| Eligibility |
Inclusion Criteria:
1. Age =18 years.
2. Advanced solid tumor with measurable disease.
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: 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 (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.
- 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.
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.
- 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 do not need to include the lesion targeted in regimen 1. The
patient must remain eligible for PD1/PDL1 Ab therapy.
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 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.
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 therapeutic agent (participation in the UVA AM004 clinical
trial is permitted)
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 with some exceptions.
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 to grade 1 or lower.
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. 12) 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.
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