| Eligibility |
Inclusion Criteria:
In order to be eligible for participation in this study, the subject must meet all of the
following:
All Cohorts:
1. Pathologically documented unresectable melanoma, American Joint Committee on Cancer
(AJCC) version 8, Stage III or IV. Subjects must have histological or cytological
confirmed diagnosis of unresectable melanoma with progressive locally advanced or
metastatic disease.
2. Subjects must be refractory to anti-PD-1 monoclonal antibodies (mAb) (pembrolizumab or
nivolumab either as monotherapy or in combination with other approved checkpoint
inhibitors or targeted therapies according to their approved label) and subjects must
meet all of the following criteria:
1. Received treatment of FDA-approved anti-PD1 mAb (dosed per label of the country
providing the clinical site) for at least 12 weeks (eg, 4 administrations of q3w
200 mg pembrolizumab or 2 administrations of q6w 400 mg pembrolizumab).
2. Progressive disease after anti-PD-1 mAb will be defined according to RECIST v1.1.
The initial evidence of PD is to be confirmed by a second assessment, no less
than 4 weeks from the date of the first documented PD, in the absence of rapid
clinical progression. For cases of rapid clinical progression, patients may be
allowed to enroll without a confirmatory scan after discussion with the sponsor.
(This determination is made by the Investigator; the Sponsor will collect imaging
scans for retrospective analysis. Once PD is confirmed, the initial date of PD
documentation will be considered the date of disease progression).
3. Documented disease progression within 12 weeks of the last dose of anti- PD-1
mAb. Subjects who were re-treated with anti-PD-1 mAb and subjects who were on
maintenance with anti-PD-1 mAb will be allowed to enter the study as long as
there is documented PD within 12 weeks of the last treatment date (with anti-PD-1
mAb).
Note: anti-PD-1 combination therapy is acceptable as the last prior treatment and may
include, anti-PD-1 anti-CTLA4 antibody combination therapy and anti-PD-1 combinations
with investigational or injectable therapy.
Cohort 2:
3. Subjects must have received ipilimumab alone or in combination with nivolumab (or
another agent) within approximately 12 months and must meet the following criteria:
1. Subject received 4 doses of ipilimumab (alone or in combination) or stopped
treatment due to treatment-related adverse event, or investigator determined that
the risks of further exposure outweigh the benefits.
2. Subjects with rapid clinical progression after fewer than 4 doses may be allowed
after discussion with the sponsor.
All Cohorts:
4. Resolution/improvement of anti-PD-1 mAb related adverse events (including immune
related AEs; irAEs) back to Grade 0-1 and =10 mg/day prednisone (or equivalent dose)
for irAEs for at least 2 weeks prior to the first dose of study drug:
1. No history of common toxicity criteria adverse events (CTCAE) Grade 4 irAEs from
anti-PD-1 mAb.
2. No history of CTCAE Grade 3 requiring steroid treatment (>10 mg/day prednisone or
equivalent dose) for >12 weeks or CTCAE Grade 2 pneumonitis regardless of steroid
treatment. No history of (non-infectious) pneumonitis or interstitial lung
disease that required steroids, and no current pneumonitis or interstitial lung
disease.
3. Minimum of 4 weeks (washout period) from the last dose of anti-PD-1 mAb
5. BRAF V600 mutation-positive melanoma could have received standard of care targeted
therapy for advanced or metastatic disease (eg, BRAF/MEK inhibitor, alone or in
combination) prior to enrolling on this study; however they do not need to have
progressed on this treatment.
6. Age = 18 years of age on day of signing informed consent.
7. Has a performance status of 0 or 1 on the ECOG Performance Scale, collected within 7
days of initial treatment.
8. Have measurable disease based on RECIST v1.1, with at least one anatomically distinct
lesion. At least one lesion must meet all the following baseline criteria:
1. Accessible for electroporation;
2. Must be accurately measured in at least one dimension (longest diameter in the
plane of measurement is to be recorded) Note: Tumor lesions situated in a
previously irradiated area are considered measurable if progression has been
demonstrated in such lesions
9. Demonstrate adequate organ function. All screening laboratories should be performed
within 10 days of treatment initiation.
10. Women of childbearing potential must have negative pregnancy test (for serum or urine
pregnancy test, within 72 hours or 24 hours, respectively, prior to receiving the
first study drug administration). If the urine test is positive or cannot be confirmed
as negative, a serum pregnancy test will be required.
11. For women of childbearing potential, must be willing to use an adequate method of
contraception from the first day of study treatment (or 14 days prior to the
initiation of study treatment for oral contraception) and through at least 120 days
following last day of study treatment. Acceptable methods include hormonal
contraception (oral contraceptives
- as long as on stable dose, patch, implant, and injection), intrauterine devices, or
double barrier methods (eg, vaginal diaphragm/ vaginal sponge plus condom, or condom
plus spermicidal jelly), sexual abstinence or a vasectomized partner. Women may be
surgically sterile or at least 1-year post-last menstrual period. Note: Abstinence is
acceptable if this is the usual lifestyle and preferred contraception for the subject.
