| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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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 | 21.1 |
| 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 assess the safety and tolerability of investigational treatment combinations based on the proportion of participants with adverse events (AEs)
2.To evaluate objective response rate (ORR) as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1)
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| E.2.2 | Secondary objectives of the trial |
| 1.To evaluate the duration of response (DOR) as assessed by BICR per RECIST 1.1 |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Has histologically or cytologically confirmed melanoma.
2.Has unresectable Stage III or Stage IV melanoma, per AJCC 8th Edition Staging Criteria, not amenable to local therapy.
3.Has the presence of at least 1 measurable lesion by CT or MRI per RECIST 1.1 as confirmed by BICR.
a.Cutaneous lesions and other superficial lesions are not considered measurable lesions but may be considered as nontarget lesions.
b.If participants have only 1 measurable lesion per RECIST 1.1, the biopsy specimen should be obtained from the nontarget lesion or archival tissue. If biopsy specimen was obtained from a lone target lesion, a repeat screening CT must be obtained post-biopsy and measurable disease confirmed by BICR.
c.Lesions that are in an area that has been previously irradiated should not be considered measurable unless there has been documented growth of the lesions since the completion of radiation.
4.Has been untreated for advanced disease except as follows:
a.BRAF V600 mutation-positive melanoma may have received SOC targeted therapy as 1L therapy for advanced disease (eg, BRAF/MEK inhibitor, alone or in combination).
b.Prior adjuvant or neoadjuvant therapy, with targeted therapy or immunotherapy (such as anti-PD-1 therapy, anti-CTLA-4 or Interferon) is permitted. Prior anti-PD-1 therapy will only be permitted if relapse did not occur during treatment or within 6 months of treatment discontinuation. No other prior adjuvant or neoadjuvant therapy will be allowed.
5.Has documentation of BRAF V600-activating mutation status or consent to BRAF V600 mutation testing during Screening (participants with BRAF mutation-positive melanoma as well as BRAF wild-type or unknown are eligible).
6.Has provided a tumor biopsy.
a.Participants must submit tumor sample during Screening for confirmation of adequacy of tumor tissue at a central pathology laboratory. Participants who do not submit a tumor tissue sample will not be randomized/allocated.
b.Tumor sample should be freshly obtained (strongly preferred). In cases where newly obtained tissue is not possible to provide; an archival sample may be acceptable.
c.If a fresh tissue sample is submitted, it is preferred that the tumor biopsy is not obtained from a lone target lesion. If the biopsy specimen was obtained from a lone target lesion, a repeat screening CT must be obtained post-biopsy and measurable disease confirmed by BICR.
7.Is male or female from 18 years to 120 years at the time of signing the informed consent.
8.Has an ECOG performance status 0 to 1 (as assessed within 7 days of the first dose of study intervention).
9. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 120 days, corresponding to time needed to eliminate study intervention(s) after the last dose of study intervention:
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent
OR
Must agree to use contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause)
10.A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a WOCBP
OR
• Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) during the intervention period and for at
least 120 days, corresponding to the time needed to eliminate any study intervention(s) after the last dose of study intervention.
• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention.
- If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
11. The participant (or legally acceptable representative if applicable) provides written informed consent/assent for the study.
12. Have adequate organ function. Specimens must be collected within 7 days prior to the first dose of study intervention.
13. Has resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia and Grade 2 neuropathy). If the participant received major surgery or radiation therapy of >30 Gy, they must have recovered from the toxicity (resolved to ≤ Grade 1) and/or complications from the intervention. |
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| E.4 | Principal exclusion criteria |
1.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 before the first dose of study intervention.
Participants with asthma that require intermittent use of bronchodilators, inhaled steroids, topical steroids, or local steroid injections would not be excluded from the study.
2.Has a known additional malignancy that is progressing or requires active treatment within the past 2 years. Exceptions to the secondary malignancy exclusion include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, new nonulcerated primary melanoma <1 mm in depth with no nodal involvement, Grade 1 follicular lymphoma or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy.
3.Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated CNS metastases may participate provided they are stable (without evidence of progression by imaging prior to the first dose of study intervention as evidenced by 2 scans at least 4 weeks apart providing stability, and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases confirmed by repeat imaging, and have not required steroids for at least 14 days before study intervention. The second scan showing stability may be used as baseline scan if acquired within the Screening Phase.
Baseline MRI brain scan will be obtained for all participants. Brain CT scan should only be used when MRI is contraindicated. The second brain MRI showing stability may be used as baseline scan if acquired within the Screening Phase.
4.Has ocular or mucosal melanoma.
5.Has known hypersensitivity to active substances or any of their excipients.
6.Has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
7.Has an active infection requiring systemic therapy.
8.Has known history of human immunodeficiency virus (HIV; HIV 1/2 antibodies). No testing of HIV is required unless mandated by local health authority.
9.Has known history of hepatitis B (defined as HBsAg reactive) or known hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
10.Has a history of (noninfectious) pneumonitis that required steroids or current pneumonitis.
11.Has a history of active tuberculosis (TB; Bacillus tuberculosis).
12.A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
13.Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137, TIGIT).
14.Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to randomization.
15.Has received prior radiotherapy within 2 weeks of the first dose of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
16.Has had major surgery (<3 weeks prior to first dose of study intervention).
17.Has received a live vaccine within 30 days before the first dose of study intervention. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
18.Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention.
19.Has a history or has current evidence of any condition, therapy, or laboratory abnormality that might confound the results of this substudy, interfere with the participation for the full duration of this substudy, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
20.Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of this substudy, starting with the Screening visit through 120 days after the last dose of study intervention.
21.Has had an allogeneic tissue/solid organ transplant. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Percentage of participants who experience an adverse event (AE)
2. Percentage of participants who discontinue study treatment due to an AE
3. Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to ~28 months
2. Up to ~24 months
3. Up to ~30 months |
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| E.5.2 | Secondary end point(s) |
| 1. Duration of response (DOR) per RECIST 1.1 |
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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 | 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| first administration of the investigational agents COMBINATION in the specified melanoma population |
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| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| rolling arm, adaptive design |
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| 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 | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| 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 |
| France |
| Germany |
| Israel |
| Italy |
| New Zealand |
| Switzerland |
| United States |
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| 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
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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 | 10 |
| 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 years | 10 |
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