| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 |
|
| 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 the objective response rate (ORR) as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1), with modification of measurable lesion criteria ≥0.5 cm in one dimension by magnetic resonance imaging (MRI) and allowing up to 5 intracranial target lesions (in addition to any extracranial target lesions). |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the DOR as assessed by BICR per RECIST 1.1 with modification of measurable lesion criteria ≥0.5 cm in 1 dimension by MRI and allowing up to 5 intracranial target lesions (in addition to any extracranial target lesions).
2. To evaluate brain metastasis response rate (BMRR) as assessed by BICR per RANO-BM with modification of measurable lesion criteria ≥0.5 cm in 1 dimension by MRI and allowing up to 5 intracranial target lesions (in addition to any extracranial target lesions).
3. To evaluate the BM-DOR as assessed by BICR per RANO-BM with modification of measurable lesion criteria ≥0.5 cm in 1 dimension by MRI and allowing up to 5 intracranial target lesions (in addition to any extracranial target lesions).
4. To evaluate PFS as assessed by BICR per RECIST 1.1 with modification of measurable lesion criteria ≥0.5 cm in one dimension by MRI and allowing up to 5 intracranial target lesions (in addition to any extracranial target lesions). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. AJCC Stage IV (any T, any N, M1D) melanoma
2. Has at least 1 and no more than 5 measurable brain metastasis disease lesions as defined by RECIST 1.1, confirmed by BICR:
-The measurable lesion(s) must be ≥10 mm and ≤30 mm in greatest diameter
- Prior SRT in ≤3 MBM, if there has been complete recovery and there are no neurologic sequelae. Growth or change in any lesion previously irradiated will not be considered measurable for study eligibility but is allowable
- History of excision of ≤2 melanoma brain metastases if there has been complete recovery and there are no neurologic sequelae. Regrowth in cavity of any previously excised lesion will not be considered measurable for study eligibility but is allowable
- The CIV will confirm this eligibility criterion prior to treatment
randomization/allocation
3. Has provided a tumor biopsy of an extracranial and/or intracranial lesion to confirm histologic or cytologic diagnosis and for biomarker analysis
a) It is strongly preferred that if extracranial disease is present, a tumor sample should be freshly obtained. In cases where newly obtained tissue is not possible to provide or if only intracranial disease is present; an archival sample may be acceptable after discussion with the Sponsor. For participants who have been treated with PD-1/L1 therapy, archival samples that have been obtained after treatment on a PD-1/L1 agent are preferred but not required
b) If a fresh tissue sample is submitted, it is preferred that the tumor biopsy is not obtained from a lone extracranial or intracranial target lesion. If the biopsy specimen was obtained from a lone target lesion, a repeat screening MRI (intracranial lesion) or CT (extracranial lesion) must be obtained postbiopsy and measurable disease confirmed by BICR
4. Neurologically asymptomatic from brain metastases and must not have required or received systemic corticosteroid therapy in the 10 days prior to beginning study intervention
5. Able to undergo MRI with Gadolinium contrast agent
6. Has not received more than 3 lines of therapy for their metastatic melanoma, inclusive of an adjuvant therapy regimen
7. Allowable prior systemic therapy: Previous treatment for unresectable or metastatic disease may include approved adjuvant regimens, IFN-α, anti-PD-1/PD-L1, anti- CTLA-4, and approved molecularly targeted agents. Steroids for physiological replacement are allowed
- Participants who have received anti-PD-1/PD-L1 therapy must have received at least 2 prior doses of an anti-PD-1/L1 mAb
8. Is male or female, from 18 to 120 years of age inclusive, at the time of providing documented informed consent
9. Has an ECOG performance status 0 to 1
10. Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
Male participants are eligible to participate if they agree to the following during treatment with the investigational agents
- 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)
11. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
-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
* 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, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive
- The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy
12. The participant (or legally acceptable representative if applicable) has provided documented informed consent/assent for the study
13. Has adequate organ function. Specimens must be collected within 7 days prior to the first dose of study intervention. Laboratory samples collected within 3 days prior to the first dose of study intervention need not be repeated on C1D1; results must be known and acceptable prior to dosing |
|
| 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 10 days before the first dose of study intervention (based upon 5 times the expected half-life of dexamethasone). Participants with asthma that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study
2. Current or history of known leptomeningeal involvement. Participants with suspected LMD by clinical symptoms only (without imaging findings) should undergo CSF analysis to substantiate the diagnosis of LMD unless CSF analysis is contraindicated
3. Previous stereotactic or highly conformal radiotherapy within 2 weeks before the start of dosing for this study
4. Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study drug
5. Untreated or unresolved intracranial hemorrhage from CNS metastasis of more than punctate size on MRI assessment obtained within 28 days prior to study enrollment
6. Has any active infection requiring systemic therapy
7. 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
8. Has ocular melanoma
9. Has known hypersensitivity to active substances or any of their excipients including previous clinically significant hypersensitivity reaction to treatment with another mAb
10. 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
11. Has known history of human immunodeficiency virus (HIV; HIV 1/2 antibodies). No testing of HIV is required unless mandated by local health authority
12. Has known history of hepatitis B (defined as HBsAg reactive) or known hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection
13. Has a history of (noninfectious) pneumonitis that required steroids or current pneumonitis
14. Has received prior systemic anticancer therapy including investigational agents within 4 weeks prior to randomization/allocation
15. Has resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia). 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 prior to starting study intervention
16. History of whole brain irradiation
17. Prior treatment with anti-PD-L2, anti-CD137, any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways (except for study interventions noted in inclusion criteria)
18. Has received prior radiotherapy within 2 weeks of first dose of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis
19. Has had major surgery (<3 weeks prior to first dose of study intervention)
20. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention. Administration of killed vaccines are allowed
21. 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
22. Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study
23. Has a history or has current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the substudy, interfere with the participation for the full duration of the substudy, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
24. Has had an allogeneic tissue/solid organ transplant |
|
| 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) |
|
| 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 |
|
| E.5.2 | Secondary end point(s) |
1. Duration of response (DOR) per RECIST 1.1
2. Brain metastasis response rate (BMRR) per Response Assessment in Neuro- Oncology Brain Metastases (RANO-BM)
3. Brain metastasis duration of response (BM-DOR) per RANO-BM
4. Progression-free survival (PFS) per RECIST 1.1 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Up to ~30 months
2. Up to ~30 months
3. Up to ~30 months
4. Up to ~30 months |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 |
|
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Rolling arm, adaptive design |
|
| 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 | 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| 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 |
| Israel |
| South Africa |
| United States |
| France |
| Poland |
| Spain |
| Switzerland |
| Greece |
| Italy |
| Hungary |
| Russian Federation |
|
| 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
|
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned days | 2 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| 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 |
Print
