pIL-12 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 pIL-12-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: pIL-12; Biological: Pembrolizumab; Device: Immunopulse	Phase 2

Detailed Description:

The study will be comprised of a Core study (24 weeks), an Extension Phase and a long-term safety follow-up.

Core study: Eligible patients will be treated with intratumoral pIL-12-EP to the accessible lesions on Days 1, 5 and 8 every 6 weeks and with IV pembrolizumab (200 mg) 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 24 weeks of treatment (Core study) with the investigators discretion, will enter an Extension phase and continue to receive the combined treatment of intratumoral pIL-12-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)
Primary Purpose:	Treatment
Official Title:	A Multicenter Phase 2, Open-Label Trial of Intratumoral 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
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 pIL-12-EP plus IV pembrolizumab	Biological: pIL-12; Intratumoral pIL-12 delivered by electroporation every 6 weeks Biological: Pembrolizumab; intravenous 3 weekly treatments; Other Name: Keytruda Device: Immunopulse; device that provides electroporation

Outcome Measures

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Primary Outcome Measures :

1. Best Overall Response Rate (BORR) [ Time Frame: over 24 weeks ]
   BORR by 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 independent central review based on RECIST v1.1
2. Duration [ Time Frame: approximately 2 years ]
   Duration by investigator assessment and by independent central review based on RECIST v1.1
3. Progression free survival (PFS) [ Time Frame: approximately 2 years ]
   PFS by investigator assessment and by independent central review based on RECIST v1.1
4. Overall survival [ Time Frame: approximately 2 years ]
   Overall survival

Eligibility Criteria

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

Criteria

Inclusion Criteria:

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

  1. Pathologically documented unresectable melanoma, AJCC Stage III or IV. Patients must have histological or cytological confirmed diagnosis of unresectable melanoma with progressive locally advanced or metastatic disease.

  2. Patients must be refractory to anti-PD-1 monoclonal antibodies (mAb) defined as pembrolizumab or nivolumab as either as monotherapy or in combination with other approved checkpoint inhibitors or targeted therapies according to their approved label, defined as (patients must meet all of the following criteria):

     1. Received at least 4 doses of anti-PD1 mAb for pembrolizumab; minimum dose of 240 mg given every two weeks 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 ≥ 60 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)

     * 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
  11. Male patients of childbearing potential 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 patient must be excluded from participating in the trial if meet any of the following:

1. Patient has disease that is suitable for local therapy administered with curative intent.
2. Patient with a diagnosis of uveal melanoma.
3. Patient has a known additional malignancy that is progressing or requires active treatment. 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 cerebral or non-measurable bone-only metastases. Patients with up to 3 (neurological performance status of 0) cerebral metastases may be enrolled, provided that all lesions have been adequately treated with stereotactic radiation therapy or gamma-knife therapy with no evidence of progression, and have not required steroids, for at least two months prior to enrolment.
5. Greater than 3 sites of visceral metastases. For patients with less than or equal to 3 visceral metastases and liver lesions must meet RECIST v1.1 criteria for SD for at least 1 month prior to enrolment.
6. Patients with electronic pacemakers or defibrillators.
7. Patients who have a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
8. Patients who have known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected); Note: Patients who have been vaccinated against Hepatitis B and who are positive only for the Hepatitis B surface antibody are permitted to participate in the study.
9. Patient has a diagnosis of immunodeficiency or is receiving systemic steroid therapy 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. Patients 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. Patient has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
12. Patients 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. Patient has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
14. Patient has a history of interstitial lung disease.
15. Patient has an active infection requiring systemic therapy.
16. Patient has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.

17. Patient has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.

    Note: Patients with ≤Grade 2 neuropathy or ≤Grade 2 alopecia are an exception to this criterion and may qualify for the study.

    Note: If patient underwent major surgery or radiation therapy of >30 Gy, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study combination therapy.

18. Participation in another clinical trial within 30 days of screening. Note: Patients participating in an observational study are an exception to this criterion and may qualify for the study with Sponsor approval
19. Patients who have had any targeted small molecule therapy or any immunotherapeutic after their confirmed progression on anti-PD-1 therapy.
20. Patient has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
21. Patients who are pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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: Jaren Mullen 858-822-6176 jmullen@ucsd.edu
Principal Investigator: Gregory Daniels, MD
United States, Florida
UF Health Cancer Center at Orlando Health	Recruiting
Orlando, Florida, United States, 32806
Contact: Marie Frankos 321-841-7303 marie.frankos@orlandohealth.com
Principal Investigator: Sajeve Thomas, MD
United States, Minnesota
Health Partners Cancer Care Center	Recruiting
Saint Paul, Minnesota, United States, 55101
Contact: Joanna Hill 651-254-2845 Joanna.Hill@parknicollet.com
Principal Investigator: Arkadiusz Dudek, MD
United States, New York
Roswell Park Cancer Institute	Recruiting
Buffalo, New York, United States, 14263
Contact: Suzanne Stack 716-845-5804 Suzanne.Stack@RoswellPark.org
Principal Investigator: Igor Puzanov, MD
United States, Pennsylvania
University of Pittsburgh Cancer Institute	Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Joshua White 412-623-6130 Whitej15@upmc.edu
Principal Investigator: John M Kirkwood, MD
United States, Utah
Huntsman Cancer Institute, University of Utah	Recruiting
Salt Lake City, Utah, United States, 84107
Contact: Tamara Willis, RN 801-587-4767 tamara.willis@hci.utah.edu
Principal Investigator: Robert H Andtbacka, MD
Australia, Queensland
Princess Alexandra Hospital	Recruiting
Woolloongabba, Queensland, Australia, 4102
Contact: Janine Thomas +617-3844-8500 janine.thomas@mater.uq.edu.au
Principal Investigator: Victoria Atkinson, MD
Australia, Victoria
Box Hill Hospital	Recruiting
Box Hill, Victoria, Australia, 3128
Contact: Nicola Elliott ‭+61398953203‬ Nicola.Elliott@monash.edu
Principal Investigator: Phillip Parente, MD
Australia, Western Australia
Affinity Clinical Research	Recruiting
Nedlands, Western Australia, Australia, 6009
Contact: Krystyne Hiscock +61894468726 Pm1@affinityresearch.com.au
Principal Investigator: Anne Long, MD
St John of God Hospital	Recruiting
Subiaco, Western Australia, Australia, 6008
Contact: Grace Till +618-6465-9204 Grace.Till@sjog.org.au
Principal Investigator: Tom van Hagen, MD

Sponsors and Collaborators

OncoSec Medical Incorporated

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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:	March 14, 2018
Last Verified:	March 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

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