A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Melanoma (Morpheus-Melanoma)

Study Identifier:
BO43328
CT.gov Identifier:
NCT05116202
EudraCT Identifier:
2021-002147-29
EU Trial (CTIS) Number:
N/A
Study Contact Information:
(210) 593-5651 or [email protected]
Study Complete

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Study Summary

To evaluate the efficacy, safety, and pharmacokinetics of treatment combinations in cancer immunotherapy (CIT)-naive participants with resectable Stage III melanoma (Cohort 1) and in participants with Stage IV melanoma (Cohort 2).

To evaluate the efficacy and safety of multiple treatment combinations in patients with melanoma

To evaluate tobemstomig, tobemstomig plus tiragolumab and atezolizumab plus tiragolumab versus nivolumab (anti-PD-1 monoclonal antibody) plus ipilimumab in stage III melanoma

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Melanoma
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
Phase I/II
Sex
Female & Male
Age
18 - 64 Years
Study Drug
Drug: Arm
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Drug: Experimental: Cohort 1: RO7247669 2100 mg
Drug: Experimental: Cohort 1: + Atezolizumab + Tiragolumab
Drug: Experimental: Cohort 1: RO7247669 2100 mg + Tiragolumab
Drug: Experimental: Cohort 1: RO7247669 600 mg
Drug: Experimental: Cohort 1: RO7247669 600 mg + Tiragolumab
Drug: Drug: RO7247669 600 mg
Drug: Eligible patients were randomized to receive one of the following treatments every 3weeks for 6weeks in the neoadjuvant setting (that is, two doses): tobemstomig 2,100mg; tobemstomig 2,100mg plus tiragolumab 600mg; atezolizumab 1,200mg plus tiragolumab 600mg; or nivolumab 3mgkg1 plus ipilimumab 1mgkg1. TLND occurred at week 7, and pathological response was evaluated according to International Neoadjuvant Melanoma Consortium (INMC) criteria
Study Status
Indicates the current recruitment status or the expanded access status
Study Complete

