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Focused Ultrasound Ablation and PD-1 Antibody Blockade in Advanced Solid Tumors (AM-003)

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ClinicalTrials.gov Identifier: NCT04116320
Recruitment Status : Recruiting
First Posted : October 4, 2019
Last Update Posted : November 25, 2019
Sponsor:
Collaborator:
Theraclion
Information provided by (Responsible Party):
Craig L Slingluff, Jr, University of Virginia

Brief Summary:
This study evaluates whether it is safe to Focused Ultrasound Ablation (FUSA) treatments with and without PD-1 blockade and with and without imiquimod. A device called the Echopulse will be used for the FUSA therapy. Patients will be assigned to 1 of 2 cohorts depending on their disease and treatment status. In Cohort 1, patients will receive FUSA therapy while receiving PD-1 blockade therapy as part of standard clinical care treatment. In Cohort 2, patients who discontinue or are ineligible for PD-1 blockade therapy will undergo FUSA without concurrent systemic therapy, with the goal of utilizing the FUSA to boost the innate immune response. The optional secondary regimen will combine FUSA (+/- PD-1 blockade) with imiquimod, which is a topical TLR7 agonist.

Condition or disease Intervention/treatment Phase
Melanoma Breast Cancer Merkel Cell Carcinoma Squamous Cell Cancer Non Small Cell Lung Cancer Cervical Cancer Urothelial Carcinoma Ovarian Cancer Hepatocellular Carcinoma Small-cell Lung Cancer Microsatellite Instability High Gastric Cancer Esophageal Cancer Device: Echopulse Drug: Imiquimod Drug: Standard of Care PD-1 Therapy Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pilot Evaluation of Focused Ultrasound Ablation and Focused Ultrasound Ablation Plus PD-1 Antibody Blockade in Advanced Solid Tumors
Actual Study Start Date : November 21, 2019
Estimated Primary Completion Date : November 30, 2022
Estimated Study Completion Date : May 30, 2023


Arm Intervention/treatment
Experimental: Cohort 1, primary regimen (Regimen 1a)
FUSA therapy and standard of care PD-1 blockade. FUSA therapy will be administered on day 8.
Device: Echopulse
The Echopulse device delivers focused ultrasound ablation (FUSA) therapy. FUSA is a technology that delivers continuous high-intensity focused ultrasound to ablate tissue.
Other Names:
  • Focused Ultrasound Ablation
  • FUSA

Drug: Standard of Care PD-1 Therapy
PD-1 therapy FDA approved for use on a 3-week schedule will be used per standard of care.

Experimental: Cohort 1, secondary regimen (Regimen 2a)
FUSA therapy will be administered on day 8.
Device: Echopulse
The Echopulse device delivers focused ultrasound ablation (FUSA) therapy. FUSA is a technology that delivers continuous high-intensity focused ultrasound to ablate tissue.
Other Names:
  • Focused Ultrasound Ablation
  • FUSA

Experimental: Cohort 2, primary regimen (Regimen 1b)
FUSA therapy, standard of care PD-1 blockade, and imiquimod. FUSA therapy will be administered on day 1.
Device: Echopulse
The Echopulse device delivers focused ultrasound ablation (FUSA) therapy. FUSA is a technology that delivers continuous high-intensity focused ultrasound to ablate tissue.
Other Names:
  • Focused Ultrasound Ablation
  • FUSA

Drug: Imiquimod
Imiquimod is a TLR7 agonist therapy.
Other Name: Aldara

Drug: Standard of Care PD-1 Therapy
PD-1 therapy FDA approved for use on a 3-week schedule will be used per standard of care.

Experimental: Cohort 2, secondary regimen (Regimen 2b)
FUSA therapy and imiquimod. FUSA therapy will be administered on day 1.
Device: Echopulse
The Echopulse device delivers focused ultrasound ablation (FUSA) therapy. FUSA is a technology that delivers continuous high-intensity focused ultrasound to ablate tissue.
Other Names:
  • Focused Ultrasound Ablation
  • FUSA

Drug: Imiquimod
Imiquimod is a TLR7 agonist therapy.
Other Name: Aldara




Primary Outcome Measures :
  1. To assess the safety and toxicity of FUSA administered alone or in combination with PD-1 antibody blockade. [ Time Frame: 30 days after the last study intervention ]
    Incidence and severity of adverse events and incidence of dose-limiting toxicities (DLTs).

