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 as well as patients naive to therapy 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:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">Phase 1b</span>/2 Study of the Combination of IMCgp100 With <span class="go-doc-concept go-doc-intervention">Durvalumab</span> and/or <span class="go-doc-concept go-doc-intervention">Tremelimumab</span> in Cutaneous <span class="go-doc-concept go-doc-disease">Melanoma</span>

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

    NCT ID: NCT02535078

    ORG ID: IMCgp100-201

    Trial Conditions

    Malignant Melanoma

    Trial Interventions

    Drug Synonyms Arms
    IMCgp100 Arm 1, Arm 2, Arm 3, Arm 4
    durvalumab MEDI4736 Arm 1, Arm 3
    tremelimumab Arm 2, Arm 3

    Trial 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 as well as patients naive to
    therapy 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.

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    Arm 1 Experimental IMCgp100 with durvalumab (MEDI4736) IMCgp100, durvalumab
    Arm 2 Experimental IMCgp100 with tremelimumab IMCgp100, tremelimumab
    Arm 3 Experimental IMCgp100 with durvalumab (MEDI4736) and tremelimumab IMCgp100, durvalumab, tremelimumab
    Arm 4 Experimental IMCgp100 (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 cutaneous melanoma defined as unresectable stage III or
    metastatic stage IV disease. Patients with non-cutaneous (uveal, acral or mucosal)
    melanoma are excluded

    4. Phase II PD-1/PD-L1 refractory cohorts: Patients with confirmed disease progression
    within 24 weeks following initiation of PD-1/PD-L1 inhibitor therapy (patients must
    have received at least 2 doses of the PD-1/PD-L1 inhibitor). No prior cytotoxic
    therapy in the advanced setting is permitted. BRAF inhibition therapy is acceptable
    before immunotherapy where clinically indicated. CTLA-4-inhibition therapy is
    acceptable as a prior line of therapy or in combination with anti-PD-1 therapy.

    5. 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: no restriction on prior therapy

    7. HLA-A2 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 Ph Ib cohorts must have evaluable disease

    11. Phase II cohorts only: Patients must have a site of disease amenable to biopsy, and
    be a candidate for tumor biopsy according to the treating institution's guidelines.
    Phase Ib patients need not have disease accessible to biopsy

    12. Those receiving prior immunotherapy must meet all of the following conditions of the
    following conditions:

    - Must not have experienced a toxicity that led to permanent discontinuation of
    prior immunotherapy

    - All AEs 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 AE 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 and are asymptomatic)

    - Must not have required the use of additional immunosuppression other than
    corticosteroids for the management of an AE, not have experienced recurrence of
    an AE if re-challenged, and not currently require maintenance doses of > 10 mg
    prednisone or equivalent per day

    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:

    - 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 109/L

    - Absolute lymphocyte count < 0.5 x 109/L

    - Platelet count < 75 x 109/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

    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

    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 receiving chronic systemic corticosteroid therapy or any other
    immunosuppressive medication that would interfere with the action of the study drugs
    in the opinion of the investigator, with the exception of replacement-dose
    corticosteroids in the setting of adrenal insufficiency (replacement dosing must be
    limited to 10 mg/day prednisone or the equivalent) and no history of adrenal crisis.
    Local therapy (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 use 2 methods of highly effective contraception from screening, 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 barrier
    methods, intrauterine devices or hormonal methods). Periodic abstinence, the rhythm
    method, and the withdrawal method are not acceptable methods of birth control. 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.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Progression-free survival

    Secondary Outcome Measures

    Objective response rate

    Overall survival

    Trial Keywords