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Focused Ultrasound Ablation and PD-1 Antibody Blockade for the Treatment of Advanced Solid Tumors

Trial Status: Active

This phase I trial studies the side effects of focused ultrasound ablation and how well it works with or without PD-1 antibody blockade (a type of immune infused therapy drug) in treating patients with solid tumors that has spread to other places in the body (advanced). PD-1 antibody blockade is a type of treatment that uses an antibody that has been created to bind to immune cells to enable them to fight off cancer more effectively. The Echopulse device is a computer driven system which guides a high intensity focused ultrasound beam (focused sound waves) to a targeted area of a tumor. Focused ultrasound ablation (FUSA) heats the targeted site which causes the cells to die. In addition to the focused ultrasound beam that can kill cells at its target, the Echopulse device also uses low energy ultrasound for imaging the tumor tissue and the tissue around the tumor to make sure that the focused ultrasound beam hit its target. Imiquimod is an immunomodulator, a drug that interacts with the immune system. Through boosting the immune system, imiquimod may help the body fight off cancer cells. The purpose of this trial is to figure out the safety and effectiveness of FUSA administration alone or with a PD-1 antibody and / or imiquimod.

Inclusion Criteria

  • Advanced solid tumor with measurable disease in regional and/or distant metastases
  • Subject must have failed or have contraindication to standard therapies as detailed below: * Melanoma ** Standard therapies, Participants must have not responded to or have contraindication to these treatments *** Checkpoint blockade including PD1/PDL1 and CTLA4 blockade, either as monotherapy or as combination *** Combination BRAF/MEK inhibition (if BRAF V600E/K+) ** Non-standard therapies, Exceptions, not required to have been given or have contraindication *** Cytotoxic chemotherapy *** High-dose Interleukin -2 *** Talimogene laherparepvec * Uveal melanoma ** Standard therapies, Participants must have not responded to or have contraindication to these treatments *** None * Breast ** Standard therapies, Participants must have not responded to or have contraindication to these treatments *** Endocrine therapy (if hormone receptor positive) *** Cytotoxic chemotherapy *** Targeted therapy (if Her2+) *** PD1/PDL1 blockade (if triple negative) * Merkel cell carcinoma ** Standard therapies, Participants must have not responded to or have contraindication to these treatments *** PD1/PDL1 blockade ** Non-standard therapies, Exceptions, not required to have been given or have contraindication *** Cytotoxic Chemotherapy * Squamous cell cancer of the head and neck ** Standard therapies, Participants must have not responded to or have contraindication to these treatments *** Cytotoxic chemotherapy *** PD1/PDL1 blockade ** Non-standard therapies, Exceptions, not required to have been given or have contraindication *** Cetuximab *** Afatinib * Squamous cell cancer of the skin ** Standard therapies, Participants must have not responded to or have contraindication to these treatments *** Cytotoxic chemotherapy *** PD1/PDL1 blockade * Other metastatic solid tumors ** Standard therapies, Participants must have not responded to or have contraindication to these treatments *** All effective, available and approved therapies
  • 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 Food and Drug Administration (FDA)-approved for treatment (e.g.: melanoma, Merkel cell carcinoma, non-small cell carcinoma of the lung, squamous cell cancer of the head and neck squamous cell cancer of the skin, cervical cancer), 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 because of their inherently low expected rate of response to PD1 therapy alone. * 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: ** Since clinical responses to PD1/PDL1 blockade usually occur within 12 weeks but may occur much later, routine clinical practice commonly includes continuation of PD1 antibody therapy for 1-2 years for patients who experience stable disease on that therapy. Thus, patients with stable disease (SD) after 12 weeks of PD1/PDL1 therapy per Response Evaluation Criteria in Solid Tumors (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.
  • 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.
  • For Cohort 1, secondary regimen (Regimen 2a): 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 antibody (Ab) therapy.
  • For Cohort 1, secondary regimen (Regimen 2a): 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.
  • 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 (examples: metastatic soft tissue sarcomas, breast cancer other than triple negative breast cancer (TNBC), ovarian cancer, cervical cancer, squamous cell cancer of the anus). * Patients with metastatic uveal melanoma, which has been demonstrated to be very poorly responsive to PD1/PDL1 blockade. * 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.
  • For Cohort 2, primary regimen (Regimen 1b): Patients who were previously undergoing PD-1 blockade therapy must not have received a dose within 4 weeks prior to FUSA treatment.
  • For Cohort 2, secondary regimen (Regimen 2b): 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.
  • For Cohort 2, secondary regimen (Regimen 2b): 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.
  • 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.
  • One or more dermal, subcutaneous or nodal metastases from an advanced solid tumor. The metastases need to be accessible for FUSA and for biopsy, and will most likely be in nodes, skin, or soft tissue. * FUSA The targeted lesion(s) must be visible by ultrasound imaging and meet the following criteria. The expectation is that the lesion will be assessed by ultrasound imaging but this may be waived by the radiologist. 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. Note: imaging studies may overestimate these differences compared to what may be achieved when there is compression from the FUSA transducer. Clinical judgement may be used in that assessment, or measurement under compression (e.g. with ultrasound) may be used to assess eligibility. However, FUSA treatment will not be done if at the time of planned treatment the tumor is beyond the maximal distance for the FUSA focal point. ** 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. A safety margin of 15 mm beyond the focus (post-focally) and laterally should be observed when high intensity focused ultrasound (HIFU) treatments with the Echopulse are delivered close to sensitive structures not specified in the table below. Air-filled structures and bones should not be located between the transducer and the ultrasound focus. ** The critical structures, with the exception of the skin, will not be in the pre-focal ultrasound path. This will be considered at enrollment and confirmed immediately prior to treatment. ** The anterior-posterior dimension of the treatment area by US should be no less than 9 mm. * Biopsies ** Biopsies may be completed with or without image guidance.
  • 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.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
  • Subjects with known 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, except as allowed. 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.
  • Absolute neutrophil count (ANC) >= 1000/mm^3
  • Platelets >= 100,000/mm^3
  • Hemoglobin >= 9 g/dL
  • Serum creatinine =< 1.5 x upper limit of normal (ULN)
  • Bilirubin =< 1.5 x ULN (except in patients with Gilbert’s disease, where bilirubin to 4 x ULN is allowed)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN
  • Alkaline phosphatase =< 2.5 x ULN
  • Glycosylated hemoglobin (HGB-A1C) < 7.5%
  • Ability and willingness to give informed consent

