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Nivolumab and Ipilimumab With or Without Sargramostim in Treating Patients With Stage III-IV Melanoma That Cannot Be Removed by Surgery

NCT02339571

Description:

This randomized phase II/III trial studies the side effects and best dose of nivolumab and ipilimumab when given together with or without sargramostim and to see how well they work in treating patients with stage III-IV melanoma that cannot be removed by surgery. Monoclonal antibodies, such as ipilimumab and nivolumab, may kill tumor cells by blocking blood flow to the tumor, by stimulating white blood cells to kill the tumor cells, or by attacking specific tumor cells and stop them from growing or kill them. Colony-stimulating factors, such as sargramostim, may increase the production of white blood cells. It is not yet known whether nivolumab and ipilimumab are more effective with or without sargramostim in treating patients with melanoma.

Related Conditions:
  • Melanoma
Recruiting Status:

Suspended

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Nivolumab and <span class="go-doc-concept go-doc-intervention">Ipilimumab</span> With or Without <span class="go-doc-concept go-doc-intervention">Sargramostim</span> in Treating Patients With Stage III-IV <span class="go-doc-concept go-doc-disease">Melanoma</span> That Cannot Be Removed by Surgery

Title

  • Brief Title: Nivolumab and Ipilimumab With or Without Sargramostim in Treating Patients With Stage III-IV Melanoma That Cannot Be Removed by Surgery
  • Official Title: Randomized Phase II/III Study of Nivolumab Plus Ipilimumab Plus Sargramostim Versus Nivolumab Plus Ipilimumab in Patients With Unresectable Stage III or Stage IV Melanoma
  • Clinical Trial IDs

    NCT ID: NCT02339571

    ORG ID: NCI-2014-02674

    NCI ID: NCI-2014-02674

    Trial Conditions

    Recurrent Melanoma of the Skin

    Stage IIIA Skin Melanoma

    Stage IIIB Skin Melanoma

    Stage IIIC Skin Melanoma

    Stage IV Skin Melanoma

    Trial Interventions

    Drug Synonyms Arms

    Trial Purpose

    This randomized phase II/III trial studies the side effects and best dose of nivolumab and
    ipilimumab when given together with or without sargramostim and to see how well they work in
    treating patients with stage III-IV melanoma that cannot be removed by surgery. Monoclonal
    antibodies, such as ipilimumab and nivolumab, may kill tumor cells by blocking blood flow to
    the tumor, by stimulating white blood cells to kill the tumor cells, or by attacking
    specific tumor cells and stop them from growing or kill them. Colony-stimulating factors,
    such as sargramostim, may increase the production of white blood cells. It is not yet known
    whether nivolumab and ipilimumab are more effective with or without sargramostim in treating
    patients with melanoma.

    Detailed Description

    PRIMARY OBJECTIVES:

    I. To compare the overall survival (OS) of nivolumab/ipilimumab/GM-CSF (sargramostim) versus
    nivolumab/ipilimumab.

    SECONDARY OBJECTIVES:

    I. To evaluate progression free survival (PFS) of patients treated with
    nivolumab/ipilimumab/GM-CSF versus nivolumab/ipilimumab.

    II. To assess for differences in tolerability, specifically the rate of grade III or higher
    adverse events, between nivolumab/ipilimumab/GM-CSF versus nivolumab/ipilimumab.

    III. To explore comparisons of immune-related response criteria to standard criteria as
    endpoint evaluations.

    TERTIARY OBJECTIVES:

    I. To evaluate if patients treated with nivolumab/ipilimumab/GM-CSF have a better global
    quality of life.

    OUTLINE: Patients are randomized to 1 of 2 treatment arms.

    ARM I: INDUCTION THERAPY: Patients receive nivolumab intravenously (IV) over 60 minutes on
    day 1, ipilimumab IV over 90 minutes on day 1, and sargramostim subcutaneously (SC) on days
    1-14. Treatment repeats every 21 days for 4 courses in the absence of disease progression or
    unacceptable toxicity.

    MAINTENANCE THERAPY: Patients receive nivolumab and sargramostim as in Induction therapy.
    Patients with partial response (PR), stable disease (SD), or complete response (CR) at 24
    weeks may continue maintenance therapy in the absence of disease progression or unacceptable
    toxicity.

