Cutaneous Melanoma, Mucosal Melanoma, Uveal Melanoma
Conditions
Brief summary
This is a first-in-human, multi-center clinical study to determine the safety, Maximum Tolerated Dose (MTD) and/or Optimal Biological Dose (OBD) as well as the optimal schedule for intravenous (IV) and/or subcutaneous (SC) administrations of RO7293583 with or without obinutuzumab pretreatment, in participants with unresectable metastatic TYRP1-positive melanomas who have progressed on standard of care (SOC) treatment, are intolerant to SOC, or are non-amenable to SOC. This study will include an initial single participant dose-escalation part one followed by a multiple participant dose-escalation part two with the possibility of expansion.
Interventions
DRUGAdalimumab
If implemented, it will be given as a single dose approximately 6 days prior to the first dose of RO7293583.
DRUGRO7293583
RO7293583 will be administered at a dose and per schedule as specified for the respective cohort.
DRUGTocilizumab
Tocilizumab will be administered as required for the management of severe cytokine release syndrome (CRS).
DRUGObinutuzumab
If implemented, it will be given either on D-7 or D-7 and D-6.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants with unresectable stage III or stage IV cutaneous melanoma or participants with unresectable, metastatic uveal or mucosal melanoma for whom SOC is not available or who are intolerant or non-amenable to SOC. * Participants with cutaneous melanoma need to have known BRAF status. * Radiologically measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. * Availability of a representative tumor specimen that is suitable for determination of TYRP1 status by means of central testing. * For participants in Part II, willingness to provide mandatory on-treatment biopsies. * Life expectancy (in the opinion of the Investigator) of ≥12 weeks. * Eastern Cooperative Oncology Group (ECOG) performance status 0-1. * Absence of rapid disease progression, threat to vital organs or non-irradiated lesions \> 2 cm in diameter at critical sites. * All acute toxic effects of any prior radiotherapy, chemotherapy, targeted or checkpoint inhibitor therapy, or surgical procedure must have resolved to Grade ≤1 or returned to baseline, except for alopecia (any grade), for Grade 2 clinically controlled sequelae of immune-related toxicities related to checkpoint inhibitor therapy like adrenal insufficiency and hypopituitarism, and for Grade 2 peripheral neuropathy. * Adequate hematological, liver and renal function.
Exclusion criteria
* Participants with a history or clinical evidence of central nervous system (CNS) primary tumors or metastases including leptomeningeal metastases unless they have been previously treated, are asymptomatic, and have had no requirement for steroids or enzyme-inducing anticonvulsants in the last 14 days before screening. * Participants with another invasive malignancy in the last 2 years. * Active, acute, or chronic inflammatory diseases of the skin affecting more than 5% of the body surface area. History of Stevens-Johnson syndrome, toxic epidermal necrolysis, or drug rash with eosinophilia and systemic symptoms. * Participants with defects in the Bruch's membrane of the eye or at risk of such defects. Participants with a history of recurrent uveitis or medical conditions that are associated with frequent uveitis. * History of or existing damage to inner ear. * Uncontrolled hypertension. * Significant cardiovascular disease. * Known active or uncontrolled bacterial, viral, fungal, mycobacterial, parasitic or other infection, or any major episode of infection requiring treatment with IV antibiotics or hospitalization within 4 weeks prior to the start of drug administration. * Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug. * Major surgery or significant traumatic injury \<28 days prior to the first RO7293583 administration or anticipation of the need for major surgery during study treatment. * Last dose of checkpoint inhibitors, targeted therapies, chemotherapy, immunostimulating or immunosuppressive therapy or other investigational drug \<28 days prior to the first RO7293583 administration. * Prior treatment with a T-cell engaging drug Specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Dose-Limiting Toxicities (DLTs) | From Day 1 of Cycle 1 up to Day 1 of Cycle 3 (each cycle is 21 days) | Dose-Limiting Toxicities (DLTs) were reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0), except for Cytokine release syndrome (CRS), which will be graded based on the American Society for Transplantation and Cellular Therapy (ASTCT) criteria. |
| Percentage of Participants with Adverse Events (AEs) | Baseline up to 60 days after last RO7293583 treatment (up to 14 months) | An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change from Baseline in RO7293583 ADA Titer | From baseline until 60 days after last RO7293583 dose (up to 14 months). | — |
| Time of Maximum Concentration (Tmax) of RO7293583 | Up to 14 months | — |
| Minimum Concentration (Cmin) of RO7293583 | Up to 14 months | — |
| SC Bioavailability (F) of RO7293583 | Up to 14 months | — |
| Clearance (CL) or Apparent Clearance (CL/F) of RO7293583 | Up to 14 months | — |
| Volume of Distribution at Steady State (Vss) of RO7293583 | Up to 14 months | — |
| Area Under the Curve (AUC) of RO7293583 | Up to 14 months | — |
| Objective Response Rate (ORR) | Baseline up to 13 months | ORR is defined as the percentage of participants with confirmed objective response (OR). Confirmed OR is defined as complete response (CR) or partial response (PR) on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. |
| Disease Control Rate (DCR) | Baseline up to 13 months | DCR is defined as the percentage of participants with CR, PR, or stable disease (SD). Per RECIST v1.1, CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression, taking as reference the smallest sum on study. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline, or the appearance of one or more new lesions. |
| Duration of Response (DOR) | Baseline up to 13 months | DOR is defined as the time from the first occurrence of documented OR to disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline; or the appearance of one or more new lesions. |
| Progression-Free Survival (PFS) | Baseline up to 24 months. | PFS is defined as the time from Cycle 1, Day 1 to the first occurrence of disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study including baseline; or the appearance of one or more new lesions. |
| Overall Survival (OS) | Baseline up to 24 months. | OS is defined as the time from Cycle 1, Day 1 to death from any cause. |
| Maximum Concentration (Cmax) of RO7293583 | Up to 14 months | — |
| Percentage of Participants with Anti-Drug Antibodies (ADAs) to RO7293583 | From baseline until 60 days after last RO7293583 dose (up to 14 months). | — |
Countries
Australia, Belgium, Canada, Denmark, Spain, United States
Outcome results
None listed