Exclusion Criteria

  • Has received the following medications or treatments at any time within 3 weeks of study day 1: * Immune therapies including: ** Interferon (e.g. Intron-A), ** Checkpoint blockade therapies other than anti-PD-1/PD-L1 antibodies (examples include antibodies to CTLA-4, or antibodies to other checkpoint molecules), ** Antibodies to costimulatory molecules (e.g. CD27, CD137), ** Small molecule immune therapies (e.g. IDO1 inhibitor) * Cytotoxic chemotherapy for cancer
  • Has received the following medications or treatments at any time within 4 weeks of study day 1: * Radiation therapy (Note: Stereotactic radiotherapy, such as gamma knife, can be used >= 1 week prior to registration) * Allergy desensitization injections * 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. * Growth factors (e.g. Procrit, Aranesp, Neulasta) * Interleukins (e.g. Proleukin) * Any investigational medication * Targeted therapies specific for mutated BRAF or for MEK * Live vaccine
  • 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 intravenous (IV) drug use
  • Is human immunodeficiency virus (HIV) positive or has evidence of active hepatitis B or C virus (testing to be done within 6 months of study entry)
  • Is currently receiving nitrosoureas or has received this therapy within the preceding 6 weeks
  • Is pregnant or breastfeeding. Female participants of childbearing potential must have a negative pregnancy test (urinary or serum beta-human chorionic gonadotropin [HCG]) 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
  • Has a medical contraindication or potential problem in complying with the requirements of the protocol in the opinion of the investigator
  • Has an active infection requiring systemic therapy
  • Has class III or IV heart disease as classified according to the New York Heart Association
  • 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 antinuclear antibody [ANA] titer) without symptoms ** Clinical evidence of vitiligo ** Other forms of depigmenting illness ** Mild arthritis requiring non-steroidal anti-inflammatory drugs (NSAID) medications ** A history of immune-related adverse events with immune therapy, if the immune-related adverse events have resolved completely.
  • 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 (ductal breast carcinoma in situ [DCIS] or lobular breast carcinoma in situ [LCIS]) ** Carcinoma in situ of the cervix
  • Has a history of (non-infectious) pneumonitis that required steroids or current evidence of interstitial lung disease or pneumonitis, unless the pneumonitis was grade 1 and is completely resolved

