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Tavo and Pembrolizumab in Patients With Stage III/IV Melanoma Progressing on Either Pembrolizumab or Nivolumab Treatment (Keynote-695)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03132675
Recruitment Status : Recruiting
First Posted : April 28, 2017
Last Update Posted : December 23, 2022
Sponsor:
Collaborator:
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
OncoSec Medical Incorporated

Brief Summary:
Keynote 695 is 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 either 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 screening period, a treatment period (up to 2 years), a long term follow-up period, and a survival follow-up period.

Eligible subjects will be treated with TAVO-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 up to 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, as long as the size of each lesion is greater than 0.3 cm × 0.3 cm.

Long-term Follow-up: All subjects will be followed after End of Treatment (EOT) visit for SAEs (through 90 days from last dose of study drug). Subjects who discontinue treatment will enter the long-term follow-up period unless they have started a new anti-cancer therapy (or other local anticancer immunotherapy) or have withdrawn consent for non-survival assessments. They will have scans, photographs, and investigator-assessed disease evaluation per RECIST v1.1 collected every 3 months until disease progression, or the subject receives a new systemic anti-cancer treatment (or other local anticancer immunotherapy).

Survival Follow-up: Once a subject receives a new systemic anti-cancer treatment (or other local anticancer immunotherapy), they will move into survival follow-up. All subjects will be followed for survival and disease status, every 3 months up to a total duration of 5 years, withdrawal of consent, or until Sponsor terminates the study.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 143 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:

Cohort 1A_Locally advanced/metastatic melanoma: pathological diagnosis of unresectable or metastatic melanoma with progression on pembrolizumab or nivolumab, confirmed according to RECIST v1.1. 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, progression is not required.

Cohort 1B_Locally advanced/metastatic melanoma: Subjects will be enrolled in order to collect safety data using the GenPulse generator. Eligibility for enrollment will be the same as that for Cohort 1A.

Cohort 2_Locally advanced/metastatic melanoma with prior exposure to ipilimumab alone or in combination with nivolumab (or other drug(s)/agent(s)): Eligible subjects will be those with pathological diagnosis of unresectable or metastatic melanoma who have been exposed to ipilimumab alone or in combination with nivolumab (or other drug/agent)

Masking: None (Open Label)
Masking Description: Blinded Independent Central Review
Primary Purpose: Treatment
Official Title: A Multicenter Phase 2, Open Label Study of Intratumoral Tavokinogene Telseplasmid (Tavo, pIL-12) + Electroporation With Pembrolizumab in Patients With Stage 3/4 Melanoma Who Are Progressing on Either Pembrolizumab or Nivolumab Treatment
Actual Study Start Date : October 3, 2017
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2025

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Melanoma
MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: tavo-EP plus IV pembrolizumab
Intratumoral Tavokinogene Telseplasmid (tavo, pIL 12) plus Electroporation (ImmunoPulse) in Combination with Intravenous Pembrolizumab
Biological: tavokinogene telseplasmid
Intratumoral tavokinogene telseplasmid (tavo, pIL-12) 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




Primary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: approximately 2 years ]
    ORR by blinded independent central review (BICR) based on RECIST v1.1


Secondary Outcome Measures :
  1. Objective Response rate (ORR) [ Time Frame: approximately 2 years ]
    ORR by investigator assessment based on RECIST v1.1

  2. Duration of Response (DOR) [ Time Frame: approximately 2 years ]
    DOR by Investigator assessment and BICR based on RECIST v1.1

  3. Progression free survival (PFS) [ Time Frame: approximately 2 years ]
    PFS by investigator assessment and BICR based on RECIST v1.1

  4. Immune Progression Free Survival (iPFS) [ Time Frame: approximately 2 years ]
    iPFS by Investigator assessment and BICR based on iRECIST

  5. Immune Overall Response Rate (iORR) [ Time Frame: approximately 2 years ]
    iORR by Investigator assessment and BICR based on iRECIST

  6. Overall survival (OS) [ Time Frame: approximately 2 years ]
    Overall survival



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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 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 (eg, 4 administrations of q3w 200 mg pembrolizumab or 2 administrations of q6w 400 mg pembrolizumab).
    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 alone or in combination with nivolumab (or another agent) within approximately 12 months and must meet the following criteria:

    1. Subject received 4 doses of ipilimumab (alone or in combination) or stopped treatment due to treatment-related adverse event, or investigator determined that the risks of further exposure outweigh the benefits.
    2. Subjects with rapid clinical progression after fewer than 4 doses may be allowed after discussion with the sponsor.

    All Cohorts:

  4. Resolution/improvement of anti-PD-1 mAb related adverse events (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-PD-1 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. No history of (non-infectious) pneumonitis or interstitial lung disease that required steroids, and no current pneumonitis or interstitial lung disease.
    3. 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:

    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
  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 pregnancy test (for serum or urine pregnancy test, within 72 hours or 24 hours, respectively, 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 the first day of study treatment (or 14 days prior to the initiation of study treatment for oral contraception) and through at least 120 days following last day of study treatment. Acceptable methods include hormonal contraception (oral contraceptives

    - as long as on stable dose, patch, implant, and injection), intrauterine devices, or double barrier methods (eg, 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 when having sex with women of childbearing potential and refrains from sperm donation during the study treatment period and through 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 or mucosal 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. Active Hep 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) pneumonitis or interstitial lung disease that required steroids or has current pneumonitis or interstitial lung disease.
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03132675


Contacts
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Contact: Gina Weaver 215-932-0262 gweaver@oncosec.com
Contact: Matthew Sieber 410-599-7614 msieber@oncosec.com

Locations
Show Show 38 study locations
Sponsors and Collaborators
OncoSec Medical Incorporated
Merck Sharp & Dohme LLC
Investigators
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Study Director: Bridget O'Keeffe, PhD OncoSec Medical Incorporated
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: OncoSec Medical Incorporated
ClinicalTrials.gov Identifier: NCT03132675    
Other Study ID Numbers: OMS-I103 (KEYNOTE 695)
Keynote-695 ( Other Identifier: Merck & Co )
MK3475-695 ( Other Identifier: Merck & Co )
First Posted: April 28, 2017    Key Record Dates
Last Update Posted: December 23, 2022
Last Verified: December 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: There is a DSMB charter that makes anonymised data available.

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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
Keywords provided by OncoSec Medical Incorporated:
Melanoma
pIL-12
pembrolizumab
tavokinogene telseplasmid
Keynote 695
IL-12
IL12
plasmid interleukin-12
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents