This will be a Phase 2 study of intratumoral tavokinogene telseplasmid (tavo; pIL-12)
Electroporation (EP) plus IV Pembrolizumab. Eligible patients will be those with pathological
diagnosis of unresectable or metastatic melanoma who are progressing or have progressed on
pembrolizumab or nivolumab.
The study will be comprised of a screening period, a treatment period (up to 2 years) and a
long term follow-up.
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
17 tavo-EP cycles and 33 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) visit for SAEs
(through 90 days from last dose of study drug) and long term survival status. EOS visit will
occur 4 weeks after last study treatment administration.
In order to be eligible for participation in this study, the subject must meet all of the
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
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 PD1 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. (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
3. Documented disease progression within 12 weeks of the last dose of anti PD1 mAb.
Subjects who were re treated with anti PD1 mAb and subjects who were on
maintenance with anti PD1 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 PD1 mAb).
3. Resolution/improvement of anti PD1 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:
1. No history of common toxicity criteria adverse events (CTCAE) Grade 4 irAEs from
anti PD1 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
3. Minimum of 4 weeks (washout period) from the last dose of anti PD1 mAb
4. Prior treatment with an approved BRAF inhibitor if BRAF V600 mutation positive.
5. Age ≥ 18 years of age on day of signing informed consent.
6. Has a performance status of 0 or 1 on the ECOG Performance Scale, collected within 7
days of initial treatment.
7. Have measurable disease based on RECIST v1.1, with at least one anatomically distinct
lesion. Lesion or lesions 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
8. Demonstrate adequate organ function. All screening laboratories should be performed
within 10 days of treatment initiation.
9. 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
10. 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.
11. 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
12. Able and willing to provide written informed consent and to follow study instructions.
1. Subject has disease that is suitable for local therapy administered with curative
2. Subject with a diagnosis of uveal or mucosal melanoma.
3. Subject has a known additional malignancy that is progressing or requires active
treatment within the past 3 years. Exceptions include basal cell carcinoma of the
skin, squamous cell carcinoma of the skin that has undergone potentially curative
therapy or in situ cervical cancer.
4. 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.
5. Greater than 3 visceral sites of metastases (this does not include nodal metastases
associated with visceral organs)
6. Subjects with stage IVc melanoma with liver or bowel metastases.
7. Subject who had an allogenic tissue/solid organ transplant.
8. Subjects with electronic pacemakers or defibrillators.
9. Subjects who have a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2
antibodies). HIV-infected subjects with a history of Kaposi sarcoma and/or
Multicentric Castleman Disease.
10. Subjects who have history of Hepatitis B or C infections or known to be positive for
Hepatitis B antigen (HBsAg) or Hepatitis B virus (HBV) DNA or Hepatitis C antibody or
RNA. 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
12. Subjects who have received a live virus vaccination within 30 days of the first dose
of treatment. Seasonal flu vaccines that do not contain live virus are permitted.
13. Subject has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its
14. Subjects who have received transfusion of blood products (including platelets or red
blood cells) or colony stimulating factors (including G CSF, GM CSF or recombinant
erythropoietin) within 4 weeks prior to study Cycle 1, Day 1 (baseline).
15. Subject has a history of (non infectious) pneumonitis that required steroids or
16. Subject has a history of interstitial lung disease.
17. Subject has an active infection requiring systemic therapy.
18. 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.
19. Subject has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to
a previously administered agent.
20. Participation in another clinical study of an investigational anti-cancer agent or has
used an investigational device within 30 days of screening.
21. Subjects who have had intervening therapy following confirmed progression on anti PD 1
therapy or anti-PD-1 combination therapy with the exception of approved BRAF/MEK
inhibitor combinations. 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.
22. Subject has known psychiatric or substance abuse disorder that would interfere with
the subject's ability to cooperate with the requirements of the study.
23. 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.