Virginia

Charlottesville
University of Virginia Cancer Center
Status: ACTIVE
Contact: Lynn Thacher Dengel
Phone: 434-924-9311

PRIMARY OBJECTIVES:

I. To assess the safety and toxicity of focused ultrasound ablation (FUSA) administered alone or in combination with PD-1 antibody blockade. (Safety)

II. To estimate the proportion of patients with increased CD8+ T cell infiltration of spot FUSA-treated metastasis. (Immunologic effect)

SECONDARY OBJECTIVE:

I. To estimate the proportion of patients with increased CD8+ T cell infiltration, after spot FUSA, in untreated metastasis, when available. (Immunologic effect)

EXPLORATORY OBJECTIVES:

I. To assess the safety and toxicity of FUSA administered with topical imiquimod, with or without PD1 blockade. (Safety)

II. To obtain preliminary data on whether FUSA plus PD-1 antibody therapy induces clinical responses in patients for whom the likelihood of such response is low with PD-1 blockade alone (patients already on PD-1 blockade without clinical response). Response will be evaluated in treated and untreated lesions. (Clinical response, cohort 1, primary regimen [with (w)/ PD-1)

III. To obtain preliminary data on patients treated with FUSA in the absence of systemic therapy. Response will be evaluated in treated and untreated lesions. (Clinical response, cohort 2, primary regimen [without (w/o) PD-1])

IV. Describe cellular and structural changes in the tumor microenvironment. (Immunologic response)

V. Describe changes in the induction of circulating T cell responses to shared and mutated tumor antigens. (Immunologic response)

VI. To obtain preliminary data on the clinical activity of combining imiquimod with FUSA for the treatment of dermal tumors. (Clinical response, secondary regimen)

VII. To obtain preliminary data on pain at tumor site at presentation and post-treatment at lesion treated with FUSA. (Impact of FUSA on local symptoms for participants presenting with painful lesions)

OUTLINE: Patients are assigned to 1 of 2 cohorts.

COHORT I:

REGIMEN I: Beginning day 1, patients receive PD-1 blockade therapy intravenously (IV) every 3 weeks for up to 85 days in the absence of disease progression or unacceptable toxicity. Patients undergo FUSA on day 8. Patients with dermal metastases who did not experience regression of treated tumor and/or untreated tumors by 12 weeks following FUSA treatment may proceed to Regimen II of either Cohort I or II.

REGIMEN II: Beginning day 1, patients receive PD-1 blockade therapy IV every 3 weeks for up to 85 days in the absence of disease progression or unacceptable toxicity. Patients undergo FUSA on day 8. Patients apply imiquimod topically to the skin metastases targeted by FUSA once daily for at least 12 weeks.

COHORT II:

REGIMEN I: Patients who discontinue or are ineligible for PD-1 blockade therapy undergo FUSA on day 1. Patients with dermal metastases who did not experience regression of treated tumor and/or untreated tumors by 12 weeks following FUSA treatment may proceed to Regimen II of Cohort II.

REGIMEN II: Patient undergo FUSA on day 1. Patients apply imiquimod topically to the skin metastases targeted by FUSA once daily for at least 12 weeks.

After completion of study treatment, patients are followed up at 30 days, and then annually thereafter.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
University of Virginia Cancer Center

Principal Investigator
Lynn Thacher Dengel

  • Primary ID 21850
  • Secondary IDs NCI-2020-04001, AM-003
  • Clinicaltrials.gov ID NCT04116320