| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| First-line treatment of patients with PRAME-positive unresectable stage III or IV metastatic melanoma |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027481 |
| E.1.2 | Term | Metastatic melanoma |
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| 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 |
Co-primary objectives of the Phase I segment:
To characterize
•The occurrence of dose-limiting toxicity.
•The anti-PRAME humoral immune response
Co-primary objectives of Phase II segment:
To characterize
•The clinical activity in terms of objective response.
•The occurrence of dose-limiting toxicity
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| E.2.2 | Secondary objectives of the trial |
For each dose tested in the Phase I segment and for the dose selected for the phase II segment:
To characterize
•Additional clinical indicators of clinical activity in the overall study cohort and in the subgroup of patients who present the predictive MAGE-A3 gene signature.
•Additional indicators of safety.
•The specific humoral and cellular immune response elicited by the recPRAME + AS15 ASCI.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Male or female patient with histologically proven cutaneous melanoma. The stage of the disease is evaluated according to the classification of the American Joint Committee on Cancer, 2002.
Phase I segment: All melanoma patients with stage IV M1b and stage IV M1c including completely resected stage IV patients but with the exception of stage IV M1c disease with serum lactate dehydrogenase (LDH) > 1.5 x Upper Limit of Normal (ULN) or with involvement of the Central Nervous System (CNS).
Phase II segment: All melanoma patients with measurable, unresectable stage III melanoma including in-transit metastasis (with (N3) or without (N2c) nodal metastasis) and stage IV M1a melanoma. The patient should have documented progressive disease within 12 weeks of registration into the trial. Patients with resected stage IV and with stage IV M1b or M1c disease cannot be included.
2.Written informed consent for PRAME expression screening and gene profiling on resected tumor tissue and for the complete study has been obtained from the patient prior to shipment of the sample for expression testing and prior to the performance of any other protocol-specific procedure.
3.The patient is at least 18 years old at the time of signing the first Informed Consent Form.
4.The patient’s tumor shows expression of the PRAME antigen as determined by RT-PCR analysis or any updated technique on fresh tissue sample.
5.Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6.The patient has adequate bone marrow reserve, renal, adrenal and hepatic function as assessed by standard laboratory criteria and defined as (with LLN/ULN signifying the lower/upper limit of normal, respectively):
•Hemoglobin equal to or higher than LLN
•Absolute leucocytes count equal to or higher than LLN
•Absolute lymphocytes count equal to or higher than LLN
•Platelet count equal to or higher than LLN
•Serum cortisol equal to or higher than LLN
•Serum creatinine equal to or lower than ULN
•Calculated creatinine clearance > 50 ml/min
•Total bilirubin equal to or lower than 1.5 x ULN
•Lactate dehydrogenase (LDH) LDH equal to or lower than1.5 x ULN in Phase I
LDH equal to or lower than ULN in Phase II
•Alanine transaminase (ALAT) equal to or lower than 2 x ULN
•Aspartate aminotransferase (ASAT) equal to or lower than 2 x ULN
These tests musts be done no more than 3 weeks before the first ASCI administration.
7.Female patients of non-childbearing potential may be enrolled in the study. Non-childbearing potential is defined as current tubal ligation, hysterectomy, ovariectomy or post-menopause.
8.Female patients of childbearing potential may be enrolled in the study, if the patient:
•has practiced adequate contraception for 30 days prior to the study product administration, and
•has a negative pregnancy test on the day of administration, and
•has agreed to continue adequate contraception during the entire treatment period and for 2 months after the completion of the study product administration series.
A pregnancy test must be done no more than 1 week before the first ASCI administration.
9.In the view of the investigator, the patient can and will comply with all the requirements of the protocol.
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| E.4 | Principal exclusion criteria |
1.The patient has at any time received systemic chemotherapy, (bio)-chemotherapy or CTLA-4 monoclonal antibodies for metastatic disease.
Note: Isolated limb perfusion, as long as this was performed at least 4 weeks before registration into this trial, is authorized.
2.The patient is scheduled to receive any other anticancer treatment than those specified in the protocol, including but not limited to (bio)-chemotherapeutic or immunomodulating agents and radiotherapy.
3.The patient has received any cancer immunotherapy containing the PRAME antigen or any cancer immunotherapy for his/her metastatic disease.
Note: Previous adjuvant treatment with interferon, anti-CTLA-4 monoclonal antibody or a cancer immunotherapeutic (“vaccine”) containing a tumor antigen other than PRAME is allowed, if the last administration of this was given at least 8 weeks before the first ASCI injection.
4.The patient requires concomitant treatment (more than 7 consecutive days) with systemic corticosteroids or any other immunosuppressive agents.
Exception: The use of prednisone, or equivalent, at a dose of less than or equal to 0.125 mg/kg/day (absolute maximum 10 mg/day), inhaled corticosteroids or topical steroids is permitted.
5.Use of any investigational or non-registered product (drug or vaccine, except influenza vaccine) other than the study product within the 30 days preceding the first ASCI dose injection or planned use during the study period
6.The patient has (had) previous or concomitant malignancies at other sites (including carcinoma in situ), except effectively treated non-melanoma skin cancers or carcinoma in situ of the cervix or effectively treated malignancy that has been in remission for over 5 years and is highly likely to have been cured.
7.The patient has an allergy to any component of the study investigational product or has a history of previous allergic reactions to vaccinations.
8.The patient has a history of confirmed adrenal dysfunction.
9.The patient has an autoimmune disease such as, but not limited to, multiple sclerosis, lupus, and inflammatory bowel disease. Patients with vitiligo are not excluded.
10.The patient is known to be positive for the human immunodeficiency virus (HIV).
11.The patient has an uncontrolled bleeding disorder.
12.The patient has a family history of congenital or hereditary immunodeficiency.
13.The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the trial procedures.
14.The patient has other concurrent severe medical problems, unrelated to the malignancy, that would significantly limit full compliance with the study or expose the patient to unacceptable risk.
15.For female patients: the patient is pregnant or lactating.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Co-primary endpoints for the Phase I segment:
1. Dose-limiting toxicity endpoint
•Occurrence of dose-limiting toxicity will be followed in all patients during the study treatment and until the end of follow-up.
Criteria/definitions:
•An ASCI related or possibly ASCI related grade 3 or higher toxicity. Grade 3 myalgia, arthralgia, headache, fever, rigors/chills and fatigue (including lethargy, malaise and asthenia) should persist for 48 hours despite therapy in order to be considered as a dose limiting toxicity.
•An ASCI related or possibly ASCI related grade 2 or higher allergic reaction occurring within 24 hours following the ASCI administration..
•An ASCI related or possibly ASCI related decrease in renal function, with a creatinine clearance < 40 mL/min.
•An ASCI-related or possibly ASCI-related symptomatic and confirmed adrenal insufficiency.
2. Immunogenicity endpoint
•Anti-PRAME humoral immune response after ASCI dose 4 (at Visit 5).
Co-primary endpoints of the Phase II segment:
1. Clinical activity endpoint
•Clinical activity in terms of objective clinical responses (CR and PR).
2. Safety endpoint
•Occurrence of dose-limiting toxicity will be followed in all patients during the study treatment and until the end of the follow-up |
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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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunogenicity and Translational Research |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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 | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| 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 | Information not present in EudraCT |
| 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 |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
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| Last visit of the last patient participating in the trial |
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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 | 7 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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