| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced unresectable melanoma. |
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| E.1.1.1 | Medical condition in easily understood language |
| Skin cancer that cannot be surgically removed. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 |
For the run-in portion of the study, the primary objective of the study is to assess safety and tolerability (how well the patient copes with the drug) of SCIB1, when administered using the TriGrid™ Delivery System - Intra Muscular device (TDS-IM v2.0) in patients receiving intravenous (IV) pembrolizumab for advanced melanoma (skin cancer).
For the full study, the purpose of the current study is to determine whether the addition of the study drug SCIB1 to the standard treatment of pembrolizumab can improve the response rate to treatment when compared with historical data of patients with advanced melanoma being treated with only pembrolizumab. |
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
i) To determine whether the addition of SCIB1 to pembrolizumab improves the duration of response relative to historical data for pembrolizumab alone in this patient population.
ii) Measure the response rate based on tumour imaging (radiology) and established criteria known as iRECIST.
iii) To assess the rate of progression-free survival (survival without the worsening of the cancer) for all patients at 1 year and 2 years (96 weeks), following initiation of treatment.
iv) To assess the overall survival rate for all patients at 1 year and 2 years (96 weeks), following initiation of treatment.
v) To assess the safety and tolerability of SCIB1, when administered using the TDS-IM v2.0 in patients receiving IV pembrolizumab.
Exploratory Objectives:
i) To explore the relationship between immune response and clinical outcome. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet the following criteria in order to be included in the study:
1) Patient has histologically confirmed, unresectable Stage III or Stage IV melanoma as defined by the American Joint Committee on Cancer (AJCC) (Gershenwald et al 2017).
2) Patient has not received prior systemic treatment for advanced disease. Prior adjuvant treatment, defined as treatment following resection of all detectable disease, is permitted; last dose must be at least 4 weeks before the first dose of SCIB1.
3) Patient been clinically evaluated and pembrolizumab has been determined to be an appropriate treatment for their advanced disease.
4) Patient’s BRAF status must be known; patients with BRAF mutation positive disease may be enrolled without BRAF-inhibitor treatment at the discretion of the Investigator, provided that they have no evidence of rapidly progressive disease (lactate dehydrogenase [LDH] above normal range, clinically significant tumor-related symptoms).
5) Patient has at least one measurable lesion per RECIST 1.1 criteria by computed tomography (CT) scan or magnetic resonance imaging (MRI). Cutaneous and other superficial lesions are non-target lesions and are not considered measurable for the purposes of this protocol.
6) Patient has an archival or fresh biopsy sample of tumor available for analysis of immunological markers including expression of programmed death-ligand 1 (PD-L1).
7) Patient is HLA-A2 positive.*
8) Patient is positive for HLA-DR4, HLA-DR7, HLA-DR53 or HLA-DQ6.*
9) Patient is at least 18 years of age.
10) Patient has a life expectancy of more than 3 months.
11) Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
12) Patient has adequate organ function as determined by the protocol laboratory values.
13) Patient must be able and willing to provide written IRB/REC-approved informed consent prior to any study-related procedure. In the event that the patient is re-screened for study participation or if a protocol amendment alters the care of an ongoing patient, a new IRB/REC-approved informed consent form (ICF) must be signed.
14) Women of child-bearing potential (including women ≤ 12 months from last menstrual period) must have a negative serum pregnancy test during Screening (within the 72 hr before planned administration of the first dose of study drug on Day 1) and be neither breastfeeding nor intending to become pregnant during study participation, and shall be warned of potential foetal harm from pembrolizumab. Women of childbearing potential must agree to use highly effective contraceptive methods prior to study entry, for the duration of study participation, and for 120 days after discontinuation of SCIB1 or pembrolizumab, whichever occurs last.
15) Men who are potentially fertile with partners of childbearing potential must agree to use highly effective contraceptive methods for the duration of study participation and for 120 days after discontinuation of study treatment.
16) Patient must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
* HLA testing will be conducted at accredited laboratories by molecular (DNA) typing.
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|
| E.4 | Principal exclusion criteria |
A patient will not be eligible for the study if he/she meets one or more of the following criteria:
1) Patient has a diagnosis of uveal or ocular melanoma.
2) Patient has active central nervous system metastases or carcinomatous meningitis (patients with a response to previous treatment for brain metastases are eligible provided that they are stable without MRI evidence of progression for at least 4 weeks prior to the first dose of study treatment, and systemic steroids have been withdrawn for at least 2 weeks).
3) Patient has previously received a treatment to block cytotoxic T lymphocyte (CTL)-associated protein 4 (CTLA-4), PD-1, PD-L1, or programmed death-ligand 2 (PD-L2) with the following exception: patients who have received adjuvant treatment with ipilimumab are eligible.
4) Patient is expected to require any other form of systemic or localized antineoplastic therapy while on study.
