The study will be comprised of a screening period, a treatment period (up to 2 years), a long
term follow-up period, and a survival follow-up period.
Eligible patients will be treated with intratumoral tavo-EP to the accessible lesions on Days
1, 5 and 8 every 6 weeks and with IV pembrolizumab (200mg) on Day 1 of each 3-week cycle for
18 tavo-EP cycles and 35 pembrolizumab cycles (from baseline) of continued treatment
(approximately 2 years), or until disease progression. As many accessible lesions may be
treated as deemed feasible by the treating physician assuming the size of each lesion is
greater than 0.3 cm x 0.3 cm.
Long-term Follow-up: All subjects will be followed after End of Study (EOS) Treatment visit
for SAEs (through 90 days from last dose of study drug). Subjects who discontinue treatment
due to disease progression will directly enter the survival follow-up period following the
End of Study Treatment visit. Subjects who discontinue treatment for any reason other than
disease progression or withdrawal of consent enter the long-term follow-up period. They will
have scans, photographs, and investigator-assessed disease evaluation per RECIST v1.1
collected every 3 months until disease progression, subject receives a new anti-cancer
treatment (with the exception of maintenance pembrolizumab).
Information on all subjects' first new anti-cancer therapy will also be collected.
Survival Follow-up: Once a subject receives a new anti-cancer treatment or progresses during
long-term follow-up, they will move into survival follow-up. All subjects will be followed
for survival and disease status-, every 3 months until treatment period, long-term follow-up
period, and survival follow-up period reaches a total duration of 5 years, withdrawal of
consent, or until Sponsor terminates the study.
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.
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 in combination with nivolumab and must meet the
following criteria:
1. Subject received 4 doses of ipilimumab + nivolumab unless subject stopped
treatment due to treatment-related adverse event.
2. Subject must have had disease progression on ipilimumab + nivolumab or stopped
treatment due to treatment-related adverse event. Subjects with progression on
maintenance nivolumab are eligible.
3. Exposure to ipilimumab + nivolumab should have occurred within 12 months of study
treatment
4. For subjects who received more than one course of treatment with ipilimumab +
nivolumab doses administered with a gap of 6 months or longer, criteria a, b and
c should be applied to the most recent ipilimumab course.
All Cohorts:
4. Resolution/improvement of anti-PD-1 mAb related AEs (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:
d. No history of common toxicity criteria adverse events (CTCAE) Grade 4 irAEs from
anti-PD-1 mAb.
e. 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.
f. 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:
g. Accessible for electroporation; h. 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 serum or urine pregnancy test
within 72 hours 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 30 days prior to the first study drug administration and 120 days
following last day study drug administration (either tavo or pembrolizumab).
Acceptable methods include hormonal contraception (oral contraceptives - as long as on
stable dose, patch, implant, and injection), intrauterine devices, or double barrier
methods (e.g. 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 during the study and 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 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 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) interstitial pneumonitis that required
steroids or current pneumonitis or any active infection requiring systemic therapy.
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.