Note: Spermicide alone is not considered sufficient and will not be accepted
12. Male subjects must be surgically sterile or must agree to use adequate method of
contraception when having sex with women of childbearing potential and refrains from
sperm donation during the study treatment period and through at least 120 days
following the last day of study drug administration.. Note: Abstinence is acceptable
if this is the usual lifestyle and preferred contraception for the subject.
13. Able and willing to provide written informed consent and to follow study instructions.
Exclusion Criteria:
1. Subject has disease that is suitable for local therapy administered with curative
intent.
2. Clinically active CNS metastases. Subjects with previously treated brain metastases
may participate provided they are radiologically stable, i.e., without evidence of
progression for at least 4 weeks by repeat imaging (note that the repeat imaging
should be performed during study screening), clinically stable and without requirement
of steroid treatment for at least 14 days prior to first dose of study drug.
3. Subject with a diagnosis of uveal or mucosal melanoma.
4. Subject with clinically unstable or uncontrolled secondary malignancy that is
progressing, or requires active treatment are excluded. In addition, subjects who have
had a secondary malignancy that has resolved within the last 6 months, are also
excluded.
5. Subject who had an allogenic tissue/solid organ transplant.
6. Subjects who have had intervening therapy following confirmed progression on anti-PD-1
therapy or anti-PD-1 combination therapy with the exception of BRAF inhibitors or
BRAF/MEK inhibitor combinations.
Note: anti-PD-1 combination therapy is acceptable as the last prior treatment and may
include, anti-PD-1 anti-CTLA4 antibody combination therapy and anti-PD-1 combinations
with investigational or injectable therapy.
7. Subjects who have received 4 or more lines of prior therapy, may be allowed to enroll
after discussion with the Medical Monitor.
8. Subjects with electronic pacemakers or defibrillators.
9. Subjects who have a known history of Human Immunodeficiency Virus (HIV) (HIV1/2
antibodies). HIV-infected subjects with a history of Kaposi sarcoma and/or
Multicentric Castleman Disease.
10. Subjects who have a known history of Hepatitis B or C infections or known to be
positive for Hepatitis B antigen (HBsAg) or Hepatitis B virus (HBV) DNA or active.
Active Hepatitis C. Active Hep C is defined by a known positive Hep C Ab result and
known quantitative HCV RNA results greater than the lower limits of detection of the
assay
11. Subject has a diagnosis of immunodeficiency or is receiving chronic systemic steroid
therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form
of immunosuppressive therapy within 7 days prior to the first dose of study drug. The
use of physiologic doses of corticosteroids may be approved after consultation with
the Sponsor.
12. Subjects who have received a live-virus or live-attenuated vaccination within 30 days
of the first dose of treatment. Note: Administration of killed vaccines are allowed.
Seasonal flu and COVID-19 vaccines that do not contain live virus are permitted.
13. Subject has severe hypersensitivity (=Grade 3) to pembrolizumab and/or any of its
excipients.
14. Subject has a history of (non infectious) pneumonitis or interstitial lung disease
that required steroids or has current pneumonitis or interstitial lung disease.
15. Subject has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the study, interfere with the subject's
participation for the full duration of the study, or is not in the best interest of
the subject to participate, in the opinion of the treating Investigator.
16. Subject has not recovered (i.e., = Grade 1 or at baseline) from adverse events due to
a previously administered agent, excluding thyroid, hypo adrenal, and diabetes if well
controlled.
Note: Subjects with =Grade 2 neuropathy or =Grade 2 alopecia and hypopigmentation are
an exception to this criterion and may qualify for the study.
Note: Participants with endocrine-related AEs Grade =2 requiring treatment or hormone
replacement may be eligible if approved by the Sponsor.
Note: If subject underwent major surgery or radiation therapy of >30 Gy within 2 weeks
of enrollment, they must have recovered adequately from the procedure and/or any
complications from the intervention prior to starting study combination therapy.
17. Participation in another clinical study of an investigational anti-cancer agent or has
used an investigational device within 30 days of screening.
Note: Subjects participating in an observational or supportive care study are an
exception to this criterion and may qualify for the study with Sponsor approval.
Note: Subjects who have entered the follow up phase of an investigational study may
participate as long as it has been 30 days after the last dose of the previous
investigational agent.
18. Subject has known psychiatric or substance abuse disorder that would interfere with
the subject's ability to cooperate with the requirements of the study.
19. Subjects who are pregnant or breast-feeding or expecting to conceive or father
children within the projected duration of the study, starting with the screening visit
through 120 days after the last dose of study treatment.
|
