Tavo and Pembrolizumab in Patients With Stage III/IV Melanoma Progressing on Pembrolizumab or Nivolumab Treatment (Keynote695)
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| ClinicalTrials.gov Identifier: NCT03132675 |
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Recruitment Status :
Recruiting
First Posted : April 28, 2017
Last Update Posted : April 29, 2021
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Stage III/IV Melanoma | Biological: tavokinogene telseplasmid Biological: Pembrolizumab Device: ImmunoPulse | Phase 2 |
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 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 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 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) Treatment visit for SAEs (through 90 days from last dose of study drug). Subjects who discontinue treatment due to disease progression will directly enter the survival follow-up period following the End of Study Treatment visit. Subjects who discontinue treatment for any reason other than disease progression or withdrawal of consent enter the long-term follow-up period. They will have scans, photographs, and investigator-assessed disease evaluation per RECIST v1.1 collected every 3 months until disease progression, subject receives a new anti-cancer treatment (with the exception of maintenance pembrolizumab).
Information on all subjects' first new anti-cancer therapy will also be collected.
Survival Follow-up: Once a subject receives a new anti-cancer treatment or progresses during long-term follow-up, they will move into survival follow-up. All subjects will be followed for survival and disease status-, every 3 months until treatment period, long-term follow-up period, and survival follow-up period reaches a total duration of 5 years, withdrawal of consent, or until Sponsor terminates the study.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 152 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Intervention Model Description: | Phase 2, non-comparative, open-label, single-arm, multicenter study of intatrumoral tavo-EP plus IV pembrolizumab. Cohort 1 Locally advanced or metastatic melanoma: Approximatey 100 evaluable subjects will be enrolled into this cohort. The sample site may increase by up to an additional 25 subjects in order to collect clinical experience with the GenPulse OMS electroporation device. Cohort 2 Locally advanced or metastatic melanoma with prior exposure to ipilimumab in combination with nivolumab: Approximately 27 subjects will be enrolled into the cohort. Eligible subjects will be those with pathological diagnosis of unresectable or metastatic melanoma who are progressing or have progressed on ipilimumab combined with nivolumab. |
| 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) Plus Electroporation in Combination With Intravenous Pembrolizumab in Patients With Stage III/IV Melanoma Who Are Progressing on Either Pembrolizumab or Nivolumab Treatment (Keynote 695) |
| Actual Study Start Date : | October 3, 2017 |
| Estimated Primary Completion Date : | December 31, 2022 |
| Estimated Study Completion Date : | July 31, 2023 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: tavo-EP plus IV pembrolizumab
Intratumoral Tavokinogene Telseplasmid (tavo, pIL 12) plus Electroporation (ImmunoPulse) in Combination with Intravenous Pembrolizumab
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Biological: tavokinogene telseplasmid
Intratumoral tavokinogene telseplasmid (tavo, pIL-12) delivered by electroporation every 6 weeks
Other Names:
Biological: Pembrolizumab Intravenous 3 weekly treatments
Other Name: Keytruda Device: ImmunoPulse Device that electroporates the tavokinogene telseplasmid
Other Name: tavo-EP |
- Overall Response Rate (ORR) [ Time Frame: approximately 2 years ]ORR by blinded independent central review (BICR) based on RECIST v1.1
- Objective Response rate (ORR) [ Time Frame: approximately 2 years ]ORR by investigator assessment based on RECIST v1.1
- Duration of Response (DOR) [ Time Frame: approximately 2 years ]DOR by Investigator assessment and BICR based on RECIST v1.1
- Progression free survival (PFS) [ Time Frame: approximately 2 years ]PFS by investigator assessment and BICR based on RECIST v1.1
- Immune Progression Free Survival (iPFS) [ Time Frame: approximately 2 years ]iPFS by Investigator assessment and BICR based on iRECIST
- Immune Overall Response Rate (iORR) [ Time Frame: approximately 2 years ]iORR by Investigator assessment and BICR based on iRECIST
- Overall survival (OS) [ Time Frame: approximately 2 years ]Overall survival
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
In order to be eligible for participation in this study, the subject must meet all of the following:
All Cohorts:
- 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.
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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-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).
- 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:
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Subjects must have received ipilimumab in combination with nivolumab and must meet the following criteria:
- Subject received 4 doses of ipilimumab + nivolumab unless subject stopped treatment due to treatment-related adverse event.
- Subject must have had disease progression on ipilimumab + nivolumab or stopped treatment due to treatment-related adverse event. Subjects with progression on maintenance nivolumab are eligible.
- Exposure to ipilimumab + nivolumab should have occurred within 12 months of study treatment
- For subjects who received more than one course of treatment with ipilimumab + nivolumab doses administered with a gap of 6 months or longer, criteria a, b and c should be applied to the most recent ipilimumab course.
All Cohorts:
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Resolution/improvement of anti-PD-1 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:
d. No history of common toxicity criteria adverse events (CTCAE) Grade 4 irAEs from anti-PD-1 mAb.
e. 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.
f. Minimum of 4 weeks (washout period) from the last dose of anti-PD-1 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 on day of signing informed consent.
- Has a performance status of 0 or 1 on the ECOG Performance Scale, collected within 7 days of initial treatment.
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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:
g. 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. All screening laboratories should be performed within 10 days of treatment initiation.
- 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.
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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.
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
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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.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
- Able and willing to provide written informed consent and to follow study instructions.
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.
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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.
- Subjects who have received 4 or more lines of prior therapy, may be allowed to enroll after discussion with the Medical Monitor.
- Subjects with electronic pacemakers or defibrillators.
- 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.
- 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 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 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.
- 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.
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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.
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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.
- 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.
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
| Contact: Chris Baker | 609-802-6632 | cbaker@oncosec.com | |
| Contact: Jendy Sell | 610.703.3418 | jsell@oncosec.com |
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| Study Director: | Jendy Sell | OncoSec Medical Incorporated |
| 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: | April 29, 2021 |
| Last Verified: | April 2021 |
| 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 |
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