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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02535078
Recruitment Status : Active, not recruiting
First Posted : August 28, 2015
Last Update Posted : April 14, 2021
MedImmune LLC
Information provided by (Responsible Party):
Immunocore Ltd

Brief Summary:

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 to evaluate the 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. This study will also evaluate the safety, tolerability, and anti-tumor activity of 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 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.

Condition or disease Intervention/treatment Phase
Malignant Melanoma Drug: IMCgp100 Drug: durvalumab Drug: tremelimumab Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 312 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Compared to IMCgp100 Alone in Patients With Advanced Melanoma
Study Start Date : November 2015
Estimated Primary Completion Date : May 2022
Estimated Study Completion Date : August 2022

Arm Intervention/treatment
Experimental: Arm 1
IMCgp100 with durvalumab (MEDI4736)
Drug: IMCgp100
soluble gp100-specific T cell receptor with anti-CD3 scFV

Drug: durvalumab
anti-PD-L1 monoclonal antibody
Other Name: MEDI4736

Experimental: Arm 2
IMCgp100 with tremelimumab
Drug: IMCgp100
soluble gp100-specific T cell receptor with anti-CD3 scFV

Drug: tremelimumab
anti-CTLA-4 monoclonal antibody

Experimental: Arm 3
IMCgp100 with durvalumab (MEDI4736) and tremelimumab
Drug: IMCgp100
soluble gp100-specific T cell receptor with anti-CD3 scFV

Drug: durvalumab
anti-PD-L1 monoclonal antibody
Other Name: MEDI4736

Drug: tremelimumab
anti-CTLA-4 monoclonal antibody

Experimental: Arm 4
IMCgp100 (single agent)
Drug: IMCgp100
soluble gp100-specific T cell receptor with anti-CD3 scFV

Primary Outcome Measures :
  1. Phase 1b Number of dose-limiting toxicities [ Time Frame: 12 months ]
    The number of dose-limiting toxicities (DLT) observed during the DLT observation period. DLT observation period for the Arms 1 to 3 Phase Ib cohorts will be the first 2 cycles of treatment (C1D1 until C2D28). The DLT observation period for Arm 4 Phase Ib will be from C1D22 to C2D14. A DLT is defined as an adverse event or abnormal laboratory value that occurs during the relevant DLT period which is assessed as having a suspected relationship to study drug, and unrelated to disease, disease progression, inter-current illness, or concomitant medications, occurs during the DLT Observation Period or is Grade 3 or higher per NCI CTCAE version 4.03, or as specified in the protocol.

Secondary Outcome Measures :
  1. Phase 2b Objective Response Rate [ Time Frame: 2 years ]
    Objective Response Rate (RECIST v1.1) Objective response rate, defined as the proportion of patients with a best response of CR or PR based on investigator assessment, as defined in RECIST v1.1.

  2. Overall survival [ Time Frame: 2 years ]
    Time from the date of first dose until death due to any cause.

  3. Safety: AEs and SAEs [ Time Frame: 2 years ]
    Safety incidence and severity of AEs and SAEs including changes in laboratory. parameters, vital signs, and electrocardiograms (ECG).

  4. Safety: Tolerability [ Time Frame: 2 years ]
    Tolerability of study treatment will be assessed by summarizing the number of treatment dose interruptions and dose reductions.

  5. Safety: Tolerability [ Time Frame: 2 years ]
    Dose interruptions

  6. Safety: Tolerability [ Time Frame: 2 years ]
    Dose Reductions

  7. Safety: Tolerability [ Time Frame: 2 years ]
    Dose Intensity

  8. Serum Pharmacokinetics [ Time Frame: 2 years ]
    AUClast : Area under the curve (AUC) from time zero to the last measurable concentration sampling time (tlast) (mass x time x volume-1)

  9. Serum Pharmacokinetics [ Time Frame: 2 years ]
    AUCinf : The AUC from time zero to infinity (mass x time x volume-1)

  10. Serum Pharmacokinetics [ Time Frame: 2 years ]
    Cmax : Maximum Plasma Concentration

  11. Serum Pharmacokinetics [ Time Frame: 2 years ]
    Tmax: The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration (time)

  12. Serum Pharmacokinetics [ Time Frame: 2 years ]
    t1/2 : Elimination half-life associated with the terminal slope (λz) of a semi logarithmic concentration-time curve (time)

  13. Correlation of PD-L1 and gp100 [ Time Frame: 2 years ]
  14. Progression Free Survival [ Time Frame: 2 years ]
    Correlation of gp100 and PD-L1 expression by immunohistochemistry evaluated in pre-treatment biopsies with anti-tumor activity.

  15. Duration of Response [ Time Frame: 2 years ]
    Time from the date of first documented response until date of documented progression or death in the absence of disease progression. The median duration of response and corresponding 90% confidence interval will be presented.

  16. Overall Survival [ Time Frame: 2 years ]
    Time from the date of first dose until death due to any cause. OS will be presented including all patients treated at the MTD or RP2D.

  17. Time to Response [ Time Frame: 2 years ]
    Time from initiation of therapy to the time that an OR per RECISTv1.1 is achieved.

  18. Disease Control Rate [ Time Frame: 2 years ]
    Proportion of patients with either a best response of PR or CR or with SD over 24 weeks after first dose in the study. The DCR and associated 90% confidence interval will be presented by treatment arm.

  19. Formation of Anti-drug Antibodies [ Time Frame: 2 years ]
    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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.
  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. HLA-A*0201 positive by Central Assay
  6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
  7. 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
  8. Ongoing treatment with systemic steroids or other immunosuppressive therapies.

Exclusion Criteria:

  1. Presence of untreated or symptomatic central nervous system metastases, or central nervous system metastases.
  2. History of severe hypersensitivity reactions to other mAbs
  3. History of treatment-related interstitial lung disease/pneumonitis
  4. Impaired baseline organ function as evaluated by out-of-range laboratory values.
  5. Clinically significant cardiac disease or impaired cardiac function.
  6. Active autoimmune disease or a documented history of autoimmune disease.
  7. Active infection requiring systemic antibiotic therapy. Patients requiring systemic antibiotics for infection must have completed therapy before Screening is initiated
  8. Known history of human immunodeficiency virus (HIV) infection. Testing for HIV status is not necessary unless clinically indicated or if required by local regulation
  9. 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
  10. Malignant disease, other than that being treated in this study. Pregnant or breast feeding.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02535078

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Sponsors and Collaborators
Immunocore Ltd
MedImmune LLC
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Study Director: Mohammed Dar Immunocore Ltd
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Responsible Party: Immunocore Ltd Identifier: NCT02535078    
Other Study ID Numbers: IMCgp100-201
First Posted: August 28, 2015    Key Record Dates
Last Update Posted: April 14, 2021
Last Verified: April 2021
Keywords provided by Immunocore Ltd:
metastatic cutaneous melanoma
checkpoint inhibitor
Bispecific T cell receptor fusion protein
Immune mobilizing monoclonal T cell receptor against cancer
mucosal melanoma
acral melanoma
Additional relevant MeSH terms:
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Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Nerve Tissue
Nevi and Melanomas
Antineoplastic Agents, Immunological
Antineoplastic Agents