Clinical Trials /

Phase 1b/2 Study of the Combination of IMCgp100 With Durvalumab and/or Tremelimumab in Cutaneous Melanoma

NCT02535078

Description:

This study is a Phase Ib/II, multi-center, open-label study of 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 anti-tumor activity of 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 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. 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 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 IMCgp100 with checkpoint inhibition may have enhanced activity in patients with pre-existing resistance.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase 1b/2 Study of the Combination of IMCgp100 With Durvalumab and/or Tremelimumab in Cutaneous Melanoma
  • Official Title: A Phase Ib/II Open-label, Multi-center Study of the Safety and Efficacy of IMCgp100 in Combination With Durvalumab (MEDI4736) or Tremelimumab or the Combination of Durvalumab and Tremelimumab in Patients With Advanced Melanoma

Clinical Trial IDs

  • ORG STUDY ID: IMCgp100-201
  • NCT ID: NCT02535078

Conditions

  • Malignant Melanoma

Interventions

DrugSynonymsArms
IMCgp100Arm 1
durvalumabMEDI4736Arm 1
tremelimumabArm 2

Purpose

This study is a Phase Ib/II, multi-center, open-label study of 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 anti-tumor activity of 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 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. 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 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 IMCgp100 with checkpoint inhibition may have enhanced activity in patients with pre-existing resistance.

Trial Arms

NameTypeDescriptionInterventions
Arm 1ExperimentalIMCgp100 with durvalumab (MEDI4736)
  • IMCgp100
  • durvalumab
Arm 2ExperimentalIMCgp100 with tremelimumab
  • IMCgp100
  • tremelimumab
Arm 3ExperimentalIMCgp100 with durvalumab (MEDI4736) and tremelimumab
  • IMCgp100
  • durvalumab
  • tremelimumab
Arm 4ExperimentalIMCgp100 (single agent)
  • IMCgp100

Eligibility 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 are acceptable for Phase Ib cohorts (Arms 1
             to 4), but are excluded in Phase II cohorts. Patients with the diagnosis of UM are
             excluded from all cohorts.

          4. Phase 1b 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. No longer applicable - (Phase II IMT naive cohorts: Patients have not received
             systemic cytotoxic or immune-based therapy for advanced melanoma. BRAF and/or MEK
             inhibition therapy is acceptable before immunotherapy where clinically indicated.
             Other systemic cytotoxic or targeted therapy in the advanced setting is not permitted
             in this subset)

          6. Phase Ib Arms 1, 2, and 3: no restriction on prior therapy

          7. HLA-A*0201 positive by Central Assay

          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 Ph Ib cohorts must have evaluable disease

         11. Phase 1b 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) 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: Subjects 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 AEs
                  within 6 months of Screening are excluded

        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 mAbs

          3. History of treatment-related interstitial lung disease/pneumonitis

          4. Patient with any out-of-range laboratory values defined as:

               -  Serum creatinine ≥ 1.5 x ULN and/or creatinine clearance (calculated using
                  Cockcroft-Gault formula, or measured) < 50 mL/min

               -  Total bilirubin > 1.5 x 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) < 1.0 x 10^9/L

               -  Absolute lymphocyte count < 0.5 x 10^9/L

               -  Platelet count < 75 x 10^9/L

               -  Hemoglobin (Hgb) < 8 g/dL

               -  Potassium, magnesium, corrected calcium or phosphate abnormality of National
                  Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) >
                  grade 1

          5. Clinically significant cardiac disease or impaired cardiac function, including any of
             the following:

               -  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 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 three 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. Testing for HIV status
             is not necessary unless clinically indicated or if required by local regulation

         10. 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

         11. 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

         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 National Cancer Institute Common Terminology Criteria for Adverse Events
             (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. Patients currently requiring chronic, systemic corticosteroid therapy at any dose for
             longer than 2 weeks. Local steroid therapies (eg, otic, ophthalmic, intra-articular or
             inhaled medications) are acceptable

         16. Use of any live vaccines against infectious diseases within 4 weeks of initiation of
             study treatment. Non-live vaccination (eg, influenza) are permitted anytime during
             treatment

         17. Major surgery as defined by the investigator within 2 weeks of the first dose of study
             treatment (minimally invasive procedures such as bronchoscopy, tumor biopsy, insertion
             of a central venous access device, and insertion of a feeding tube are not considered
             major surgery)

         18. Radiotherapy within 2 weeks of the first dose of study drug, with the exception of
             palliative radiotherapy to a limited field, such as for the treatment of bone pain or
             a focally painful tumor mass

         19. Use of hematopoietic colony-stimulating growth factors (eg, G-CSF, GMCSF, M-CSF) ≤ 2
             weeks prior start or study drug. Patients must have completed therapy at least 2 weeks
             before the screening period begins with any hematopoietic colony-stimulating growth
             factors. 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

         20. Pregnant or lactating women, where pregnancy is defined as the state of a female after
             conception and until the termination of gestation, confirmed by a positive hCG
             laboratory test

         21. Women of child-bearing potential who are sexually active with a non-sterilized male
             partner, defined as all women physiologically capable of becoming pregnant, unless
             they are using highly effective contraception from screening throughout study
             treatment, and must agree to continue using such precautions for 6 months after the
             final dose of investigational product; cessation of birth control after this point
             should be discussed with a responsible physician. Highly effective methods include the
             following:

               -  Total abstinence from sexual relations for the duration of the treatment when
                  applicable to the lifestyle of the patient. Periodic abstinence (eg, calendar,
                  ovulation, symptothermal, post-ovulation methods) and withdrawal are not
                  acceptable methods of contraception

               -  Female sterilization (have had surgical bilateral oophorectomy with or without
                  hysterectomy) or tubal ligation at least 6 weeks before taking study treatment.
                  In case of oophorectomy alone, this applies only when the reproductive status of
                  the woman has been confirmed by follow up hormone level assessment

               -  Male sterilization (at least 6 months prior to Screening). For female patients on
                  the study the vasectomized male partner should be the sole partner for that
                  patient

               -  The combination of any 2 of the following methods when both are used
                  simultaneously:

                    1. Use of oral, injected, or implanted hormonal methods of contraception or
                       other forms of hormonal contraception that have comparable efficacy (failure
                       rate <1%), for example hormone vaginal ring or transdermal hormone
                       contraception

                    2. Placement of an intrauterine device or intrauterine system

                    3. Barrier methods of contraception: condom or occlusive cap (diaphragm or
                       cervical/vault caps) when used with spermicidal foam, gel, film, cream, or
                       used of a spermicidal vaginal suppository Women of child-bearing potential
                       must have a negative serum pregnancy test at Screening. Otherwise, female
                       patients must be post-menopausal (no menstrual period for at least 12 months
                       prior to Screening), or surgically sterile.

         22. Male patients must be surgically sterile or use double barrier contraception method
             from enrollment through treatment and for 6 months following administration of the
             last dose of study drug.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival
Time Frame:12 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Objective response rate
Time Frame:12 months
Safety Issue:
Description:
Measure:Overall survival
Time Frame:2 years
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Immunocore Ltd

Trial Keywords

  • IMCgp100
  • gp100
  • metastatic cutaneous melanoma
  • checkpoint inhibitor
  • PD-1
  • PD-L1
  • CTLA-4
  • durvalumab
  • tremelimumab

Last Updated

January 16, 2020