Melanoma Clinical Trial
Phase 1b/2 Study of the Combination of IMCgp100 With Durvalumab and/or Tremelimumab in Advanced Cutaneous Melanoma
This study is a Phase Ib/II, multi-center, open-label study of tebentafusp (IMCgp100) as a single agent and in combination with durvalumab (MEDI4736) and/or tremelimumab in metastatic cutaneous melanoma. The purpose of this study is to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and to evaluate the anti-tumor activity of tebentafusp (IMCgp100) in combination with durvalumab (MEDI4736, programmed death-ligand 1 [PD-L1] inhibitor), tremelimumab (CLTA-4 inhibitor), and the combination of durvalumab with tremelimumab compared to single-agent tebentafusp (IMCgp100) alone. The study will enroll patients who have metastatic melanoma that is refractory to treatment with an anti-PD-1 inhibitor in the metastatic setting. This study will also evaluate the safety, tolerability, and anti-tumor activity of tebentafusp (IMCgp100) monotherapy in patients with advanced non-uveal melanoma who progressed on prior PD-1 inhibitors approved for the treatment of advanced melanoma; patients with BRAF mutations must be refractory to approved BRAF-based therapy.
Recent biologic evidence indicates that optimal responses to programmed cell death-1 (PD-1) directed therapy require the presence of CD8+ T cells in the tumor microenvironment and thus therapies such as tebentafusp (IMCgp100) that recruit these effector cells to the tumor may overcome pre-existing resistance to checkpoint blockade. This emerging biology of checkpoint inhibitor resistance suggests the combination of tebentafusp (IMCgp100) with checkpoint inhibition may have enhanced activity in patients with pre-existing resistance.
Age ≥ 18 years
Written informed consent must be obtained from all patients prior to any study procedures
Patients with advanced non-uveal melanoma defined as unresectable stage III or metastatic stage IV disease. Patients with acral or mucosal melanoma are acceptable. Patients with melanoma of unknown primary are acceptable for Phase 1b escalation cohorts (Arms 1 to 5) but are excluded in Phase 2. NOTE: Patients with the diagnosis of UM are excluded from all cohorts
Phase 1b (Arm 4 and Arm 5) and Phase 2: Patients with disease progression following initiation of treatment with an approved PD-(L)1 inhibitor. Patients with BRAF mutations should be refractory to approved BRAF-inhibitor if clinically feasible. CTLA 4 inhibition therapy is acceptable as a prior line of therapy or in combination with anti-PD-(L)1 therapy. For Phase 2, no prior chemotherapy in the advanced setting is permitted
Phase 1b Arms 1-3: no restriction on prior therapy
HLA-A*02:01 positive by central assay or by an 510K approved assay run in CLIA-certified laboratory
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
Life expectancy of at least 3 months
Phase 2 cohorts only: Patients must have measurable disease according to RECIST v1.1 criteria. Patients enrolled in Phase 1b cohorts may have either measurable or only non-measurable disease (ie, non-target lesion only)
Phase 1b (Arm 4) and Phase 2 cohorts only: Patients must have a site of disease amenable to biopsy (ie, must not also be a target lesion OR if a target lesion must be > 2cm), and be a candidate for tumor biopsy according to the treating institution's guidelines. NOTE: Phase 1b Arms 1-3 and 5 patients are not required to have disease accessible to biopsy
For Arms 1-3 only (ie, applies only to patients assigned to receive tebentafusp in combination with checkpoint inhibitor[s]): Those receiving prior immunotherapy must meet all the following conditions:
Must not have experienced an immune-related adverse event (irAE) where the irAE was the reason for permanent discontinuation of prior immunotherapy in the most recent prior treatment regimen
All irAEs while receiving prior immunotherapy must have resolved to ≤ Grade 1 or baseline prior to screening for this study. Must not have experienced a ≥ Grade 3 immune-related AE within the past 16 weeks or any Grade 4 life-threatening irAE (regardless of duration) or neurologic or ocular AE of any grade while receiving prior immunotherapy. (NOTE: Patients with endocrine AE of any grade are permitted to enroll if they are stably maintained on appropriate replacement therapy, but must have no history of adrenal crisis and be asymptomatic)
Patients currently receiving chronic corticosteroid treatment (longer than 8 weeks duration) for management of pre-existing AEs, or patients with a history of chronic corticosteroid treatment longer than 8 weeks duration for AEs within 6 months of screening are excluded
Presence of untreated or symptomatic central nervous system (CNS) metastases, leptomeningeal disease, or cord compression.
