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

NCT02842125 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: MultiVir Ad-p53-001
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 1

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.

Conditions

Metastatic Solid Tumor Cancer; Recurrent Head and Neck Cancer

Keywords

Head and Neck Squamous Cell Cancer; solid tumors; nivolumab; Ad-P53; metastatic; capecitabine; pembrolizumab

Outcome Measures

Primary Outcomes (4)

• Safety assessed by CTCAE

  Incidence of treatment-emergent and treatment-related adverse events (all AEs, laboratory AEs, SAEs and Fatal AEs, in accordance with the CTCAE

  Screening to 30-days following Final Treatment (approximately 22 weeks)

• Incidence of dose-limiting toxicities (DLTs)

  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

  Day 1 to 30-days Following Last Treatment (approximately 21 weeks)

• Determination of maximum-tolerated dose (MTD)

  Determination of maximum tolerated dose (MTD) by review of DLTs, of the combination of Ad-p53 and Xeloda or Ad-p53 and Ketruda

  Day 1 to 30 days following Final Treatment (Approximately 21 Weeks)

• Progression-Free Survival (PFS) of patients using RECIST 1.1

  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) \[Wolchok 2009\].

  Time Frame: Day 1 to progression through end of study, approximately 18 months

Secondary Outcomes (3)

• Progression-Free Survival (PFS) of patients using RECIST 1.1

  Day 1 to progression through end of study, approximately 2 years

• Efficacy determined by Immune Related Response Criteria (irRC) [Wolchok 2009]

  Day 1 of Treatment through 30-days following last treatment (20 weeks)

• Efficacy as determined by biomarker testing and immunohistochemistry testing

  Day 1 of Treatment to End of Study (approximately 18 months)

Study Arms (3)

Ad-p53 with Xeloda 33.3% of patients

EXPERIMENTAL

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.

Drug: Ad-P53; Drug: Xeloda

Ad-p53 with Keytruda 33.3% of patients

EXPERIMENTAL

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.

Drug: Ad-P53; Drug: Keytruda

Ad-p53 with Opdivo 33.3% of patients

EXPERIMENTAL

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.

Drug: Ad-P53; Drug: Opdivo

Interventions

Ad-P53 DRUG

Adenoviral Investigational Product Ad-P53 to treat metastases using an intra-arterial catheter, with oral metronomic capecitabine

Ad-p53 with Keytruda 33.3% of patients; Ad-p53 with Opdivo 33.3% of patients; Ad-p53 with Xeloda 33.3% of patients

Xeloda DRUG

Oral metronomic chemotherapeutic agent

Also known as: capecitabine

Ad-p53 with Xeloda 33.3% of patients

Keytruda DRUG

Antineoplastic, Monoclonal Antibody; PD-1/PD-L1 Inhibitors

Also known as: Pembrolizumab

Ad-p53 with Keytruda 33.3% of patients

Opdivo DRUG

Antineoplastic, Monoclonal Antibody; PD-1/PD-L1 Inhibitors

Also known as: Nivolumab

Ad-p53 with Opdivo 33.3% of patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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:
• 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

Sponsors & Collaborators

• MultiVir, Inc.: lead

Study Sites (1)

MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Head and Neck Neoplasms; Neoplasm Metastasis

Interventions

advexin; Capecitabine; pembrolizumab; Nivolumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Vivek Subbiah, MD

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 3 Arms, no cross-over

Study Record Dates

• First Submitted: July 1, 2016
• First Posted: July 22, 2016
• Study Start: November 20, 2018
• Primary Completion: May 8, 2020
• Study Completion: May 8, 2020
• Last Updated: June 2, 2020

Record last verified: 2020-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)