  2. To estimate the proportion of patients with increased CD8+ T cell infiltration of spot FUSA-treated metastasis. [ Time Frame: Day 43 (cohort 1) or Day 36 (cohort 2) ]
    Proportion of participants achieving at least a 2-fold increase in CD8+ T cell infiltration per mm2.


Secondary Outcome Measures :
  1. To estimate the proportion of patients with increased CD8+ T cell infiltration, after spot FUSA, in untreated metastasis, when available. [ Time Frame: Day 43 (cohort 1) or Day 36 (cohort 2) ]
    Proportion of participants achieving at least a 2-fold increase in CD8+ T cell infiltration per mm2



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥18 years.
  2. Advanced solid tumor with measurable disease in regional and/or distant metastases.
  3. Subject must have failed or have contraindication to standard therapies
  4. For Cohort 1, primary regimen (Regimen 1a): Patients with advanced solid malignancy for which PD1 or PDL1 antibody monotherapy administered on a 3-week schedule is FDA-approved for treatment, who have one or more tumor deposits that are accessible to focused ultrasound treatment, and who are eligible to receive (or to continue to receive) PD1 or PDL1 blockade therapy. Uveal melanoma patients are not eligible for Regimen 1a.

    Note: These patients may receive the primary protocol therapy (Regimen 1a) concurrent with PD1/PDL1 antibody therapy even if they may be eligible for other effective FDA-approved therapies in the following settings:

    Patients with stable disease after 12 weeks of PD1/PDL1 therapy per RECIST criteria may be eligible for Regimen 1a if their disease has remained stable on therapy and if their treating physician would normally continue PD1/PDL1 therapy even if they were not treated on this trial.

  5. For Cohort 1, secondary regimen (Regimen 2a): For those patients treated with primary regimen 1a, select participants may be enrolled in a secondary regimen. This would include participants in the following scenarios:

    • Stable disease.
    • Response in lesion treated in regimen 1, but persistent disease or progression in a separate lesion.
    • Initial partial response but still persistent disease at the treated lesion.
    • Initial response followed by progression at treated lesion or separate site, after discontinuation of PD-1/PD-L1 antibody. If there is a response and then progression at the site treated in Regimen 1 and the residual tumor meets inclusion criteria, this lesion may be re-treated on the secondary regimen. For participants who progress at a site unique from the treated lesion, they may enroll in Regimen 2 and have this new lesion treated, as long as they meet all inclusion criteria requirements.

    The patient must have a treatable tumor deposit in the dermis. The lesion to be FUSA treated in regimen 2 does not need to be the same lesion targeted in regimen 1. The patient must remain eligible for PD1/PDL1 Ab therapy. The length between the FUSA treatments in primary regimen and secondary regimen should be no less than 6 weeks. Patients who experienced an unanticipated device effect in the primary regimen are not eligible for the secondary regimen.

  6. For Cohort 2, primary regimen (Regimen 1b): The following patient subsets would be eligible for the Cohort 2 primary regimen, as long as they have failed (progressed or not tolerated) or are not eligible for all effective available approved therapies known to confer clinical benefit:

    • Patients with advanced solid malignancy for which PD1 or PDL1 blockade is not FDA-approved.
    • Patients with metastatic uveal melanoma
    • Patients with advanced solid malignancies for which PD1 or PDL1 blockade is FDA approved but who are not eligible to receive that therapy because of prior failure, toxicity, baseline autoimmune disease, or frailty.
    • Patients who previously responded to PD1/PDL1 therapy but then progressed, if there are no other systemic therapies available to them.

    Patients who were previously undergoing PD-1 blockade therapy must not have received a dose within 4 weeks prior to FUSA treatment.

  7. For Cohort 2, secondary regimen (Regimen 2b): For those patients treated with primary regimen 1a or 1b, select participants may be enrolled in a secondary regimen. This would include participants in the following scenarios:

    • Stable disease.
    • Response in lesion treated in regimen 1, but persistent disease or progression in a separate lesion.
    • Initial partial response but still persistent disease at the treated lesion.
    • Initial response followed by progression at the treated lesion or a separate site after discontinuation of PD-1/PD-L1 antibody. If there is a response and then progression at the site treated in Regimen 1 and the residual tumor meets inclusion criteria, this lesion may be re-treated on the secondary regimen. For participants who progress at a site unique from the treated lesion, they may enroll in Regimen 2 and have this new lesion treated, as long as they meet all inclusion criteria requirements.

