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About
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.
Full 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.
Enrollment
Sex
Ages
Volunteers
Inclusion and exclusion criteria
Inclusion Criteria:
Signed informed consent
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.
Histologically or cytologically confirmed solid tumors or hepatocellular carcinoma with known disease progression.
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
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.
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.
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.
ECOG Performance Status 0 - 1
Either no brain metastases or irradiated stable brain metastases
Life expectancy at least 3 months
No prior autologous or allogeneic organ or tissue transplantation
PT/international normalized ratio (INR) ≤ULN; aPTT ≤ULN.
ANC ≥1500 cells/mm3
Platelet count ≥100,000 cells/mm3
Hemoglobin ≥9.0 g/dL
Creatinine <2.0 mg/dL or creatinine clearance ≥50 mL/min
Total bilirubin <1.5 x ULN
AST and ALT <3.0 x ULN
Alkaline phosphatase ≤5 x ULN
Negative pregnancy test in women of childbearing potential
Fertile patients must use effective contraception
No non-approved investigational agents or procedures ≤4 weeks of study entry
Patients with PRIMARY HEPATIC CANCER must have an undetectable viral load for Hepatitis B and C.
Patients with Primary Hepatic Cancer have not recently been treated with antivirals.
Troponin blood level within normal limits.
Favorable biomarker profile defined by either wild type p53 gene sequence or less than 20% p53 positive tumor cells by immunohistochemistry
Echocardiogram with normal ejection fractions
Normal lung oxygen saturation by pulse oximeter, as determined by the Principal Investigator based on patient history and status.
Arm C patients must have loco-regional recurrent head and neck squamous cell carcinoma (HNSCC), excluding endolaryngeal recurrence, meeting the following criteria:
Exclusion Criteria
Subjects must not be candidates for hepatic surgery or locoregional therapy of liver tumors with curative intent.
Liver tumors must not be estimated to invade approximately more than one-third of the liver.
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.
No macroscopic intra-vascular invasion by tumors of the main portal vein, hepatic vein or vena cava.
Chronic liver dysfunction prior to development of liver metastases (Child-Pugh C or greater).
Active alcohol dependence
Prior radiation performed to areas of measurable disease ≤ four weeks of study entry unless there is documented evidence of disease progression.
Use of systemic anti-cancer therapy ≤ 4 weeks, or six weeks if the systemic therapy contains a nitrosourea or mitomycin C.
Neuropathy (≥grade 2 CTCAE)
History of allergic reactions to any components of the treatments
Prior additional malignancy within 2 years except for non-melanoma skin cancer, carcinoma in situ of the breast, oral cavity or cervix.
Severe, active comorbidity, including any of the following:
Chronic treatment for more than 6 months with systemic corticosteroids at doses above 10 mg prednisolone or equivalent before study entry
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.
Subjects must not have tumors adjacent to vital structures such as carotid arteries.
Primary purpose
Allocation
Interventional model
Masking
4 participants in 3 patient groups
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Data sourced from clinicaltrials.gov
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