Tavo and Pembrolizumab in Patients With Stage III/IV Melanoma Progressing on Pembrolizumab or Nivolumab Treatment (PISCES)

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Stage III/IV Melanoma	Biological: tavokinogene telseplasmid; Biological: Pembrolizumab; Device: ImmunoPulse	Phase 2

Detailed Description:

The study will be comprised of a Core study (27 weeks), an Extension Phase and a long-term safety follow-up.

Core study: 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 on Day 1 of each 3-week cycle for 24 weeks. As many accessible lesions, may be treated, as deemed feasible by the treating physician .

Extension phase: Patients who completed 27 weeks of treatment (Core study) with the investigators discretion, will enter an Extension phase and continue to receive the combined treatment of intratumoral tavo-EP and pembrolizumab for up to 35 cycles of pembrolizumab from baseline (approximately 2 years) or until subsequent disease progression.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	48 participants
Intervention Model:	Single Group Assignment
Intervention Model Description:	Phase 2, Simon 2-stage, non-comparative, open-label, single-arm, multicenter study
Masking:	None (Open Label)
Masking Description:	Blinded Independent Central Review
Primary Purpose:	Treatment
Official Title:	A Multicenter Phase 2, Open Label Study of Intratumoral Tavo Plus Electroporation in Combination With Intravenous Pembrolizumab in Patients With Stage III/IV Melanoma Who Are Progressing on Either Pembrolizumab or Nivolumab Treatment
Actual Study Start Date :	October 3, 2017
Estimated Primary Completion Date :	October 1, 2020
Estimated Study Completion Date :	December 1, 2020

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Treatment; intratumoral tavo-EP plus IV pembrolizumab	Biological: tavokinogene telseplasmid; Intratumoral tavokinogene telseplasmid delivered by electroporation every 6 weeks; Other Names: pIL-12; tavo-EP; Biological: Pembrolizumab; Intravenous 3 weekly treatments; Other Name: Keytruda; Device: ImmunoPulse; Device that electroporates the tavokinogene telseplasmid; Other Name: tavo-EP

Outcome Measures

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Primary Outcome Measures :

1. Best Overall Response Rate (BORR) [ Time Frame: over 24 weeks ]
   BORR by blinded independent central review based on RECIST v1.1

Secondary Outcome Measures :

1. Objective Response rate [ Time Frame: approximately 2 years ]
   ORR by investigator assessment and by blinded independent central review based on RECIST v1.1 and iRECIST
2. Best Objective Response rate [ Time Frame: approximately 2 years ]
   ORR by investigator assessment based on RECIST v1.1 and iRECIST or blinded independent review by iRECIST
3. Duration [ Time Frame: approximately 2 years ]
   Duration by investigator assessment and by blinded independent central review based on RECIST v1.1 and iRECIST
4. Progression free survival (PFS) [ Time Frame: approximately 2 years ]
   PFS by investigator assessment and by blinded independent central review based on RECIST v1.1 and iRECIST
5. Overall survival [ Time Frame: approximately 2 years ]
   Overall survival

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• In order to be eligible for participation in this trial, the subject must meet all the following:

  1. Pathologically documented unresectable melanoma, AJCC 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 (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 at least 4 doses of anti-PD1 mAb (minimum dose of 2 mg/kg or fixed dose of 200 mg given Q3W for pembrolizumab; minimum dose of 240 mg given Q2W for nivolumab in monotherapy; minimum dose of 1 mg/kg given Q3W for nivolumab in combination with ipilimumab)
     2. Progressive disease after anti-PD1 mAb will be defined according to RECIST v1.1.
     3. Documented disease progression within 24 weeks of the last dose of anti-PD1 mAb.

  3. Resolution/improvement of anti-PD1 mAb-related AEs

     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 treatment.
     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.

  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)

  8. Demonstrate adequate organ function as defined below. All screening laboratories should be performed within 10 days of treatment initiation.

     System Laboratory Value Hematological Absolute neutrophil count (ANC) ≥1.5 × 109/L Platelets ≥100 × 109/L Hemoglobin ≥9 g/dL or ≥5.6 mmol/L* Renal Creatinine OR ≤1.5 × the upper limit of normal (ULN) OR Measured or calculated** creatinine clearance (CrCl) Glomerular filtration rate (GFR) can also be used instead of creatinine or CrCl ≥ 30 mL/min for patient with creatinine levels >1.5 × institutional ULN Hepatic Total bilirubin ≤1.5 × ULN OR direct bilirubin ≤ULN for patients with total bilirubin levels > 1.5× ULN Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN OR ≤5 × ULN for patients with liver metastases Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 × ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants Activated Partial Thromboplastin Time (aPTT)

     * Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks

     ** Creatinine clearance should be calculated per institutional standard.

  9. Women of childbearing potential must have negative serum or urine pregnancy test within 72 hours prior to receiving the first study drug administration.
  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. Spermicide alone is not considered sufficient in Canada and will not be accepted.
  11. Male patients 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.
  12. Able and willing to provide written informed consent and to follow study instructions.

