| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Unresectable or metastatic melanoma that is progressing or has progressed on pembrolizumab or nivolumab |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025671 |
| E.1.2 | Term | Malignant melanoma stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025670 |
| E.1.2 | Term | Malignant melanoma stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| Overall Response Rate by blinded independent central review (BICR) based on RECIST v1.1. |
|
| E.2.2 | Secondary objectives of the trial |
Assess safety and tolerability of the combined treatment in subjects with unresectable or metastatic melanoma who previously have progressed on prior approved anti-PD-1 antibodies
Assess duration of response (DOR), ORR, immune OR (iORR), PFS, immune PFS (iPFS), and OS of combination therapy
Assess long-term safety and tolerability of the combination therapy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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.
2. Progressive disease after anti PD1 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. (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 PD1 mAb. Subjects who were re treated with anti PD1 mAb and subjects who were on maintenance with anti PD1 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 PD1 mAb).
3. Resolution/improvement of anti PD1 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:
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, collected within 7 days of initial treatment.
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 Note: Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions
8. Demonstrate adequate organ function. All screening laboratories should be performed within 10 days of treatment initiation.
9. 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.
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 (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.
11. 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.
12. Able and willing to provide written informed consent and to follow study instructions. |
|
| E.4 | Principal exclusion criteria |
1. Subject has disease that is suitable for local therapy administered with curative intent.
2. Subject with a diagnosis of uveal or mucosal 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. 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.
5. Greater than 3 visceral sites of metastases (this does not include nodal metastases associated with visceral organs)
6. Subjects with stage IVc melanoma with liver or bowel metastases.
7. Subject who had an allogenic tissue/solid organ transplant.
8. Subjects with electronic pacemakers or defibrillators.
9. Subjects who have a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). HIV-infected subjects with a history of Kaposi sarcoma and/or Multicentric Castleman Disease.
10. Subjects who have history of Hepatitis B or C infections or known to be positive for Hepatitis B antigen (HBsAg) or Hepatitis B virus (HBV) DNA or Hepatitis C antibody or RNA. 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
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 vaccination within 30 days of the first dose of treatment. Seasonal flu 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. Subjects who have received transfusion of blood products (including platelets or red blood cells) or colony stimulating factors (including G CSF, GM CSF or recombinant erythropoietin) within 4 weeks prior to study Cycle 1, Day 1 (baseline).
15. Subject has a history of (non infectious) pneumonitis that required steroids or current pneumonitis.
16. Subject has a history of interstitial lung disease.
17. Subject has an active infection requiring systemic therapy.
18. 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.
19. Subject has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.
20. Participation in another clinical study of an investigational anti-cancer agent or has used an investigational device within 30 days of screening.
21. Subjects who have had intervening therapy following confirmed progression on anti PD 1 therapy or anti-PD-1 combination therapy with the exception of approved BRAF/MEK inhibitor combinations. 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.
22. Subject has known psychiatric or substance abuse disorder that would interfere with the subject's ability to cooperate with the requirements of the study.
23. 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall Response Rate by blinded independent central review (BICR) based on RECIST v1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Objective Response rate by investigator assessment based on RECIST v1.1
Duration of Response by Investigator assessment and BICR based on RECIST v1.1
Progression free survival by investigator assessment and BICR based on RECIST v1.1
Immune Progression Free Survival by Investigator assessment and BICR based on iRECIST
Immune Overall Response Rate by Investigator assessment and BICR based on iRECIST
Overall survival |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Germany |
| Italy |
| Poland |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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