose determined by tumor size, in combination with IV physician's choice of approved checkpoint inhibitor, typically starting on Day 5 Cycle 1.
  • Ad-P53

Eligibility Criteria

        Inclusion Criteria

          1. Signed informed consent.

          2. Male or female greater than or equal to 18 years of age (females of childbearing
             potential must be non-pregnant with a negative pregnancy test and non-lactating).
             Males and females must use contraception for the duration of the study.

          3. Primary diagnosis must be histologically confirmed.

          4. Progression or Recurrence of solid tumors or lymphoma suitable for
             anti-PD-1/anti-PD-L1, and either receiving or having progressed on
             anti-PD-1/anti-PD-L1 therapy (see Table 3). Preferably, Ad-p53 and
             anti-PD-1/anti-PD-L1 treatment will be initiated at study entry. However, Ad-p53 may
             be added to ongoing anti-PD-1/anti-PD-L1 treatment provided that patients have stable
             or progressive disease or response status unknown on anti-PD-1/anti-PD-L1 therapy.
             Anti-PD-1/anti-PD-L1 treatment may be continued without any interruption while
             screening for Ad-p53 and study eligibility. If a patient with HNSCC is receiving
             combination pembrolizumab plus chemotherapy, the first Ad-p53 Study Treatment should
             be administered 2 weeks following the completion of final chemotherapy treatments, and
             5 days before their next anti-PD-1 scheduled dose. Ad-p53 intratumoral injections
             should not be given within 24 hours of immune checkpoint inhibitor infusions.

          5. As far as possible, all target lesions utilized for RECIST response determination
             should be suitable for ultra-sound, CT or endoscopic guided intra-tumoral injection
             and the total sum of Ad-p53 Injection Doses (mL) should be less than or equal to 25 mL
             (see Ad-p53 Injection Manual) as the Maximum Tolerated Dose of Ad-p53 is 2.5x1013
             virus particles/treatment day. If all target lesions cannot be treated with Ad-p53,
             but the patient is otherwise suitable for the study, this should be reviewed with the
             Sponsor.

          6. Patients entered on the study must have disease that that is evaluable for response
             using RECIST 1.1 criteria with a minimum measurable lesion size of the longest axis
             greater than or equal to 1.0 cm (CT/MRI) or greater than or equal to2.0 cm
             (non-helical CT), or nodal shortest diameter greater than or equal to 1.5 cm by
             CT/MRI.

          7. No brain metastases or treated and stable brain metastases

          8. ECOG Performance Status 0-1

          9. Life expectancy greater than or equal to 6 months.

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

               1. ANC greater than or equal to 1500 cells/mm3

               2. AST/SGOT and/or ALT/SGPT greater than or equal to 3.0 x ULN

               3. Alkaline phosphatase greater than or equal to 5 x ULN

               4. Platelet count greater than or equal to 100,000 cells/mm3

               5. Hemoglobin ≥9.0 g/dL

               6. Creatinine less than 2.0 mg/dL or creatinine clearance greater than or equal to
                  50 mL/min

               7. Total bilirubin less than 1.5 x ULN

               8. Serum albumin greater than or equal to 3.0 g/dL

         11. Favorable tumor p53 biomarker profile as defined by wild type p53 gene sequence, or
             less than 20 percent p53 positive tumor cells by immunohistochemistry (IHC), or p53
             gene mutations that will not inhibit normal p53 function such as gene deletions,
             truncations, or frame-shift mutations that result in non-functional p53
             tetramerization. Mutant p53 gene profiles should be reviewed with the Sponsor to
             confirm eligibility.

         12. Normal troponin blood levels.

         13. Echo with normal ejection fractions.

         14. QTcb less than or equal to 470 ms

         15. Normal lung oxygen saturation by pulse oximeter.

         16. Coagulation status should be suitable for intra-tumoral injections. Prothrombin Time
             (PT) less than or equal to 1.5 x ULN (or INR less than or equal to 1.3)*, Partial
             thromboplastin time (PTT) less than or equal to 1.5 x ULN* *Prolongation in INR, PT,
             and PTT when the result is from therapeutic anticoagulation treatment are permitted
             for patients whose injectable lesions are cutaneous and/or subcutaneous such that
             direct pressure could be applied in the event of excessive bleeding.