Exclusion Criteria:

The subject must be excluded from participating in the trial if meet any of the following:

1. Subject has disease that is suitable for local therapy administered with curative intent.
2. Subject with a diagnosis of uveal 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 or non-measurable bone-only 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, 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. Liver lesions must meet RECIST v1.1 criteria for SD for at least 1 month prior to enrolment.
6. Subjects with electronic pacemakers or defibrillators.
7. Subjects who have a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
8. Subjects who have known active Hepatitis B (defined as HBsAg reactive) or Hepatitis C virus infection (defined as HCV RNA [qualitative] is detected)
9. 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.
10. 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.
11. Subject has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
12. Subject who have received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including G-CSF, GM-CSF or recombinant erythropoietin) within 4 weeks prior to study Cycle 1, Day 1 (baseline).
13. Subject has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
14. Subject has a history of interstitial lung disease.
15. Subject has an active infection requiring systemic therapy.
16. Subject has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, 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.
17. Subject has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
18. Participation in another clinical study of an investigational agent or has used an investigational device within 30 days of screening.
19. Subjects who have had any targeted small molecule therapy or any immunotherapy after their confirmed progression on anti-PD-1 therapy.
20. Subject has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.
21. Subjects who are pregnant or breastfeeding, 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 studytreatment.

Contacts and Locations

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Contacts

Contact: Sharron Gargosky, PhD	858-255-4729	sgargosky@oncosec.com

Locations

United States, California
University of California, San Diego	Recruiting
La Jolla, California, United States, 92093
Contact 858-822-6176
United States, Florida
University of Miami Sylvester Cancer Center	Recruiting
Miami, Florida, United States, 33136
Contact 305-243-2122
UF Health Cancer Center at Orlando Health	Recruiting
Orlando, Florida, United States, 32806
Contact 321-841-7303
United States, Minnesota
Health Partners Cancer Care Center	Recruiting
Saint Paul, Minnesota, United States, 55101
Contact 651-254-2845
United States, New York
Roswell Park Cancer Institute	Recruiting
Buffalo, New York, United States, 14263
Contact 716-845-5804
United States, Ohio
Gabrail Cancer Center	Recruiting
Canton, Ohio, United States, 44718
Contact 330-492-3345 ext 208
University of Toledo	Recruiting
Toledo, Ohio, United States, 43614
Contact 419-383-6962
United States, Pennsylvania
St. Luke's University Health Network	Recruiting
Bethlehem, Pennsylvania, United States, 18015
Contact 484-503-4152
University of Pittsburgh Cancer Institute	Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact 412-623-6130
United States, Utah
Huntsman Cancer Institute	Recruiting
Salt Lake City, Utah, United States, 84107
Contact 801-587-4767
Australia, New South Wales
Westmead Hospital	Recruiting
Westmead, New South Wales, Australia, 2145
Contact +61 2 8890 5686
Australia, Queensland
Princess Alexandra Hospital	Recruiting
Woolloongabba, Queensland, Australia, 4102
Contact +61 7 3844 8500
Australia, Victoria
Box Hill Hospital	Recruiting
Box Hill, Victoria, Australia, 3128
Contact ‭+61 3 9895 3203‬
The Alfred Hospital	Recruiting
Melbourne, Victoria, Australia, 3004
Contact +61 3 9076 2629
Australia, Western Australia
Affinity Clinical Research	Recruiting
Nedlands, Western Australia, Australia, 6009
Contact +61 8 9446 8726
St John of God Hospital	Recruiting
Subiaco, Western Australia, Australia, 6008
Contact +61 8 6465 9204
Canada, Quebec
McGill University Health Centre	Recruiting
Montréal, Quebec, Canada, H4A 3J1
Contact 514-934-1934 ext 35033

Sponsors and Collaborators

OncoSec Medical Incorporated

Investigators

Study Director:	Sharron Gargosky, PhD	OncoSec Medical Incorporated

More Information

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Responsible Party:	OncoSec Medical Incorporated
ClinicalTrials.gov Identifier:	NCT03132675 History of Changes
Other Study ID Numbers:	OMS-I103
First Posted:	April 28, 2017
Last Update Posted:	June 15, 2018
Last Verified:	June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes
Plan Description:	There is a DSMB charter that make anonymised data available

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		Yes
Device Product Not Approved or Cleared by U.S. FDA:		Yes
Pediatric Postmarket Surveillance of a Device Product:		No

Keywords provided by OncoSec Medical Incorporated:

Melanoma; pIL-12; pembrolizumab; tavokinogene telseplasmid

Additional relevant MeSH terms:

Melanoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms	Neoplasms, Nerve Tissue; Nevi and Melanomas; Pembrolizumab; Nivolumab; Antineoplastic Agents