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Age ≥18 years |
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Advanced solid tumor with measurable disease |
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Subject must have failed or have contraindication to standard therapies |
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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 |
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Note: Participants eligible for this regimen may receive the primary protocol |
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therapy (Regimen 1a) concurrent with PD1/PDL1 antibody therapy if |
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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 |
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Response with persistent disease: subjects who have a clinical response (SD or 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 |
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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 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 |
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For Cohort 1, secondary regimen (Regimen 2a): For those patients treated with primary |
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regimen 1a, select participants may be enrolled in a secondary regimen. This |
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would include participants in the following scenarios |
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Stable disease |
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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 |
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Initial partial response but still persistent disease at the treated lesion |
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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 |
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Patients enrolling to Regimen 2a must have a target lesion amenable to intratumoral |
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injection with polyICLC per the treating clinician's discretion. The lesion(s) to be |
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FUSA treated in regimen 2 do not need to include the lesion targeted in regimen 1. The |
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patient must remain eligible for PD1/PDL1 Ab therapy |
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For Cohort 2, primary regimen (Regimen 1b): The following patient subsets would be |
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eligible for the Cohort 2 primary regimen, as long as they have failed (progressed or |
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not tolerated) or are not eligible for all effective available approved therapies |
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regimen |
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known to confer clinical benefit |
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Patients with advanced solid malignancy for which PD1 or PDL1 blockade is not |
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FDA-approved |
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Patients with advanced solid malignancies for which PD1 or PDL1 blockade is FDA |
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approved but who are not eligible to receive that therapy because of prior |
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Patients with metastatic uveal melanoma |
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failure, toxicity, baseline autoimmune disease, or frailty |
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Patients who previously responded to PD1/PDL1 therapy but then progressed, if |
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there are no other systemic therapies available to them |
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Patients who were previously undergoing PD-1 blockade therapy must not have received a |
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dose within 4 weeks prior to FUSA treatment |
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For Cohort 2, secondary regimen (Regimen 2b): For those patients treated with primary |
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regimen 1a or 1b, select participants may be enrolled in a secondary regimen. This |
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would include participants in the following scenarios |
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Stable disease |
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Response in lesion treated in regimen 1, but persistent disease or progression in |
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Initial partial response but still persistent disease at the treated lesion |
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a separate lesion |
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Initial response followed by progression at the treated lesion after |
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discontinuation of PD-1/PD-L1 antibody. If there is a response and then |
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progression at the site treated in Regimen 1 and the residual tumor meets |
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inclusion criteria, this lesion may be re-treated on the secondary regimen. For |
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participants who progress at a site unique from the treated lesion, they may |
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enroll in Regimen 2 and have this new lesion treated, as long as they meet all |
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inclusion criteria requirements |
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Participants with lesions unique from the lesion treated in regimen 1 may enroll |
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in regimen 2 and have additional lesion(s) treated, as long as they meet all |
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inclusion criteria requirements. Up to three lesions may be treated in the second |
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For FUSA |
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Patients enrolling to Regimen 2b must have a target lesion amenable to intratumoral |
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injection with polyICLC per the treating clinician's discretion. The lesion to be FUSA |
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treated in regimen 2 does not need to be the same lesion targeted in regimen 1 |
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Crossover from primary regimen 1a is allowed if the patient is no longer eligible for |
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continued PD1/PDL1 Ab therapy (e.g. due to autoimmune toxicity), and if there is no |
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other effective systemic therapy option. The length between the FUSA treatments in |
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regimen 1 and regimen 2 should be no less than 6 weeks. Patients who experienced an |
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unanticipated device effect in the primary regimen are not eligible for the secondary |
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For Biopsies |
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regimen |
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Biopsies may be completed with or without image guidance |
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One or more dermal, subcutaneous or nodal metastases from an advanced solid tumor. The |
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metastases need to be accessible for FUSA and for biopsy |
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The targeted lesion(s) must be visible by ultrasound imaging and meet the following |
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provided |
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criteria. Brain lesions may not be targeted for treatment |
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The tumor site that was previously radiated has progressed |
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Approximately 1 cm (or more) diameter of treatable tumor volume for lesions to be |
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treated with FUSA |
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The target treatment area needs to be contained within a region at least 5 mm |
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No brain metastasis is > 2 cm in diameter at the time of registration |
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from the skin surface and less than or equal to 23 mm from the skin surface |
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Neurologic symptoms have returned to baseline |
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The target treatment area must be at a safe distance from all critical |
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There is no evidence of new or enlarging brain metastases |
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structures, including but not limited to ribs or other bony structures, vital |
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organs, named blood vessels or nerves |
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The critical structures, with the exception of the skin, will not be in the |