        Exclusion Criteria

          1. History of allergic reactions to any components of the treatments (Ad-p53 or
             checkpoint inhibitors).

          2. Active alcohol dependence

          3. Neuropathy of less than or equal to grade 2 CTCAE.

          4. Except for ongoing treatment with anti-PD-1 or anti-PD-L1 which is permitted (see
             Inclusion Criterion #4 above), there should be no other antibody-based therapy,
             targeted small-molecule therapy, hormonal therapy, chemotherapy, radiation, biological
             or investigational therapy within 14 days of first administration of Study Treatment
             (C1D1). Subjects with prior cytotoxic or investigational products less than 2 weeks
             prior to trial treatment might be eligible after discussion between investigator and
             Sponsor, if toxicities from the prior treatment have been resolved to Grade 1 (NCI
             CTCAE). If a patient with HNSCC is receiving combination pembrolizumab plus
             chemotherapy, the first Ad-p53 Study Treatment should be administered 2 weeks
             following the completion of final chemotherapy treatments and 5 days before their next
             anti-PD-1/anti-PD-L1 scheduled dose. Ad-p53 intratumoral injections should not be
             given within 24 hours of immune checkpoint inhibitor infusions.

          5. Prior additional malignancy within 2 years except for non-melanoma skin cancer,
             carcinoma in situ of the breast, oral cavity, cervix or other cancers, unless approved
             by the Sponsor.

          6. Prior autologous or allogenic organ or tissue transplantation.

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

               1. Active clinically serious infection (grade 2 or greater, CTCAE) or requiring
                  intravenous antibiotics at the time of study treatment.

               2. Thrombotic or embolic event within the last 6 months unless approved by the
                  Sponsor.

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

               4. Uncontrolled hypertension despite treatment with anti-hypertensive medication
                  (systolic blood pressure less than160 mmHg or diastolic blood pressure less than
                  100 mmHg)

               5. Must not have active, known or suspected autoimmune disease or be
                  immunosuppressed

               6. Known acute or chronic hepatitis B or hepatitis C infection with signs of
                  immunosuppression

               7. Known significant immunodeficiency due to underlying illness (e.g. HIV/AIDS)
                  and/or immunosuppressive medication including high-dose corticosteroids; HIV
                  patients may be approved by the Sponsor if on treatment with appropriate viral
                  titers.

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

               9. Active brain metastases or leptomeningeal metastases are not allowed

              10. Subjects must not have evidence of autoimmune pneumonitis or inflammatory lung
                  disease on CT scan and chest x-ray. Pneumonitis secondary to radiation scarring
                  is permitted in the absence of dyspnea.

          8. QTCb less than 470 ms

          9. Systemic corticosteroid treatment for more than 6 months at doses above 10 mg
             prednisolone or equivalent before study entry

         10. 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.

         11. Subjects may not have target tumors for Ad-p53 injection 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:Preliminary assessment of Duration of Response (DoR), progression free survival (PFS) by RECIST 1.1 in injected lesions only
Time Frame:Day 1 to progression through end of study, approximately 2 years
Safety Issue:
Description:Preliminary assessment of Duration of Response (DoR), progression free survival (PFS) by RECIST 1.1; ORR, DoR and PFS by RECIST 1.1 using the Ad-p53 injected lesions as the target lesions in those patients where all RECIST target lesions are not treated with Ad-p53; ORR, DoR and PFS by Immune Related Response Criteria (irRC) (Wolchok 2009); overall survival (OS). These efficacy parameters will be correlated with biomarkers (p53 gene sequence, p53 IHC, tumor mutational burden, PD-1/PD-L1 IHC expression and nanostring gene expression profiles.

Details

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

Trial Keywords

  • checkpoint inhibitor
  • anti-PD-1
  • anti-PD-L1
  • immune therapy
  • squamous cell cancer
  • solid tumor
  • lymphoma
  • carcinoma
  • breast cancer triple negative
  • cervical cancer
  • gastric cancer
  • gastroesophageal junction cancer
  • esophageal cancer
  • head and neck squamous cell cancer
  • hepatocellular cancer
  • Hodgkin's disease
  • non-small cell lung cancer
  • small cell lung cancer
  • melanoma
  • merkel cell cancer
  • MSI-H/dMMR
  • renal cell carcinoma
  • urothelial carcinoma

Last Updated

May 30, 2020