Requirements information
Inclusion criteria
  • Inclusion Criteria for Cohort 1:
  • ECOG performance status (PS) of 0 or 1
  • Histologically confirmed resectable Stage III melanoma according to AJCC-8 and no history of in-transit metastases within the last 6 months
  • Fit and planned for CLND
  • Measurable disease according to RECIST v1.1
  • Availability of a representative tumor specimen
  • Adequate hematologic and end-organ function
  • For patients receiving therapeutic anticoagulation: stable anticoagulant regimen
  • Negative HIV test, negative hepatitis B surface antibody (HBsAb), and negative total hepatitis B core antibody (HBcAb) test, and negative hepatitis C virus (HCV) at screening. Patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count >= 200/μL, and have an undetectable viral load.
  • Inclusion Criteria for Cohort 2:
  • ECOG PS of 0 or 1
  • Life expectancy >= 3 months, as determined by the investigator
  • Histologically confirmed Stage IV (metastatic) cutaneous melanoma according to AJCC-8
  • Disease progression during or following at least one but no more than two lines of treatment for metastatic disease
  • Measurable disease according to RECIST v1.1
  • Availability of a representative tumor specimen
  • Adequate hematologic and end-organ function
  • For patients receiving therapeutic anticoagulation: stable anticoagulant regimen
  • Negative HIV test, negative hepatitis B surface antibody (HBsAb), and negative total hepatitis B core antibody (HBcAb) test, and negative hepatitis C virus (HCV) at screening. Patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count >= 200/μL, and have an undetectable viral load.
  • Eligible patients were 18 years of age or older with resectable stage III melanoma with measurable lymph node metastases (per RECIST version 1.1) that could be biopsied and had an ECOG performance status of 0 or 1
  • Patients must have met all of the following criteria to qualify:
  • Signed informed consent form
  • Aged 18 years or older at the time of signing the informed consent form
  • ECOG performance status of 0 or 1
  • Ability to comply with the protocol, in the investigator’s judgment
  • Histologically confirmed resectable stage III melanoma (T: T0, Tx or T1–4; N: cN1–3 or pN1b/2b/3b; M: M0 according to the American Joint Committee on Cancer, 8th Edition (AJCC-8)26 and no history of in-transit metastases within the last 6 months)
  • Patients may have presented with primary melanoma with concurrent regional nodal metastasis or a history of primary melanoma or unknown primary melanoma with clinically detected regional nodal recurrence and may have belonged to any of the following groups:
  • ∘ Primary cutaneous melanoma with concurrent clinically/radiologically apparent regional lymph node metastases
  • ∘ Clinically/radiologically detected recurrent melanoma at the proximal regional lymph node(s) basin
  • ∘ Clinically/radiologically detected nodal melanoma (if single site) arising from an unknown primary
  • Fit and planned for TLND (as assessed by the surgeon prior to randomization according to local guidelines)
  • Measurable disease (at least one target lesion) according to RECIST version 1.1
  • ∘ At least one macroscopic lymph node metastasis (measurable according to RECIST version 1.1) to be biopsied
  • Availability of a representative tumor specimen that is suitable for biomarker testing via central laboratory
  • ∘ Baseline tumor tissue samples were collected from all patients by biopsy of a metastatic lymph node at screening.
  • ∘ In addition, archival primary tumor tissue was submitted from all patients. In exceptional cases where no archival primary tissue was available (for example, for patients with unknown primary tumor), enrollment was permitted. For archival tissue, a formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) with sufficient size and tumor content representation, preferably including the invasive margin or, if available, at least 16 slides containing unstained, freshly cut, serial sections, was submitted along with an associated pathology report.
  • Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment:
  • ∘ Absolute neutrophil count ≥1.5 × 109 per liter (1,500 per microliter)
  • ∘ Lymphocyte count ≥0.5 × 109 cells per liter (500 per microliter)
  • Borderline machine lymphocyte counts may have been confirmed by a manual count.
  • ∘ Platelet count ≥100 × 109 per liter (100,000 per microliter)
  • ∘ Hemoglobin ≥90 g l−1 (9 g dl−1)
  • ∘ Aspartate transferase, alanine aminotransferase and alkaline phosphatase ≤2.5× upper limit of normal (ULN)
  • ∘ Total bilirubin ≤1.5× ULN, with the following exception:
  • ▪ Patients with known Gilbert disease: bilirubin level ≤3× ULN
  • ∘ Creatinine ≤1.5× ULN or creatinine clearance ≥30 ml min−1 (calculated using the Cockcroft–Gault formula)
  • ∘ Serum albumin ≥25 g l−1 (2.5 g dl−1)
  • ∘ For patients not receiving therapeutic anticoagulation: international normalized ratio and activated partial thromboplastin time ≤1.5× ULN
  • For patients receiving therapeutic anticoagulation: stable anticoagulant regimen (that is, no new thrombosis, thromboembolic event or bleeding episode within 3 months prior to study treatment start)
  • Negative HIV test at screening, with the following exception: Patients with a positive HIV test at screening were eligible provided they were stable on antiretroviral therapy, had a CD4 count ≥200 per microliter and had an undetectable viral load.
  • ∘ Patients without a prior positive HIV test result underwent an HIV test at screening, unless not permitted per local regulations.
  • Negative hepatitis B surface antibody and negative total hepatitis B core antibody (HBcAb) test at screening. If a patient had a negative hepatitis B surface antigen test and a positive total HBcAb test at screening, a hepatitis B virus (HBV) DNA test was also performed to rule out active HBV.
  • Negative hepatitis C virus (HCV) antibody test at screening or positive HCV antibody test followed by a negative HCV RNA test at screening
  • ∘ The HCV RNA test was performed only for patients who had a positive HCV antibody test.
  • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures
  • For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures and agreement to refrain from donating sperm
Exclusion criteria
  • Exclusion Criteria for Cohort 1:
  • Mucosal, uveal and acral lentiginous melanoma
  • Distantly metastasized melanoma
  • History of in-transit metastases within the last 6 months
  • Prior radiotherapy
  • Prior immunotherapy, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies, and other systemic therapy for melanoma
  • Treatment with investigational therapy within 28 days prior to initiation of study treatment
  • Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment
  • Prior allogeneic stem cell or solid organ transplantation
  • Known immunodeficiency or conditions requiring treatment with systemic immunosuppressive medication, or anticipation of need for systemic immunosuppressant medication during study treatment