5) Patient is taking any systemic steroid therapy within one week of the first dose of study drug or is receiving any other form of immune suppressant medication. Topical steroids, such as those for the management of asthma, are permitted.
6) Patient is receiving treatment with any investigational product within 28 days (or 5 half-lives of the treatment concerned if longer than 28 days) prior to the first dose of study treatment.
7) Patient has a previous (within 5 years) or current malignancy with the exception of melanoma, and curatively treated local tumors such as carcinoma-in-situ of the breast, cervix, basal or squamous cell carcinoma of the skin, prostate cancer with Gleason grade < 6 and prostate specific antigen within normal range.
8) Patient has a concurrent illness which would preclude study conduct and assessment, including, but not limited to uncontrolled medical conditions, uncontrolled and active infection (considered opportunistic, life threatening, or clinically significant), uncontrolled risk of bleeding, or uncontrolled diabetes mellitus, or pulmonary disease (including obstructive pulmonary disease, pulmonary fibrosis, and history of symptomatic bronchospasm), or alcoholic liver disease, or primary biliary cirrhosis. Caution should be used for patients with suspected or diagnosed epilepsy.
9) Patient has any electronic stimulation device such as cardiac demand pacemaker, automatic implantable cardiac defibrillator, nerve stimulator or deep brain stimulator.
10) Patient has a skin-fold measurement of the cutaneous and subcutaneous tissue for all eligible injection sites (deltoid or quadriceps muscles with intact lymph drainage) that is > 50 mm.
11) Patient has New York Heart Association (NYHA) class III or IV heart disease, myocardial infarction within previous 6 months, a heart rate of ≤ 50 beats per minute, a history of significant cardiac abnormality and/or clinically significant abnormal baseline ECG reading, active ischemia, or any other uncontrolled cardiac condition such as angina pectoris, clinically significant arrhythmia requiring therapy including anticoagulants, uncontrolled hypertension (> 140/90 mm Hg), significant cerebrovascular disease, or congestive heart failure.
12) Patient has a history of severe hypersensitivity reaction to treatment with a mAb.
13) Patient has an active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents (patients with vitiligo or resolved childhood asthma/atopy are an exception and are not excluded for these conditions). Patients that require intermittent use of bronchodilators or local steroid injections, and patients with hypothyroidism stable on hormone replacement, are not excluded from the study.
14) Patient has received a vaccine within the 28 days prior to first dose of study treatment.
15) Patient has a known history of human immunodeficiency virus (HIV), or has any positive test for hepatitis B virus (HBV) or hepatitis C virus (HCV) indicating active acute or chronic infection.
16) Patient has a known current or recent history (within the last year) of substance abuse including illicit drugs or alcohol.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
In the run-in portion of the study- Safety and tolerability of SCIB1 in patients receiving pembrolizumab as assessed by the recording of adverse events, (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events; CTCAE v4.03), vital signs, physical examination, serum chemistry and hematology, thyroid function test, injection site assessment, urinalysis, 12-lead electrocardiogram, performance status, and concomitant medications. A tolerability questionnaire will also be completed following the electroporation procedure. The target DLT rate is 0 or 1 in 6 evaluable patients.
Full study - Outcome Response Rate measured using the RECIST 1.1 criteria. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| RECIST at screening, Day 85, Day 127 and Day 169 and then every 12 weeks until the patient stops treatment. |
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| E.5.2 | Secondary end point(s) |
i) Duration of response, measured from the point of first response
(complete response or partial response) to the date of disease progression (per
RECIST 1.1) or death due to any cause.
ii) Outcome Response Rate as determined using the modified RECIST criteria for immune based therapeutics (iRECIST; Seymour et al 2017).
iii) Progression Free Survival rate at 1 year, defined as the proportion of patients who have not progressed (per RECIST 1.1), or started new anticancer therapy, or died at a time point of 1 year from the first dose of study SCIB1 or pembrolizumab.
iv) Overall survival rate at 1 year, defined as the proportion of patients who remain alive 1 year after the first dose of SCIB1 or pembrolizumab.
v) Safety and tolerability, by measurements as defined for the run-in
cohort above.
Exploratory Endpoints:
i) Immune response (enzyme-linked immunospot [ELISPOT], lymphocyte
proliferation, and other assays) performed on peripheral blood samples
from patients at a limited number of sites.
ii) Immune biomarkers and T-lymphocyte subset analysis in tumour biopsy samples. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At screening, Day 85, Day 127 and Day 169 and then every 12 weeks until the patient stops treatment and thereafter 3 monthly intervals +/- 2 weeks for 1 year following the last dose administration of SCIB1 or pembrolizumab (whichever occurs last). |
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| 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 | Yes |
| 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Tolerability of electroporation IMP dose delivery device. |
|
| 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 | No |
| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| 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 |
|
| 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
|
| Last participant, last follow up data collected. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 13 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 13 |
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