Advanced Malignant Cutaneous Melanoma MedDRA version: 21.1 Level: LLT Classification code 10025655 Term: Malignant melanoma of skin System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.1 Level: PT Classification code 10025671 Term: Malignant melanoma stage IV System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.1 Level: PT Classification code 10025670 Term: Maligna
Conditions
Interventions
Product Code: IMCgp100
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: IMCgp100
Current Sponsor code: IMCgp100
Other descriptive name: IMCGP100
Concentration unit: mg/m
Sponsors
Immunocore Limited
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age = 18 years 2. Written informed consent must be obtained from all patients prior to any study procedures. 3. 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 source are acceptable for Phase Ib cohorts (Arms 1 to 4), but are excluded in Phase II cohorts. Patients with the diagnosis of uveal melanoma are excluded from all cohorts. 4.Phase Ib Arm 4 and Phase II: Patients with disease progression following initiation of treatment with an approved PD-1 inhibitor. No prior cytotoxic therapy in the advanced setting is permitted. Patients with BRAF mutations must be refractory to approved BRAF-based therapy. CTLA-4-inhibition therapy is acceptable as a prior line of therapy or in combination with anti-PD-1 therapy 5. Note: intentionally left blank by Sponsor in order to align with Protocol revision. 6. Phase Ib Arms 1, 2 and 3: no restriction on prior therapy. 7. Human leukocyte antigen-A*0201 (HLA- A*0201) positive 8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 9. Life expectancy of at least 3 months 10. Phase II cohorts only: patients must have measurable disease according to RECIST v.1.1 criteria. Patients enrolled in Phase Ib cohorts must have evaluable disease 11. Phase Ib Arm 4 and Phase II cohorts only: Patients must have a site of disease amenable to biopsy that is not an index lesion, and be a candidate for tumor biopsy according to the treating institution's guidelines. Phase Ib Arms 1-3 patients need not have disease accessible to biopsy 12. Those receiving prior immunotherapy must meet all of the following conditions: -Must not have experienced an immune-related adverse event (irAE) which 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 AE (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 adverse events, or patients with a history of chronic corticosteroid treatment longer than 8 weeks’ duration for adverse events within 6 months of Screening are excluded Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 112 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 112
Exclusion criteria
Exclusion criteria: 1. Presence of untreated or symptomatic central nervous system metastases, or central nervous system metastases that currently require local therapy (such as radiotherapy or surgery), or require doses of corticosteroids within the prior 4 weeks. 2. History of severe hypersensitivity reactions to other monoclonal antibodies (mAb)s. 3. History of treatment-related interstitial lung disease/pneumonitis. 4. Patient with any out of range laboratory values. • Serum creatinine > 1.5 x ULN and/or creatinine clearance (calculated using Cockcroft-Gault formula, or measured) 1.5 x upper limit of normal (ULN), except for patients with Gilbert’s syndrome who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN • Alanine aminotransferase (ALT) > 3 x ULN • Aspartate aminotransferase (AST) > 3 x ULN • Absolute neutrophil count (ANC) grade 1 5. Clinically significant cardiac disease or impaired cardiac function. • Clinically significant and/or uncontrolled heart disease such as congestive heart failure (New York Heart Association NYHA grade = 2), uncontrolled hypertension or clinically significant arrhythmia currently requiring medical treatment • QTcF >470 msec on screening electrocardiogram (ECG) or congenital long QT syndrome • Acute myocardial infarction or unstable angina pectoris < 6 months prior to Screening 6. Active autoimmune disease or a documented history of autoimmune disease within 3 years before Screening (or as indicated below), including the following: • A documented history of inflammatory bowel disease (ulcerative colitis or Crohn’s disease, within 3 years) • Patients with vitiligo, alopecia, managed hypothyroidism (on stable replacement doses), psoriasis, resolved childhood asthma/atopy, well-controlled asthma and type I diabetes mellitus are NOT excluded 7. Recent (< 12 months) active diverticulitis (PhIb combination arms and PhII only) 8. Active infection requiring systemic antibiotic therapy. Patients requiring systemic antibiotics for infection must have completed therapy before Screening is initiated. 