    ARM II: INDUCTION THERAPY: Patients receive nivolumab and ipilimumab as in Arm I. Treatment
    repeats every 21 days for 4 courses in the absence of disease progression or unacceptable
    toxicity.

    MAINTENANCE THERAPY: Patients receive nivolumab as in Induction therapy. Patients with PR,
    SD, or CR at 24 weeks may continue maintenance therapy in the absence of disease progression
    or unacceptable toxicity.

    After completion of study treatment, patients are followed up every 3 months for 2 years and
    then every 6 months for 3 years.

    Trial Arms

    Name Type Description Interventions
    Arm I (nivolumab, ipilimumab, sargramostim) Experimental INDUCTION THERAPY: Patients receive nivolumab IV over 60 minutes on day 1, ipilimumab IV over 90 minutes on day 1, and sargramostim SC on days 1-14. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive nivolumab and sargramostim as in Induction therapy. Patients with PR, SC, or CR at 24 weeks may continue maintenance therapy in the absence of disease progression or unacceptable toxicity.
    Arm II (nivolumab, ipilimumab) Experimental INDUCTION THERAPY: Patients receive nivolumab and ipilimumab as in Arm I. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive nivolumab as in Induction therapy. Patients with PR, SD, or CR at 24 weeks may continue maintenance therapy in the absence of disease progression or unacceptable toxicity.

    Eligibility Criteria

    Inclusion Criteria:

    - Eastern Cooperative Oncology Group (ECOG) performance status: 0 or 1

    - Patients must have known v-raf murine sarcoma viral oncogene homolog B1 (BRAF)
    mutational status of tumor; wild-type (WT) or mutated, prior to registration

    - Women must not be pregnant or breast-feeding; all females of childbearing potential
    must have a blood test or urine study within 2 weeks prior to registration to rule
    out pregnancy; a female of childbearing potential is any woman, regardless of sexual
    orientation or whether they have undergone tubal ligation, who meets the following
    criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has
    not been naturally postmenopausal for at least 24 consecutive months (i.e., has had
    menses at any time in the preceding 24 consecutive months)

    - Women of childbearing potential and sexually active males must be strongly advised to
    use an accepted and effective method of contraception or to abstain from sexual
    intercourse for the duration of their participation in the study

    - Patients must have unresectable stage III or stage IV melanoma; patients must have
    histological or cytological confirmation of melanoma that is metastatic or
    unresectable and clearly progressive

    - Patients must have measurable disease; all sites of disease must be evaluated within
    4 weeks prior to randomization

    - Patients may have had prior systemic therapy in the adjuvant setting; however,
    patients may not have had any prior treatment for advanced (measurable metastatic)
    disease or have had prior treatment with a BRAF or mitogen-activated protein kinase
    kinase (MEK) inhibitor or a cytotoxic T-lymphocyte antigen 4 (CTLA4) or programmed
    death (PD)1 pathway blocker; patients may not have had any prior ipilimumab or BRAF
    inhibitors in the adjuvant setting

    - Patients must have discontinued chemotherapy, immunotherapy or other investigational
    agents used in the adjuvant setting >= 4 weeks prior to entering the study and
    recovered from adverse events due to those agents; mitomycin and nitrosoureas must
    have been discontinued at least 6 weeks prior to entering the study; patients must
    have discontinued radiation therapy >= 2 weeks prior to entering the study and
    recovered from any adverse events associated with treatment; prior surgery must be >=
    4 weeks from registration and patients must be fully recovered from post-surgical
    complications

    - Patients must not receive any other investigational agents while on study or within
    four weeks prior to registration

    - Patients are excluded for receiving any non-oncology vaccine therapy used for
    prevention of infectious diseases for up to four weeks (28 days) prior to or after
    any dose of ipilimumab

    - Patients are ineligible if they have any currently active central nervous system
    (CNS) metastases; patients who have treated brain metastases (with either surgical
    resection or stereotactic radiosurgery) that have been stable on head magnetic
    resonance imaging (MRI) or contrast computed tomography (CT) scan for at least 4
    weeks following treatment and within 4 weeks prior to randomization are eligible;
    patients must not have taken any steroids =< 14 days prior to randomization for the
    purpose of managing their brain metastases; patients with only whole brain
    irradiation for treatment of CNS metastases will be ineligible