  • Active or history of autoimmune disease or immune deficiency
  • Exclusion Criteria for Cohort 2:
  • Mucosal and uveal melanoma
  • Treatment with investigational therapy within 28 days prior to initiation of study treatment
  • Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment
  • Prior allogeneic stem cell or solid organ transplantation
  • Known immunodeficiency or conditions requiring treatment with systemic immunosuppressive medication, or anticipation of need for systemic immunosuppressant medication during study treatment
  • Active or history of autoimmune disease or immune deficiency
  • Symptomatic, untreated, or progressing CNS metastases
  • Active or history of carcinomatous meningitis/leptomeningeal disease
  • Uncontrolled tumor-related pain
  • Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures
  • Uncontrolled or symptomatic hypercalcemia
  • Patients were excluded from the trial if they had a history of in-transit metastases within the last 6months or had received prior radiotherapy or systemic cancer therapy for their disease.
  • Patients who met any of the following criteria were excluded from study entry:
  • Mucosal and uveal melanoma
  • Acral lentiginous melanoma is excluded.
  • Distantly metastasized melanoma
  • History of in-transit metastases within the last 6months
  • Prior radiotherapy
  • Prior immunotherapy, including anti-CTLA-4, anti-PD-1 and anti-PD-L1 therapeutic antibodies, and other systemic therapy for melanoma
  • Treatment with investigational therapy within 28days prior to initiation of study treatment
  • Treatment with systemic immunostimulatory agents (including, but not limited to, IFN and interleukin-2) within 4weeks or five drug-elimination half-lives (whichever is longer) prior to initiation of study treatment
  • Prior allogeneic stem cell or solid organ transplantation
  • Known immunodeficiency or conditions requiring treatment with systemic immunosuppressive medication (including, but not limited to, cyclophosphamide, azathioprine, methotrexate, thalidomide and anti-TNF agents) or anticipation of need for systemic immunosuppressant medication during study treatment, with the following exceptions:
  • Patients on replacement doses of corticosteroids to manage hypopituitary or adrenal insufficiency are eligible for the study.
  • Patients who received acute, low-dose, systemic immunosuppressant medications or a one-time pulse dose of systemic immunosuppressant medication (for example, 48hours of corticosteroids for a contrast allergy) were eligible for the study. Patients requiring chronic low-dose systemic corticosteroid treatment (that is, a maximal dose of corticosteroids ≤10mgd1 equivalent prednisone) were eligible.
  • Patients who received mineralocorticoids (for example, fludrocortisone), corticosteroids for chronic obstructive pulmonary disease or asthma or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency were eligible for the study.
  • Treatment with a live, attenuated vaccine within 4weeks prior to initiation of study treatment or anticipation of need for such a vaccine during study treatment or within 5months after the final dose of study treatment
  • Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre syndrome or multiple sclerosis, with the following exceptions:
  • Patients with a history of autoimmune-related hypothyroidism who were on thyroid replacement hormone were eligible for the study.
  • Patients with controlled type 1 diabetes mellitus who were on a stable insulin regimen were eligible for the study.
  • Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic manifestations only (for example, patients with psoriatic arthritis were excluded) were eligible for the study provided all of following conditions were met:
  • Rash covered less than 10% of body surface area.
  • Disease was well controlled at baseline and required only low-potency topical corticosteroids.
  • There was no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors or high-potency or oral corticosteroids within the previous 12months.
  • History of idiopathic pulmonary fibrosis, organizing pneumonia (for example, bronchiolitis obliterans), drug-induced pneumonitis or idiopathic pneumonitis or evidence of active pneumonitis on screening chest computed tomography scan. Patients with a history of cancer immunotherapy-related pneumonitis lower than grade 2 were eligible.
  • History of malignancy other than malignant melanoma within 2years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (for example, 5-year overall survival rate >90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ or stage I uterine cancer
  • Active tuberculosis
  • Severe infection within 4weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia or severe pneumonia or any active infection that, in the opinion of the investigator, could impact patient safety
  • Treatment with therapeutic or prophylactic oral or intravenous antibiotics within 2weeks prior to initiation of study treatment
  • Significant cardiovascular disease, such as New York Heart Association cardiac disease (class II or higher), myocardial infarction or cerebrovascular accident within 3months prior to initiation of study treatment, unstable arrhythmia or unstable angina
  • Uncontrolled hypertension (defined as resting systolic blood pressure >150mmHg and/or diastolic blood pressure >100mmHg in two or more serial measurements)
  • Major surgical procedure, other than for diagnosis, within 4weeks prior to initiation of study treatment or anticipation of need for a major surgical procedure other than TLND during the study
  • Placement of central venous access catheter (for example, port or similar) was not considered a major surgical procedure and was, therefore, permitted.
  • Any other disease, metabolic dysfunction, physical examination finding or clinical laboratory finding that contraindicated the use of an investigational drug, may have affected the interpretation of the results, impaired the ability of the patient to participate in the study or may have rendered the patient at high risk from treatment complications
  • History of severe allergic reactions to chimeric or humanized antibodies or fusion proteins
  • Known hypersensitivity to Chinese hamster ovary cell products or recombinant human antibodies
  • Known allergy or hypersensitivity to any of the study drugs or their excipients
  • Known intolerance to any of the drugs required for premedication (acetaminophen, ranitidine, diphenhydramine and methylprednisolone)
  • Pregnancy or breastfeeding or intention of becoming pregnant during the study
  • Women of childbearing potential must have had a negative serum pregnancy test result within 14days prior to initiation of study treatment.
  • Eligible only for the control arm

Clinical Study Information for Healthcare Providers

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Study Locations

Location
Investigator
Status
Condition(s) Treated at Site
Location
START Madrid, Spain (CIOCC)
Madrid, Spain, 28050
Investigator
Irene Moreno
Status
Terminated/Withdrawn
Condition(s) Treated at Site
Melanoma