Keynote695: Tavo and Pembrolizumab in Patients With Stage III/IV Melanoma Progressing on Pembrolizumab or Nivolumab Treatment

Sponsor

OncoSec Medical Incorporated (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03132675

Collaborator

Merck Sharp & Dohme LLC (Industry)

152

Enrollment

Locations

Arm

69.9

Anticipated Duration (Months)

4.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Keynote 695 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 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 Design

Study Type:

Interventional

Anticipated 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.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 :

Oct 3, 2017

Anticipated Primary Completion Date :

Dec 31, 2022

Anticipated Study Completion Date :

Jul 31, 2023

Arms and Interventions

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 Names: Keytruda Device: ImmunoPulse Device that electroporates the tavokinogene telseplasmid Other Names: tavo-EP

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 Names:

Keytruda

Device: ImmunoPulse

Device that electroporates the tavokinogene telseplasmid

Other Names:

tavo-EP

Outcome Measures

Primary Outcome Measures

Overall Response Rate (ORR) [approximately 2 years]
ORR by blinded independent central review (BICR) based on RECIST v1.1

Secondary Outcome Measures

Objective Response rate (ORR) [approximately 2 years]
ORR by investigator assessment based on RECIST v1.1
Duration of Response (DOR) [approximately 2 years]
DOR by Investigator assessment and BICR based on RECIST v1.1
Progression free survival (PFS) [approximately 2 years]
PFS by investigator assessment and BICR based on RECIST v1.1
Immune Progression Free Survival (iPFS) [approximately 2 years]
iPFS by Investigator assessment and BICR based on iRECIST
Immune Overall Response Rate (iORR) [approximately 2 years]
iORR by Investigator assessment and BICR based on iRECIST
Overall survival (OS) [approximately 2 years]
Overall survival

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.
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:

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:

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:

No history of common toxicity criteria adverse events (CTCAE) Grade 4 irAEs from anti-PD-1 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-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.
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:

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.
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

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.
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.

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.
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.

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The University of Arizona Cancer Center	Tucson	Arizona	United States	85724
2	Yuma Regional Medical Center, Yuma Cancer Center	Yuma	Arizona	United States	85364
3	University of California, San Diego	La Jolla	California	United States	92093
4	UCSF Medical Center	San Francisco	California	United States	94115
5	University of Colorado Anschutz Medical Campus University of Colorado Cancer Center	Aurora	Colorado	United States	80045
6	University of Miami Sylvester Cancer Center	Miami	Florida	United States	33136
7	UF Health Cancer Center at Orlando Health	Orlando	Florida	United States	32806
8	Moffit Cancer Center	Tampa	Florida	United States	33612
9	Northwestern University, Northwestern Medicine Feinger School of Medicine	Chicago	Illinois	United States	60611
10	Ochsner Cancer Institute	New Orleans	Louisiana	United States	70121
11	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
12	University of Michigan, Michigan Medicine Melanoma Oncology Clinic - Rogel Cancer Center	Ann Arbor	Michigan	United States	48109
13	Health Partners Cancer Care Center	Saint Paul	Minnesota	United States	55101
14	Dartmouth Hitchcock Clinic	Lebanon	New Hampshire	United States	03756
15	Atlantic Health System	Morristown	New Jersey	United States	07860
16	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
17	Health Quest Systems, Inc.	Poughkeepsie	New York	United States	12601
18	Duke University	Durham	North Carolina	United States	27710
19	Gabrail Cancer Center	Canton	Ohio	United States	44718
20	University of Toledo	Toledo	Ohio	United States	43614
21	St. Luke's University Health Network	Bethlehem	Pennsylvania	United States	18015
22	Penn State Health Hershey Medical Center	Hershey	Pennsylvania	United States	17033
23	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
24	Texas Oncology/Baylor	Dallas	Texas	United States	75246
25	Houston Methodist Cancer Center	Houston	Texas	United States	77030
26	Huntsman Cancer Institute	Salt Lake City	Utah	United States	84107
27	Westmead Hospital	Westmead	New South Wales	Australia	2145
28	Princess Alexandra Hospital	Woolloongabba	Queensland	Australia	4102
29	Cavalry Central Districts Hospital	Elizabeth Vale	South Australia	Australia	5112
30	Box Hill Hospital	Box Hill	Victoria	Australia	3128
31	The Alfred Hospital	Melbourne	Victoria	Australia	3004
32	Affinity Clinical Research	Nedlands	Western Australia	Australia	6009
33	St John of God Hospital	Subiaco	Western Australia	Australia	6008
34	The Moncton Hospital	Moncton	New Brunswick	Canada	E1C 6Z8
35	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G2M9
36	McGill University Health Centre	Montréal	Quebec	Canada	H4A 3J1
37	University of Zurich, Dermatology Clinic	Zürich	Canton Of Zurich	Switzerland