| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with previously untreated, unresectable or metastatic (advanced) melanoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with untreated advanced skin cancer |
|
| 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 | 10027481 |
| E.1.2 | Term | Metastatic melanoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| The primary objective is to investigate the efficacy of IO102-IO103 in combination with pembrolizumab (compared with pembrolizumab alone) in terms of PFS. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives are to further explore the efficacy of IO102-IO103 in combination with pembrolizumab compared with pembrolizumab alone in terms of ORR, DRR, CRR and OS (see Section 6.2 and Section 17 of the protocol for the full list of secondary efficacy endpoints) and to investigate the safety and tolerability of the treatment. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically or cytologically confirmed stage III (unresectable) or stage IV melanoma., as per American Joint Committee on Cancer 8th edition guidelines not amenable to local therapy (90).
2. Patients are treatment naive, that is, no previous systemic anticancer therapy for unresectable or metastatic melanoma. For clarification, the following patients are eligible:
a. Patients with BRAFV600 mutation-positive melanoma are eligible if treatment naive and without rapidly progressive disease as per investigator assessment.
b. Patients who have received previous adjuvant and/or neoadjuvant therapy with targeted therapy or immune therapy are eligible if administered the last dose at least 6 months before inclusion in this trial (randomization), and if relapse did not occur during active treatment or within 6 months of treatment discontinuation.
3. ECOG performance status score 0 or 1 assessed 7-10 days before randomization
4. Life expectancy of >24 weeks at the time of signed informed consent per investigator assessment.
5. At least 1 measurable lesion (not a cutaneous lesion) according to RECIST v1.1 and confirmed by IRC.
6. Provision of archival (max 3 months), or newly acquired biopsy tissue not previously irradiated, and blood at screening for biomarker assessments. FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
Note:
• Use of archival tissue >3 months old, may be considered after communication with and agreement by the Sponsor.
• If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date slides are cut (details pertaining to tumor tissue submission can be found in the Lab Manual).
7. Adequate organ function as defined by:
a. Haematology:
i. Absolute neutrophil count ≥1500/μL or ≥1.5 × 10^9/L
ii. Platelets ≥100,000/μL or ≥100 × 10^9/L
iii. Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L
b. Renal:
i. Creatinine ≤1.5 × upper limit of normal (ULN), or
ii. Measured or calculated creatinine clearance (CrCl) ≥60 mL/min for patients with creatinine levels > 1.5 × institutional ULN; Glomerular filtration rate can also be used in place of creatinine or CrCl
c. Hepatic:
i. Total bilirubin ≤1.5 × ULN or direct bilirubin ≤ ULN for patients with total bilirubin levels between 1.5 × ULN and ≤3 × ULN
ii. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × ULN (≤5 × ULN for patients with liver metastases)
iii. Alkaline phosphatase ≤2.5 × ULN
d. Endocrine:
i. Thyroid stimulating hormone (TSH) within normal limits, or
ii. Total triiodothyronine (T3) is within normal limits, or
iii. Free T3 and free thyroxine (T4) are within the normal limits
e. Coagulation:
i. International randomized ratio, prothrombin time (PT) or activated PT time (aPTT) ≤1.5 × ULN unless patient is receiving anticoagulant therapy if PT or aPTT is within therapeutic range of intended use of anticoagulants
8. Has recovered from major surgery or radiation therapy–(> 30 Gray [Gy]) induced AEs.
9. AEs from previous anticancer therapies or interventions have resolved to at least Grade 1 or
baseline value from screening (except for alopecia). Patients with Grade </-2 neuropathy may
be eligible. Patients with endocrine-related AEs Grade </-2 requiring treatment or hormone
replacement may be eligible.
10. Patients are able and willing to provide written informed consent for the trial in accordance with ICH-GCP and local legislation before admission to the trial. The patient may also provide consent for future biomedical research; however, the patient may still participate in the trial without participating in future biomedical research.
11. Aged ≥18 years on day of signing informed consent.
12. A woman is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
a. Not a woman of childbearing potential (WOCBP)
b. A WOCBP who agrees to follow contraceptive guidance to 120 days after last dose.
13. Patients who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis b virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load before randomization.
Note: Patients should remain on anti-viral therapy throughout trial treatment and follow local guidelines for HBV anti-viral therapy after completion of trial treatment. Hepatitis B screening tests are not required unless:
• Known history of HBV infection
• As mandated by local health authority
14. Patients with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening. Note: Patients must have completed curative anti-viral therapy at least 4 weeks before randomization. Hepatitis C screening tests are not required unless:
a. Known history of HCV infection
b. As mandated by local health authority.
|
|
| E.4 | Principal exclusion criteria |
1. Uveal/ocular melanoma
2. Patients with known or suspected central nervous system (CNS) metastases or with the CNS as the only site of active disease are excluded with the following exception:
• Patients with controlled (stable) brain metastases will be allowed to enroll
3. Patient has received previous radiotherapy within 2 weeks of start of trial treatment (visit 2). A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
4. Patients with BRAFV600-positive disease who are experiencing rapidly progressing disease and/or have received standard first-line therapy with BRAF and/or MEK inhibitor for unresectable or metastatic disease.
