This is a Phase 2 study of the combination of Ad-p53 administered intra-tumorally in
combination with physician's choice of FDA approved immune checkpoint inhibitor therapy in
patients with recurrent or metastatic cancers. This is a safety and efficacy study with a
single cohort, consisting of the combination of Ad-p53 and infusions of immune checkpoint
inhibitors. Immune checkpoint inhibitor treatments will be administered in accordance with
FDA package inserts. Comparison will be made to historical data. General safety and
preliminary efficacy will be determined using RECIST 1.1, ECOG status and Immune-Related
Response Criteria. Biomarker testing of archival or fresh tissue is performed during the
study. Enrollment will be up to 40 patients.
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 therapy.
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.
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 to 2.0 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 less than or equal to 3.0 x ULN
3. Alkaline phosphatase less 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 anti-coagulation 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 immune
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.