History of severe hypersensitivity reactions to study medications
History of treatment-related interstitial lung disease/pneumonitis
Impaired baseline organ function as evaluated by out-of-range laboratory values.
Clinically significant cardiac disease or impaired cardiac function
Active autoimmune disease or a documented history of autoimmune disease
Recent (< 12 months of planned first dose of study treatment) active diverticulitis (Phase 1b combination arms)
Active infection requiring systemic antibiotic therapy. NOTE: Patients requiring systemic antibiotics for infection must have completed therapy before planned first dose of study treatment
Known history of human immunodeficiency virus (HIV) infection. Testing for HIV status is not necessary unless clinically indicated or if required by local regulation
Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, currently requiring medical intervention, per institutional protocol. Testing for HBV or HCV status is not necessary unless clinically indicated or the patient has a history of HBV or HCV infection requiring treatment with currently an unknown status. History of treated hepatitis is not exclusionary
Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years after completion of treatment; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy; and completely resected carcinoma in situ of any type
Any medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results
Systemic anti-cancer therapy within 2 weeks of the planned first dose of study treatment. For cytotoxic agents that have major delayed toxicity and any prior immunotherapy approach, 3 weeks is indicated as washout period
Presence of NCI CTCAE ≥ Grade 2 toxicity (except alopecia, peripheral neuropathy, and ototoxicity, which are excluded if ≥ NCI CTCAE Grade 3) due to prior cancer therapy
Systemic treatment with steroids or any other immunosuppressive drug use within 4 weeks of the planned first dose of study treatment, with the following exceptions:
Treatment for well-controlled and asymptomatic adrenal insufficiency is permitted, but replacement dosing is limited to prednisone ≤ 12 mg daily or the equivalent.
Local steroid therapies (eg, optic, ophthalmic, intra-articular, or inhaled medications) are acceptable
Premedication for allergy to contrast reagent or premedication regimen instituted per protocol
Steroids for management of CNS metastases > 2 weeks prior to the planned first dose of study treatment
Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment
Major surgery as defined by the investigator within 2 weeks of the first dose of study treatment.
Radiotherapy within 2 weeks of the first dose of study treatment, with the exception of palliative radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful tumor mass
Use of hematopoietic colony-stimulating growth factors (eg, G-CSF, GMCSF, MCSF) ≤ 2 weeks prior start or study treatment. NOTE: Patients must have completed therapy with hematopoietic colony-stimulating factors at least 2 weeks before the first dose of study treatment is given. An erythroid stimulating agent is allowed as long as it was initiated at least 2 weeks prior to the first dose of study treatment and the patient is not red blood cell transfusion dependent
Pregnant or breast-feeding women
Women of child-bearing potential who are sexually active with a non-sterilized male partner, unless they are using highly effective contraception during study treatment, and must agree to continue using such precautions for 1 week after the final dose of investigational product; cessation of birth control after this point should be discussed with a responsible physician.
Male patients must be surgically sterile or use double barrier contraception method and are not allowed to donate sperm from enrollment through treatment and for 3 months following administration of the last dose of study drug
Patients who are relatives or dependents of the investigator
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There are 4 Locations for this study
Los Angeles California, 90025, United States
New York New York, 10065, United States
Philadelphia Pennsylvania, 19107, United States
Pittsburgh Pennsylvania, 15213, United States
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