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Metastatic Solid Tumor CancerPhase 1/2NCT02842125

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

A Phase 1/2 study testing Ad-P53, Xeloda and Keytruda in people with Metastatic Solid Tumor Cancer and Recurrent Head and Neck Cancer, run by MultiVir, Inc. at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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). Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Ad-P53, Xeloda and Keytruda
Could I receive a placebo?
No, everyone receives an active treatment
How many people
4 participants
Where
1 siteUnited States
Study dates
20 Nov 2018to 8 May 2020
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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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.
  • 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:
  • 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.

Who cannot join

  • 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
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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.
  • 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
  • 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
  • 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.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • MD Anderson Cancer Center

    Houston, Texas, 77030

Other trials in United States

About this study

Official title: Phase 1/2 Evaluation of Adenoviral p53 (Ad-p53) in Combination With Capecitabine (Xeloda) or Anti-PD-1 in Patients With Unresectable Liver Metastases of Colorectal Carcinoma(CRC) and Other Solid Tumors, Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC) and Primary Hepatic Cancers With Known Disease Progression on Standard Therapy

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.

Read the 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.

Being tested
Ad-P53, Xeloda, Keytruda, Opdivo
Keywords
Head and Neck Squamous Cell Cancer, solid tumors, nivolumab, Ad-P53, metastatic, capecitabine, pembrolizumab
Medical subject headings
Head and Neck Neoplasms, Neoplasm Metastasis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Ad-P53Drug

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

  • XelodaDrug

    Also called capecitabine

    Oral metronomic chemotherapeutic agent

  • KeytrudaDrug

    Also called Pembrolizumab

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

  • OpdivoDrug

    Also called Nivolumab

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

Study groups in NCT02842125
Study groupRoleWhat they receive
Ad-p53 with Xeloda 33.3% of patientsExperimentalUp 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.
Receives: Drug: Ad-P53; Drug: Xeloda
Ad-p53 with Keytruda 33.3% of patientsExperimentalUp 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.
Receives: Drug: Ad-P53; Drug: Keytruda
Ad-p53 with Opdivo 33.3% of patientsExperimentalUp 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.
Receives: Drug: Ad-P53; Drug: Opdivo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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

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

  2. 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

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

  3. 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

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

  4. 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].

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

Secondary outcomes (3)

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

    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.

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

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

    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.

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

  3. Efficacy as determined by biomarker testing and immunohistochemistry testing

    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.

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted22 Jul 2016 (estimated)
  2. Study start20 Nov 2018
  3. Primary completion8 May 2020
  4. Study completion8 May 2020

Why it stopped: Arm C rolled into parallel study; Arms A and B halted for greater efficacy in Arm C

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Model description
3 Arms, no cross-over
Masking
None (open label)
Enrolment
4 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02842125
Sponsor's protocol ID
MultiVir Ad-p53-001
Status last verified
May 2020
First submitted
1 Jul 2016
Last updated
2 Jun 2020
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Ad-P53, Xeloda and Keytruda in people with Metastatic Solid Tumor Cancer and Recurrent Head and Neck Cancer, run by MultiVir, Inc. at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 32 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 2 Jun 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Arm C rolled into parallel study; Arms A and B halted for greater efficacy in Arm C). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Safety assessed by CTCAE (time frame: Screening to 30-days following Final Treatment (approximately 22 weeks)). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02842125.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jun 2020.

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