5. Active known or suspected autoimmune disease that has required systemic treatment in the past 2 years.
6. Presence of other primary malignancies, with the exception of nonmelanoma skin cancer, carcinoma in situ or stage I nonulcerative melanoma, in situ cervical cancer, in situ breast cancer, and prostate cancer for patients who are receiving androgen deprivation therapy only. Other primary malignancies are only acceptable if there is no ongoing active disease and no biomarker indication of active disease.
7. Active infection requiring systemic therapy
8. History of active tuberculosis
9. Active noninfectious pneumonitis/interstitial lung disease or a history of noninfectious pneumonitis/interstitial lung disease which required systemic steroids
10. History of HIV infection. HIV testing is not required unless mandated by local health authorites.
11. Concurrent active hepatitis B virus (defined as HBsAg positive and/or detectable HBV DNA) and /or concurrent Hepatitis C Virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection.
12. Received a live or live-attenuated vaccine within 30 days before the first dose of trial treatment. Administration of killed vaccines, mRNA based (e.g., covid-19) and vector based vaccines are allowed.
13. Patient suffering from symptoms related to COVID-19 infection, who does not have immunity from vaccination or previous infection, and who cannot provide a negative PCR COVID-19 test from the last 72 hours.
14. Known or suspected hypersensitivity to components of IMP or PD-1 inhibitor.
15. Known adrenal insufficiency function (that is, basal cortisol level <140 nmol/L or < 5 μg/dL
16. Received any of the following medications or procedures:
a. Within 2 weeks before time of treatment initiation:
i. Systemic or topical corticosteroids at immunosuppressive doses >10 mg/day of hydrocortisone or >5 mg/day of prednisone equivalent. Inhaled or topical steroids and adrenal replacement steroid doses >5 mg/day prednisone equivalent are permitted in the absence of active autoimmune disease.
ii. Palliative radiation or gamma knife radiosurgery
iii. Treatment with complementary medications (e.g., herbal supplements or traditional Chinese medicines) to treat the disease being studied. Such medications are permitted if they are used as supportive care.
b. Within 4 weeks before time of treatment initiation:
i. Allergen hyposensitization therapy
ii. Growth factors
iii. Major surgery or the patient has not recovered from surgery at the time of treatment
initiation
17. In the opinion of the investigator, the patient is unlikely to comply with the clinical trial protocol or has a known psychiatric or substance abuse disorder.
18. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient’s participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
19. Patients in close affiliation with the trial personnel, patients being a member of the clinical trial personnel, or being an employee of the sponsor or a clinical research organization involved in the trial.
20. Patients who are institutionalized by court order or by the local authority.
21. A WOCBP who is breastfeeding or pregnant.
22. Patients who have had an allogenic tissue/solid organ transplant.
23. Is currently participating in the active treatment phase of another clinical trial or has participated in a trial of an investigational agent or has used an investigational device within 6 months before the first dose of trial treatment.
24. Has received any previous therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or coinhibitory TCR (e.g., CTLA-4, OX-40, CD137) within 6 months before randomization.
25. Has received any previous therapy with IO102 and/or IO103.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS, defined as the time from randomization to the first documented disease progression (based on Independent Review Committee in accordance with RECIST v1.1) or death from any cause. Patients who have not progressed or died at the time of analysis will be censored at the date of assessment from their last disease assessment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints:
• Overall Response Rate (ORR) defined as the percentage of patients achieving a confirmed partial response (PR) or confirmed complete response (CR). ORR will be determined by the IRC in accordance with RECIST v1.1.
• Durable Response Rate (DRR), defined as the percentage of patients achieving a PR or CR >182 days. DRR will be determined by the IRC in accordance with RECIST v1.1
• Complete Response Rate (CRR) which will be determined by the IRC in accordance with RECIST v1.1
• OS, defined as the time from randomization until death from any cause. Patients not known to have died will be censored at the date they were last known to be alive
Other secondary endpoints:
• Duration of Response (DoR) based on IRC
• Time to Response (TTR) based on IRC
• Time to Complete Response (TTCR) based on IRC
• Disease Control Rate (DCR) based on IRC
• PFS and ORR, which will be assessed by the investigator according to RECIST v1.1
• Progression-free rate at 6 months (PFR6) based on IRC
• Progression-free rate at 12 months (PFR12) based on IRC
Safety and tolerability endpoints:
• Incidence of AEs
• Incidence of SAEs
• Incidence of treatment-related AEs
• Incidence of treatment-related SAEs
• Incidence of AEs causing discontinuation of trial treatment
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Per statement for each endpoint |
|
| 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 | 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) | 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 | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Pembrolizumab given as background treatment |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 37 |
| 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 |
| Czechia |
| Denmark |
| Germany |
| Italy |
| Netherlands |
| Spain |
| United States |
| France |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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