9. Known history of human immunodeficiency virus (HIV) infection. 10. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, currently requiring medical intervention, per institutional protocol. 11. Malignant disease, other than that being treated in this study. 12. 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. 13. Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment. For cytotoxic agents that have major delayed toxicity and any prior immunotherapy approach, 4 weeks is indicated as washout period. 14. 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. 15. Chronic, systemic corticosteroid use 16. Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment. 17. Major surgery as defined by the investigator within 2 weeks of the first dose o
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase Ib: To characterize the safety and tolerability, and subsequently identify the MTD or RP2D, of the combination of durvalumab or tremelimumab with IMCgp100 (Arms 1 and 2) and tremelimumab + durvalumab with IMCgp100 (Arm 3). To describe the safety of singleagent IMCgp100 at doses higher than 68 mcg on a weekly basis (Arm 4a); identify the MTD or RP2D of single-agent IMCgp100 administered at doses higher than 68 mcg on a weekly basis (Arm 4a) using a slower intra-patient dose escalation. To describe the safety of administering single-agent IMCgp100 at a dose of 68 mcg three times per week (Arm 4b). Phase II: To evaluate the ORR of IMCgp100 using RECIST v.1.1 criteria as a single agent (Arm 4) and in combination with checkpoint inhibition with durvalumab (Arm 1), tremelimumab (Arm 2), or the combination of durvalumab and tremelimumab (Arm 3).;Secondary Objective: To characterize the safety and tolerability of single agent IMCgp100 (given alone in Arm 4) and in combination with durvalumab and/or tremelimumab. To characterize the PK profile of single agent IMCgp100 (given alone in Arm 4) and in combination with durvalumab and/or tremelimumab in Arms 1, 2, and 3. To assess potential predictors of efficacy of gp100 and/or PDL1 expression or baseline lactate dehydrogenase (LDH) level with IMCgp100 in combination with durvalumab and/or tremelimumab in Arms 1, 2, and 3 and IMCgp100 alone in Arm 4. To assess the preliminary anti tumor efficacy of IMCgp100 alone and in combination with durvalumab and/or tremelimumab. To evaluate the incidence of anti IMCgp100, anti durvalumab and anti tremelimumab antibody formation following multiple infusions of IMCgp100 alone and in combination with durvalumab and/or tremelimumab.;Primary end point(s): Phase Ib: Number of Dose limiting toxicity(ies) (DLTs) Phase II: Objective response rate (ORR) per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1;Timepoint(s) of evaluation of this end point: DLTs observe | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Safety incidence and severity of AEs and SAEs including changes in laboratory parameters, vital signs and electrocardiogram (ECG) Tolerability: Dose interruptions, reductions and dose intensity of all administered study medications Serum PK parameters (eg, AUC, Cmax, time of maximum concentration [Tmax], and t1/2) of all administered study medications) Correlation of PD-L1 and gp100 evaluated in biopsies taken in the Screening period with anti-tumor activity Progression free survival (PFS), duration of response, time to response, and disease control rate (DCR) Formation of Anti-drug antibody (ADA);Timepoint(s) of evaluation of this end point: AEs and SAEs: From baseline at each study visit. PK: samples taken at various timepoints during both phase Ib and II. PFS: time from first dose of IMCgp100 until date of disease progression or death. Duration of response: time from first documented response until date of documented progression or death in the absence of disease progression. Time to response: time from initiation of therapy to time that Overall Survival (OR) per RECISTv1.1 is achieved. DCR: proportion of patients with either a best response of PR or CR or with SD over 24 weeks after first dose in the study. ADA samples: pre-dose at C1D1, C2D15, C3D15 and all odd numbered cycles through C13 (“CX”) and at 30-day End of Treatment visit. ADA samples to coincide with PK samples in Ph II during odd numbered cycles (CX’). | — |
Countries
Denmark, France, Germany, Italy, United Kingdom, United States
Contacts
Public ContactMark Moyer
Immunocore, Ltd.
Outcome results
None listed