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pre-focal ultrasound path |
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The anterior-posterior dimension of the treatment area by US should be no less |
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than 9mm |
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Lesions that have been selected for focused ultrasound or lesions that have been |
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selected for biopsies as untreated controls may have been previously radiated |
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A baseline biopsy of the tumor site is obtained following progression and prior |
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to study entry |
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ECOG performance status 0-2 |
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Subjects with brain metastases may participate if all of the following are true |
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There has been no evident growth of any brain metastasis since the most recent |
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treatment |
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Subjects are not using steroids for at least 7 days prior to registration |
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Regardless of dose, however, subjects who are on a steroid taper for management |
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of brain metastases are not eligible until 7 days after completion of that |
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steroid taper |
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Brain metastases will not be targeted for FUSA treatment |
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Adequate organ function |
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Ability and willingness to give informed consent |
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A subject will be excluded from participating in the trial if the subject
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Immune therapies including
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checkpoint blockade therapies other than anti-PD-1/PD-L1 antibodies
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antibodies to costimulatory molecules (e.g. CD27, CD137)
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small molecule immune therapies (e.g. IDO1 inhibitor)
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Cytotoxic chemotherapy for cancer
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Allergy desensitization injections
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High doses of systemic corticosteroids, with the following qualifications and
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exceptions
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Topical and nasal corticosteroids are acceptable
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Targeted therapies specific for mutated BRAF or for MEK
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Live vaccine
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Has received the following medications or treatments at any time within 3 weeks of
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Has an active infection requiring systemic therapy
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study day 1
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interferon (e.g. Intron-A®)
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Note: The following are not exclusionary
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Clinical evidence of vitiligo
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Other forms of depigmenting illness
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Mild arthritis requiring NSAID medications
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Has received the following medications or treatments at any time within 4 weeks of
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study day 1
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Radiation therapy (Note: Stereotactic radiotherapy, such as gamma knife, can be
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used ≥ 1 week prior to registration)
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Squamous cell cancer of the skin without known metastasis
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Basal cell cancer of the skin without known metastasis
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Daily doses of 10 mg or less prednisone (or equivalent) per day administered
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Carcinoma in situ of the breast (DCIS or LCIS)
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parenterally or orally are allowed in patients with normal adrenal and
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pituitary function
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In patients with adrenal or pituitary insufficiency replacement steroid
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doses are allowed
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Inhaled steroids (e.g.: Advair®, Flovent®, Azmacort®) are permitted at low
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doses (less than 500 mcg fluticasone per day, or equivalent)
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Growth factors (e.g. Procrit®, Aranesp®, Neulasta®)
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Interleukins (e.g. Proleukin®)
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Any investigational therapeutic agent (participation in the UVA AM004 clinical
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trial is permitted)
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Has a known addiction to alcohol or drugs and is actively taking those agents, or has
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recently (within 1 year) taken these agents or has ongoing illicit IV drug use
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Is HIV positive or has evidence of active Hepatitis B or C virus with some exceptions
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Is currently receiving nitrosoureas or has received this therapy within the preceding
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weeks
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Is pregnant or breastfeeding. Female participants of childbearing potential must have
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a negative pregnancy test obtained within 2 weeks prior to registration. Males and
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females must agree, in the consent form, to use effective birth control methods during
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the course of treatment and following treatment in accordance with the labeling
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guidelines for each approved therapy
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Has a medical contraindication or potential problem in complying with the requirements
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of the protocol in the opinion of the investigator
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Has Class III or IV heart disease as classified according to the New York Heart
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Association
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Has had prior autoimmune disorders requiring cytotoxic or immunosuppressive therapy,or
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autoimmune disorders with visceral involvement. Participants with an active autoimmune
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disorder requiring these therapies are also excluded
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The presence of laboratory evidence of autoimmune disease (e.g. positive ANA
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titer) without symptoms
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A history of immune-related adverse events with immune therapy, if the
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immune-related adverse events have resolved to grade 1 or lower
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History of another cancer
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Note: the following diagnoses are exceptions and are permitted as long as they have
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been treated successfully and without clinical evidence of disease
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Any cancer that has been treated successfully, without evidence of subsequent
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recurrence or metastasis for over 5 years
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Any cancer without distant metastasis that has been treated successfully, without
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evidence of recurrence or metastasis for over 2 years
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Carcinoma in situ of the cervix
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12) Previous treatment with polyICLC within 4 weeks. If a subject was previously
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treated with intratumoral polyICLC and experienced a significant (grade ≥3) toxicity
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related to the polyICLC treatment, the tumor that was treated should not be re-treated
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as part of this protocol
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