    Patients enrolling to Regimen 2b must have a treatable tumor deposit in the dermis. The lesion to be FUSA treated in regimen 2 does not need to be the same lesion targeted in regimen 1. Crossover from primary regimen 1a is allowed if the patient is no longer eligible for continued PD1/PDL1 Ab therapy (e.g. due to autoimmune toxicity), and if there is no other effective systemic therapy option. The length between the FUSA treatments in regimen 1 and regimen 2 should be no less than 6 weeks. Patients who experienced an unanticipated device effect in the primary regimen are not eligible for the secondary regimen.

  8. One or more dermal, subcutaneous or nodal metastases from an advanced solid tumor. The metastases need to be accessible for FUSA and for biopsy.

    For FUSA:

    The targeted lesion(s) must be visible by ultrasound imaging and meet the following criteria. Brain lesions may not be targeted for treatment.

    • Approximately 1 cm (or more) diameter of treatable tumor volume for lesions to be treated with FUSA.
    • The target treatment area needs to be contained within a region at least 5 mm from the skin surface and less than or equal to 23 mm from the skin surface.
    • The target treatment area must be at a safe distance from all critical structures, including but not limited to ribs or other bony structures, vital organs, named blood vessels or nerves.
    • The critical structures, with the exception of the skin, will not be in the pre-focal ultrasound path.
    • The anterior-posterior dimension of the treatment area by US should be no less than 9mm.

    For Biopsies:

    Biopsies may be completed with or without image guidance.

  9. Lesions that have been selected for focused ultrasound or lesions that have been selected for biopsies as untreated controls may have been previously radiated provided:

    • The tumor site that was previously radiated has progressed.
    • A baseline biopsy of the tumor site is obtained following progression and prior to study entry.
  10. ECOG performance status 0-2.
  11. Subjects with brain metastases may participate if all of the following are true:

    • There has been no evident growth of any brain metastasis since the most recent treatment
    • No brain metastasis is > 2 cm in diameter at the time of registration.
    • Neurologic symptoms have returned to baseline,
    • There is no evidence of new or enlarging brain metastases,
    • Subjects are not using steroids for at least 7 days prior to registration. Regardless of dose, however, subjects who are on a steroid taper for management of brain metastases are not eligible until 7 days after completion of that steroid taper.
    • Brain metastases will not be targeted for FUSA treatment.
  12. Adequate organ function
  13. Ability and willingness to give informed consent.

Exclusion Criteria:

A subject will be excluded from participating in the trial if the subject:

  1. Has received the following medications or treatments at any time within 3 weeks of study day 1:

    1. Immune therapies including:

      • interferon (e.g. Intron-A®),
      • checkpoint blockade therapies other than anti-PD-1/PD-L1 antibodies,
      • antibodies to costimulatory molecules (e.g. CD27, CD137),
      • small molecule immune therapies (e.g. IDO1 inhibitor)
    2. Cytotoxic chemotherapy for cancer
  2. Has received the following medications or treatments at any time within 4 weeks of study day 1:

    1. Radiation therapy (Note: Stereotactic radiotherapy, such as gamma knife, can be used ≥ 1 week prior to registration)
    2. Allergy desensitization injections
    3. High doses of systemic corticosteroids, with the following qualifications and exceptions:

