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
- Conditions
- Recurrent Head and Neck CancerMetastatic Solid Tumor Cancer
- Interventions
- Registration Number
- NCT02842125
- Lead Sponsor
- MultiVir, Inc.
- Brief Summary
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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 4
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Signed informed consent
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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.
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Histologically or cytologically confirmed solid tumors or hepatocellular carcinoma with known disease progression.
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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
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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.
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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.
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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.
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ECOG Performance Status 0 - 1
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Either no brain metastases or irradiated stable brain metastases
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Life expectancy at least 3 months
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No prior autologous or allogeneic organ or tissue transplantation
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PT/international normalized ratio (INR) ≤ULN; aPTT ≤ULN.
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ANC ≥1500 cells/mm3
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Platelet count ≥100,000 cells/mm3
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Hemoglobin ≥9.0 g/dL
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Creatinine <2.0 mg/dL or creatinine clearance ≥50 mL/min
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Total bilirubin <1.5 x ULN
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AST and ALT <3.0 x ULN
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Alkaline phosphatase ≤5 x ULN
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Negative pregnancy test in women of childbearing potential
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Fertile patients must use effective contraception
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No non-approved investigational agents or procedures ≤4 weeks of study entry
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Patients with PRIMARY HEPATIC CANCER must have an undetectable viral load for Hepatitis B and C.
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Patients with Primary Hepatic Cancer have not recently been treated with antivirals.
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Troponin blood level within normal limits.
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Favorable biomarker profile defined by either wild type p53 gene sequence or less than 20% p53 positive tumor cells by immunohistochemistry
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Echocardiogram with normal ejection fractions
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Normal lung oxygen saturation by pulse oximeter, as determined by the Principal Investigator based on patient history and status.
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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
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Subjects must not be candidates for hepatic surgery or locoregional therapy of liver tumors with curative intent.
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Liver tumors must not be estimated to invade approximately more than one-third of the liver.
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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.
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No macroscopic intra-vascular invasion by tumors of the main portal vein, hepatic vein or vena cava.
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Chronic liver dysfunction prior to development of liver metastases (Child-Pugh C or greater).
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Active alcohol dependence
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Prior radiation performed to areas of measurable disease ≤ four weeks of study entry unless there is documented evidence of disease progression.
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Use of systemic anti-cancer therapy ≤ 4 weeks, or six weeks if the systemic therapy contains a nitrosourea or mitomycin C.
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Neuropathy (≥grade 2 CTCAE)
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History of allergic reactions to any components of the treatments
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Prior additional malignancy within 2 years except for non-melanoma skin cancer, carcinoma in situ of the breast, oral cavity or cervix.
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Severe, active comorbidity, including any of the following:
- Active clinically serious infection requiring intravenous antibiotics at the time of study entry (CTCAE Grade 2)
- Hepatic insufficiency not due to tumor resulting in clinical jaundice or bilirubin >1.5 x ULN and/or coagulation defects
- Thrombotic or embolic event within the last 6 months including portal vein thrombosis
- Must not require concomitant treatment with anticoagulants
- QTcb >470 ms
- Bleeding or evidence or history of clinically significant bleeding diathesis or coagulopathy within the last 3 months
- Uncontrolled hypertension on anti-hypertensive medication (systolic blood pressure >150 mmHg or diastolic blood pressure >95 mmHg)
- Must not have been diagnosed with autoimmune disease or be immunosuppressed
- Patients with non-hepatocellular carcinoma must not have acute or chronic hepatitis B or hepatitis C infection
- Known significant immunodeficiency due to underlying illness (e.g. HIV/AIDS) and/or immunosuppressive medication including high-dose corticosteroids.
- Severe bleeding, hemoptysis, gastrointestinal hemorrhage, CNS bleeding, clinically significant hemorrhage or vaginal bleeding during the last 6 months
- Subjects must not have evidence of pneumonitis or inflammatory lung disease on CT scan and x-ray
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Chronic treatment for more than 6 months with systemic corticosteroids at doses above 10 mg prednisolone or equivalent before study entry
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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.
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Subjects must not have tumors adjacent to vital structures such as carotid arteries.
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Ad-p53 with Xeloda 33.3% of patients Ad-P53 Up 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 with Xeloda 33.3% of patients Xeloda Up 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 with Keytruda 33.3% of patients Keytruda Up 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 with Opdivo 33.3% of patients Ad-P53 Up 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 with Opdivo 33.3% of patients Opdivo Up 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 with Keytruda 33.3% of patients Ad-P53 Up 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.
- Primary Outcome Measures
Name Time Method Safety assessed by CTCAE Screening to 30-days following Final Treatment (approximately 22 weeks) Incidence of treatment-emergent and treatment-related adverse events (all AEs, laboratory AEs, SAEs and Fatal AEs, in accordance with the CTCAE
Incidence of dose-limiting toxicities (DLTs) Day 1 to 30-days Following Last Treatment (approximately 21 weeks) To evaluate the safety, as assessed by the incidence of dose limiting toxicities, of the combination of Ad-P53 and Xeloda or Ad-p53 and Keytruda
Determination of maximum-tolerated dose (MTD) Day 1 to 30 days following Final Treatment (Approximately 21 Weeks) Determination of maximum tolerated dose (MTD) by review of DLTs, of the combination of Ad-p53 and Xeloda or Ad-p53 and Ketruda
Progression-Free Survival (PFS) of patients using RECIST 1.1 Time Frame: Day 1 to progression through end of study, approximately 18 months PFS in patients treated with Ad-p53 and nivolumab 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
Name Time Method Progression-Free Survival (PFS) of patients using RECIST 1.1 Day 1 to progression through end of study, approximately 2 years 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.
Efficacy determined by Immune Related Response Criteria (irRC) [Wolchok 2009] Day 1 of Treatment through 30-days following last treatment (20 weeks) 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.
Efficacy as determined by biomarker testing and immunohistochemistry testing Day 1 of Treatment to End of Study (approximately 18 months) 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.
Trial Locations
- Locations (1)
MD Anderson Cancer Center
🇺🇸Houston, Texas, United States