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Clinical Trial 20329

Cancer Type: Cutaneous
Study Type: Treatment
NCT#: NCT03132675

Phase: Phase II
Prinicipal Investigator:

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Overview

Study Title

The PISCES study: A Multicenter Phase 2, Open-Label Study of Intratumoral Tavokinogene Telseplasmid (tavo, pIL-12) plus Electroporation in Combination with Intravenous Pembrolizumab in Patients with Stage III/IV Melanoma who are Progressing on either Pembrolizumab or Nivolumab Treatment

Summary

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.

Objective

- To assess objective response rate (ORR) by blinded1 independent central review (BICR) based on RECIST v1.1. - To assess safety and tolerability of the combined treatment in subjects with unresectable or metastatic melanoma who previously have progressed on prior approved anti-PD-1 antibodies (either as monotherapy or in combination with another approved checkpoint inhibitor). - To assess duration of response (DOR), objective response rate (ORR), immune ORR (iORR), progression free survival (PFS), immune PFS (iPFS), and overall survival (OS) of combination therapy. - To assess long-term safety and tolerability of the combination therapy.

Treatments

Therapies

Medications

Pembrolizumab (Keytruda); Tavo-EP ()

Inclusion Criteria

  • Pathologically documented unresectable melanoma, American Joint Committee on Cancer (AJCC) version 8, Stage III or IV.
  • 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:
  • Received treatment of FDA-approved anti PD1 mAb (dosed per label of the country providing the clinical site) for at least 12 weeks.
  • 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. 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).
  • 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).
  • 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:
  • No history of common toxicity criteria adverse events (CTCAE) Grade 4 irAEs from anti PD1 mAb.
  • 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.
  • Minimum of 4 weeks (washout period) from the last dose of anti PD1 mAb
  • 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.
  • Age ≥ 18 years of age
  • Has a performance status of 0 or 1 on the ECOG Performance Scale, collected within 7 days of initial treatment.
  • 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:
  • 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
  • Demonstrate adequate organ function
  • 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.
  • 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)
  • 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.

  • Exclusion Criteria

  • Subject has disease that is suitable for local therapy administered with curative intent.
  • 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.
  • Subject with a diagnosis of uveal melanoma.
  • 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.
  • Subject who had an allogenic tissue/solid organ transplant.
  • Subjects with electronic pacemakers or defibrillators.
  • 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.
  • 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 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
  • 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.
  • 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.
  • Subject has severe hypersensitivity (>Grade 3) to pembrolizumab and/or any of its excipients.
  • Subject has a history of (non infectious) interstitial pneumonitis that required steroids or current pneumonitis or any active infection requiring systemic therapy.
  • 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.
  • Subject has not recovered (i.e., > Participation in another clinical study of an investigational anti-cancer agent or has used an investigational device within 30 days of screening.
  • 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. 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.
  • Subject has known psychiatric or substance abuse disorder that would interfere with the subject's ability to cooperate with the requirements of the study.
  • 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.

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