      • Daily doses of 10 mg or less prednisone (or equivalent) per day administered parenterally or orally are allowed in patients with normal adrenal and pituitary function.
      • In patients with adrenal or pituitary insufficiency replacement steroid doses are allowed.
      • Inhaled steroids (e.g.: Advair®, Flovent®, Azmacort®) are permitted at low doses (less than 500 mcg fluticasone per day, or equivalent)
      • Topical and nasal corticosteroids are acceptable.
    4. Growth factors (e.g. Procrit®, Aranesp®, Neulasta®)
    5. Interleukins (e.g. Proleukin®)
    6. Any investigational medication
    7. Targeted therapies specific for mutated BRAF or for MEK
    8. Live vaccine
  3. Has a known addiction to alcohol or drugs and is actively taking those agents, or has recently (within 1 year) taken these agents or has ongoing illicit IV drug use.
  4. Is HIV positive or has evidence of active Hepatitis B or C virus (testing to be done within 6 months of study entry).
  5. Is currently receiving nitrosoureas or has received this therapy within the preceding 6 weeks
  6. Is pregnant or breastfeeding. Female participants of childbearing potential must have a negative pregnancy test obtained within 2 weeks prior to registration. Males and females must agree, in the consent form, to use effective birth control methods during the course of treatment and following treatment in accordance with the labeling guidelines for each approved therapy.
  7. Has a medical contraindication or potential problem in complying with the requirements of the protocol in the opinion of the investigator.
  8. Has an active infection requiring systemic therapy.
  9. Has Class III or IV heart disease as classified according to the New York Heart Association.
  10. Has had prior autoimmune disorders requiring cytotoxic or immunosuppressive therapy,or autoimmune disorders with visceral involvement. Participants with an active autoimmune disorder requiring these therapies are also excluded.

    Note: The following are not exclusionary:

    • The presence of laboratory evidence of autoimmune disease (e.g. positive ANA titer) without symptoms
    • Clinical evidence of vitiligo
    • Other forms of depigmenting illness
    • Mild arthritis requiring NSAID medications
    • A history of immune-related adverse events with immune therapy, if the immune-related adverse events have resolved completely.
  11. History of another cancer

    Note: the following diagnoses are exceptions and are permitted as long as they have been treated successfully and without clinical evidence of disease:

    • Any cancer that has been treated successfully, without evidence of subsequent recurrence or metastasis for over 5 years
    • Any cancer without distant metastasis that has been treated successfully, without evidence of recurrence or metastasis for over 2 years
    • Squamous cell cancer of the skin without known metastasis
    • Basal cell cancer of the skin without known metastasis
    • Carcinoma in situ of the breast (DCIS or LCIS)
    • Carcinoma in situ of the cervix
  12. Has a history of (non-infectious) pneumonitis that required steroids or current evidence of interstitial lung disease or pneumonitis.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04116320


Contacts
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Contact: Rachael Reed, BS 434-982-6584 rmr3bx@virginia.edu
Contact: Rupert Egan, MS 434-982-1901 rje5k@virginia.edu

Locations
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United States, Virginia
University of Virginia Recruiting
Charlottesville, Virginia, United States, 22908
Contact: Craig L. Slingluff, MD    434-924-1730    cls8h@virginia.edu   
Contact: Rachael Reed    434-982-6584    rmr3bx@virginia.edu   
Principal Investigator: Lynn Dengel, MD         
Sponsors and Collaborators
Craig L Slingluff, Jr
Theraclion
Investigators
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Principal Investigator: Lynn Dengel, MD, MSc University of Virginia
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Craig L Slingluff, Jr, Professor of Surgery; Director, Human Immune Therapy Center, University of Virginia
ClinicalTrials.gov Identifier: NCT04116320    
Other Study ID Numbers: 21850
First Posted: October 4, 2019    Key Record Dates
Last Update Posted: November 25, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: De-identified individual participant data that underlie the results of this study may be shared.
Supporting Materials: Study Protocol
Time Frame: Data may be available after the main findings from the final research data set have been accepted for publication.
Access Criteria: Requests for data access will be accepted only with an accompanying signed Data Access Agreement.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: Yes
Keywords provided by Craig L Slingluff, Jr, University of Virginia:
Echopulse
Focused Ultrasound Ablation
FUSA
imiquimod
Aldara
Pembrolizumab
Keytruda
Atezolizumab
Tecentriq
Additional relevant MeSH terms:
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Carcinoma, Merkel Cell
Carcinoma
Lung Neoplasms
Small Cell Lung Carcinoma
Neoplasms, Squamous Cell
Carcinoma, Squamous Cell
Microsatellite Instability
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Adenocarcinoma
Polyomavirus Infections
DNA Virus Infections
Virus Diseases
Tumor Virus Infections
Carcinoma, Neuroendocrine
Genomic Instability
Pathologic Processes
Imiquimod