    - Patients must not have other current malignancies, other than basal cell skin cancer,
    squamous cell skin cancer, in situ cervical cancer, ductal or lobular carcinoma in
    situ of the breast; patients with other malignancies are eligible if they have been
    continuously disease-free for > 3 years prior to the time of registration; patients
    with history of retrovirus-associated deoxyribonucleic acid (DNA) sequence (RAS)
    mutation-positive tumors are not eligible regardless of interval from the current
    study; note: prospective RAS testing is not required; however, if the results of
    previous RAS testing are known, they must be used in assessing eligibility

    - White blood count >= 3,000/uL

    - Absolute neutrophil count (ANC) >= 1,500/uL

    - Platelet count >= 100,000/uL

    - Hemoglobin >= 9 g/dL

    - Serum creatinine =< 1.5 x upper limit of normal (ULN) or serum creatinine clearance
    (CrCl) >= 40 ml/min

    - Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (=< 5
    x ULN for patients with documented liver metastases)

    - Alkaline phosphatase =< 2 x ULN (=< 5 x ULN for patients with known liver involvement
    and =< 7x ULN for patients with known bone involvement)

    - Total bilirubin =< 1.5 x ULN except subjects with normal direct bilirubin or those
    with known Gilbert's syndrome

    - Serum lactate dehydrogenase (LDH) =< 10 X ULN

    - Patients must not have any serious or unstable pre-existing medical conditions (aside
    from malignancy exceptions specified above), including but not limited to, ongoing or
    active infection requiring parenteral antibiotics on day 1, history of bleeding
    diathesis or need for concurrent anticoagulation (international normalized ratio
    [INR] =< 1.5 and partial thromboplastin time [PTT] within 1.1 x ULN), or psychiatric
    illness/social situations that would limit compliance with study requirements,
    interfere with subject's safety, or obtaining informed consent

    - Patients with evidence of active hepatitis B Virus (HBV) or hepatitis C Virus (HCV)
    infection are not eligible; patients with cleared HBV and HCV infection will be
    allowed

    - Patients must not have autoimmune disorders or conditions of immunosuppression that
    require current ongoing treatment with systemic corticosteroids (or other systemic
    immunosuppressants), including oral steroids (e.g., prednisone, dexamethasone) or
    continuous use of topical steroid creams or ointments or ophthalmologic steroids; a
    history of occasional (but not continuous) use of steroid inhalers is allowed;
    replacement doses of steroids for patients with adrenal insufficiency are allowed;
    patients who discontinue use of these classes of medication for at least 2 weeks
    prior to randomization are eligible if, in the judgment of the treating physician
    investigator, the patient is not likely to require resumption of treatment with these
    classes of drugs during the study

    - Exclusion from this study also includes patients with a history of symptomatic
    autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis
    [scleroderma], systemic lupus erythematosus, Sjgren's syndrome, autoimmune
    vasculitis [e.g., Wegener's granulomatosis]); motor neuropathy considered of
    autoimmune origin (e.g., Guillain-Barre syndrome and myasthenia gravis); other CNS
    autoimmune disease (e.g., poliomyelitis, multiple sclerosis)

    - Patients with autoimmune hypothyroid disease or type I diabetes on replacement
    treatment are eligible

    - Patients must not have a history of inflammatory bowel disease or diverticulitis
    (history of diverticulosis is allowed)

    - Patients must not have other significant medical, surgical, or psychiatric conditions
    or require any medication or treatment that in the opinion of the investigator may
    interfere with compliance, make the administration of the study drugs hazardous or
    obscure the interpretation of adverse events (AEs), such as a condition associated
    with frequent diarrhea; patients must not have an active infection requiring current
    treatment with parenteral antibiotics

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    OS

    Secondary Outcome Measures

    Clinical response, assessed using the utility of irRC

    Immune response, assessed using the utility of Immune related response criteria (irRC)

    Incidence of toxicities, defined using the Common Terminology Criteria for Adverse Events version 4.0 criteria

    PFS, evaluated based on international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)

    Trial Keywords