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

Inclusion Criteria

• Age >= 18 years
• 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) *** Prior treatment with CDK4/6 inhibitors is required for subjects with hormone receptor (HR)+ metastatic breast cancer *** For subjects with metastatic triple negative breast cancer who have BRCA mutations, those subjects must have undergone standard therapies with poly (ADP-ribose) polymerase (PARP) inhibitor therapy prior to enrollment * 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. * Participants eligible for this regimen may receive the primary protocol therapy (Regimen 1a) concurrent with PD1/PDL1 antibody therapy if: ** Progressive disease: subjects with progressive disease following PD1/PDL1 antibody therapy are eligible for this cohort if it is clinically appropriate for them to continue on systemic PD1/PDL1 antibody per the treating clinician even if they did not begin treatment on this trial. Examples may include a patient with a small new lesion but stable disease in other sites, or very slight tumor growth in multiple sites, in a patient without other approved therapy options. Participants who progress following PD1/PDL1 antibody therapy may undergo interval resection of enlarging lesions and still be included in this cohort as long as they have persistent unresectable disease that is accessible to FUSA treatment. ** Response with persistent disease: subjects who have a clinical response (stable disease [SD] or partial response [PR]) and have residual lesion(s) accessible to FUSA treatment. Participants with PR are only eligible if it is clinically appropriate for them to continue on PD1/PDL1 therapy per the judgement of the treating clinician ** Stable disease: The majority of clinical responses to PD1/PDL1 blockade 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 with stable disease on that therapy. Thus, patients with 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 provider recommends continuation of 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. ** Participants with lesions unique from the lesion treated in regimen 1 may enroll in regimen 2 and have additional lesion(s) treated, as long as they meet all inclusion criteria requirements. Up to three lesions may be treated in the second regimen. * Patients enrolling to Regimen 2a must have a target lesion amenable to intratumoral injection with polyICLC per the treating clinician’s discretion. The lesion(s) to be FUSA treated in regimen 2 does not need to include the 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 adverse device effect in the primary regimen are not eligible for the secondary regimen
• 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): 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. * Participants with lesions unique from the lesion treated in regimen 1 may enroll in regimen 2 and have additional lesion(s) treated, as long as they meet all inclusion criteria requirements. Up to three lesions may be treated in the second regimen
• Patients enrolling to Regimen 2b must have a target lesion amenable to intratumoral injection with polyICLC per the treating clinician’s discretion. 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
• 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%
• For subjects with breast cancer: * Prior treatment with CDK4/6 inhibitors is required for subjects with HR+ metastatic breast cancer * For subjects with metastatic triple negative breast cancer who have BRCA mutations, those subjects must have undergone standard therapies with PARP inhibitor therapy prior to enrollment
• 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), unless: * The subject has HIV but has been taking antiretroviral therapy, and agrees to take antiretroviral therapy throughout the study * The subject has active Hepatitis B or C but does not have a detectable viral load (testing to be within 6 months prior to screening date)
• 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
• Previous treatment with polyICLC within 4 weeks. If a subject was previously treated with intratumoral polyICLC and experienced a significant (grade >= 3) toxicity related to the polyICLC treatment, the tumor that was treated should not be re-treated as part of this protocol