| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with advanced Melanoma |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10053571 |
| E.1.2 | Term | Melanoma |
| E.1.2 | System Organ Class | 100000004864 |
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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 |
1. To evaluate progression-free-survival (PFS) in patients with advanced MEL receiving either Pembrolizumab or IPI.
2. To evaluate overall survival (OS) in patients with advanced MEL receiving either Pembrolizumab or IPI.
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| E.2.2 | Secondary objectives of the trial |
1. To evaluate safety, tolerability and adverse experience profile of Pembrolizumab versus IPI.
2. To evaluate overall response rate (ORR) in patients with advanced MEL receiving either Pembrolizumab or IPI.
3. To evaluate OS, PFS and ORR in a subgroup of patients with high PD-L1 expression level receiving either Pembrolizumab or IPI.
4. To further characterize the pharmacokinetics (PK) of Pembrolizumab
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Merck will conduct Future Biomedical Research on DNA (blood and tissue) specimens collected during this clinical trial.
Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overeaching goal is to use such information to develop safer, more effective drugs, and/or ensure that subjects receive the correct dose of the correct drug at the correct time. |
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| E.3 | Principal inclusion criteria |
1) Patient must have a histologically confirmed diagnosis of unresectable stage III or metastatic MEL not amenable to local therapy.
•Patient may not have a diagnosis of uveal or ocular melanoma.
•Patients who have not received prior systemic treatment (excluding adjuvant or neoadjuvant therapy) for MEL (first line) or who have received one prior systemic treatment (excluding adjuvant or neoadjuvant therapy) for MEL (second line) are both eligible. However, the enrollment of either first line or second line patients will be limited to approximately 387 patients (60% of the total patients). After this limit is reached for either of the groups, only patients from the other group will be enrolled.
•Patients must have testing for a BRAF mutation prior to study entry. Patients with BRAF V600E mutant melanoma may have received prior BRAF inhibitor therapy as first-line systemic therapy and be eligible for this study as second line treatment.
At the discretion of the investigator, patients with BRAF V600E mutant melanoma who have NOT received a BRAF inhibitor are also eligible for this study as first line treatment if they meet the following additional criteria:
•LDH < local ULN
•No clinically significant tumor related symptoms in the judgment of the investigator
•Absence of rapidly progressing metastatic melanoma in the judgment of the investigator
2) Patient is male or female and ≥18 years of age on day of signing informed consent, either by the patient or a parent or legal guardian.
3) Patient must have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale (Appendix 6.4).
4) Patient must have adequate organ function.
5) Patient has a tumor sample (archival or newly obtained biopsy) that is adequate for PD-L1 assessment prior to randomization. Patients must submit the tumor sample during screening for PD-L1 expression testing at a central pathology laboratory. Patients will be eligible to participate regardless of the level of PD-L1 expression, but will be stratified by PD-L1 expression level (high or low PD-L1 expression level) at the time of randomization. Patients who do not submit a sample adequate for PD-L1 determination will not be randomized. Patients with an inadequate archival sample may obtain a new biopsy and patients with an inadequate newly obtained biopsy may undergo re biopsy at the discretion of the investigator.
6) Female patient of childbearing potential has a negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the patient to be eligible.
7) Female patients enrolled in the study, who are not free from menses for >18 months, post hysterectomy/oophorectomy, or surgically sterilized, must be willing to use either 2 adequate barrier methods or a barrier method plus a hormonal method of contraception to prevent pregnancy or to abstain from heterosexual activity throughout the study, starting with Visit 1 through 120 days after the last dose of study therapy. Approved contraceptive methods include 2 of the following barrier methods or one barrier method combined with a hormonal contraceptive: intra uterine device, diaphragm with spermicide, cervical cap with spermicide, male condoms, or female condom with spermicide. Spermicides or condoms alone are not an acceptable method of contraception.
Male patients must agree to use an adequate method of contraception starting with the first dose of study drug through 120 days after the last dose of study therapy.
8) The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
9) Patient has at least one measurable lesion per RECIST criteria on imaging studies (CT or MRI). Cutaneous lesions and other superficial lesions that are detectable only by physical examination are not considered measurable lesions for the purposes of this protocol, but may be considered as non-target lesions.
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| E.4 | Principal exclusion criteria |
1 Patient had prior treatment with IPI or other anti-CTLA-4 agent, any anti-PD-1, anti-PD-L1, or anti- PD-L2 agent.
2 Patient who has had chemotherapy, radioactive, or biological cancer therapy within four weeks prior to the first dose of study drug, or who has not recovered to CTCAE Grade 1 or better from the AEs due to cancer therapeutics administered more than four weeks earlier.
3 Patient is currently participating or has participated in a study of an investigational agent or using an investigational device within 30 days of the first dose of study drug. (A patient in the Survival Follow up phase of an investigational agent where no further treatment is expected is eligible).
4 Patient is expected to require any other form of systemic or localized antineoplastic therapy while on study.
5 Patient is on any systemic corticosteroid therapy within one week before the planned date for first dose of randomized treatment or on any other form of immunosuppressive medication.
6 Patient has a history of a malignancy (other than the disease under treatment in the study) within 5 years prior to first study drug administration. This should exclude adequately treated Stage 1 or Stage 2 basal/squamous cell carcinoma of the skin, carcinoma in situ of the cervix or breast, or other in situ cancers. Shorter intervals can be considered after discussion with Sponsor.
7 Patient has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by MRI for at least four weeks prior to the first dose of study drug), have no evidence of new or enlarging brain metastases and are off systemic steroids for at least two weeks.
8 Patient previously had a severe hypersensitivity reaction to treatment with another mAb.
9 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 would be an exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Patients with hypothyroidism stable on hormone replacement will not be excluded from the study.
10 Patient has an active infection requiring systemic therapy.
11 Patient has known history of Human Immunodeficiency Virus (HIV) (HIV ½ antibodies).
12 Patient has a known history of or is positive for Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA [qualitative] is detected).
13 Patient has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator.
14 Patient has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
15 Patient is, at the time of signing informed consent, a regular user (including “recreational use”) of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol).
16 Patient is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.
17 Patient has received a live vaccine within 30 days prior to first dose.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoint for the trial has been reached.
The primary endpoints of this study were progression-free survival (PFS), defined as the time from randomization to the first documented disease progression (based on blinded independent central review using RECIST 1.1) or death due to any causes, whichever occurs first, and overall survival (OS), defined as the time from randomization to death due to any cause. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
PFS: Interim analysis 1 and 2
OS : Interim analysis 1, 2 and final analysis |
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| E.5.2 | Secondary end point(s) |
| Overall response rate (ORR), defined as the proportion of the patients in the analysis population who have best response as complete response (CR) or partial response (PR). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 44 |
| 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 |
| Austria |
| Belgium |
| Canada |
| Chile |
| Colombia |
| France |
| Germany |
| Israel |
| Netherlands |
| New Zealand |
| Norway |
| Spain |
| Sweden |
| United Kingdom |
| United States |
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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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 27 |
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