Sargramostim and/or Vaccine Therapy in Preventing Disease Recurrence in Patients With Advanced Melanoma

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01989572
First received: November 18, 2013
Last updated: July 22, 2014
Last verified: March 2014

November 18, 2013
July 22, 2014
February 2000
January 2013   (final data collection date for primary outcome measure)
  • Overall Survival [ Time Frame: assessed every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry, and annually if >5 years ] [ Designated as safety issue: No ]
    Overall survival is defined as time from randomization to death from any cause.
  • Recurrence Free Survival [ Time Frame: assessed every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry, and annually if >5 years ] [ Designated as safety issue: No ]
    Recurrence free survival is defined as time from randomization to first disease recurrence or death from any cause (whichever occur first), censoring cases without recurrence or death at the last date of known free of recurrence free survival events.
Overall survival [ Time Frame: Up to 15 years ] [ Designated as safety issue: No ]
Performed using a two-sided log-rank test stratified on HLA-A2 status, site of metastases, and number of metastatic lesions, using an overall type I error of 0.05. Overall survival of PEP+ vs PEP- groups in the HLA-A2+ population will be compared.
Complete list of historical versions of study NCT01989572 on ClinicalTrials.gov Archive Site
  • Overall Survival in Human Leukocyte Antigens-A2 (HLA-A2) Positive Patients [ Time Frame: assessed every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry, and annually if >5 years ] [ Designated as safety issue: No ]
    Overall survival is defined as time from randomization to death from any cause.
  • Recurrence Free Survival in HLA-A2 Positive Patients [ Time Frame: assessed every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry, and annually if >5 years ] [ Designated as safety issue: No ]
    Recurrence free survival is defined as time from randomization to first disease recurrence or death from any cause (whichever occur first), censoring cases without recurrence or death at the last date of known free of recurrence free survival events.
  • 5-year Overall Survival Rate [ Time Frame: assessed every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry, and annually if >5 years ] [ Designated as safety issue: No ]
    Overall survival is defined as time from randomization to death from any cause, and 5-year overall survival rate is estimated via Kaplan-Meier method.
  • 5-year Recurrence Free Survival Rate [ Time Frame: assessed every 3 months if patient is < 2 years from study entry and every 6 months if patient is 2-5 years from study entry, and annually if >5 years ] [ Designated as safety issue: No ]
    Recurrence free survival is defined as time from randomization to first disease recurrence or death from any cause (whichever occur first), censoring cases without recurrence or death at the last date of known free of recurrence free survival events, and 5-year overall survival rate is estimated via Kaplan-Meier method.
Disease-free survival [ Time Frame: From randomization to date of recurrence or death, whichever comes first, assessed up to 15 years ] [ Designated as safety issue: No ]
The cure rate model will be used to compare the peptide positive versus the peptide negative groups. The truncated O'Brien-Fleming boundaries will be used for the interim analyses with an overall two-sided type I error rate of 0.05. The stratified log-rank test, stratifying on the presence and absence of sargramostim, will be used in this comparison.
Not Provided
  • Change in number of T-cells [ Time Frame: Baseline up to day 43 ] [ Designated as safety issue: No ]
    The statistical analysis for this endpoint will involve doing a two-sample Wilcoxon rank sum test for the null hypothesis that d equals zero against the alternative that d does not equal zero.
  • Change in number of circulating dendritic cells [ Time Frame: Baseline up to day 43 ] [ Designated as safety issue: No ]
    The statistical analysis for this endpoint will involve doing a two-sample Wilcoxon rank sum test for the null hypothesis that d equals zero against the alternative that d does not equal zero.
  • Immune response in terms of cluster of differentiation (CD)8 T-cells and CD4 T-cell responses [ Time Frame: Up to 3 months ] [ Designated as safety issue: No ]
    The raw ELISPOT counts will be used in a repeated measures analysis to estimate changes in the mean counts as a function of treatment group
 
Sargramostim and/or Vaccine Therapy in Preventing Disease Recurrence in Patients With Advanced Melanoma
A Randomized, Placebo-Controlled Phase III Trial of Yeast Derived GM-CSF Versus Peptide Vaccination Versus GM-CSF Plus Peptide Vaccination Versus Placebo in Patients With "No Evidence of Disease" After Complete Surgical Resection of "Locally Advanced" and/or Stage IV Melanoma

This randomized phase III trial studies sargramostim (Granulocyte-macrophage colony-stimulating factor, GM-CSF) or vaccine therapy alone to see how well they work compared to sargramostim and vaccine therapy together in preventing disease recurrence in patients with locally advanced or stage IV melanoma that has been removed by surgery. Sargramostim may stimulate the immune system in different ways and stop tumor cells from growing. Vaccines made from peptides may help the body build an effective immune response to kill tumor cells. It is not yet known whether yeast derived sargramostim and vaccine therapy are more effective alone or together in preventing recurrence of melanoma.

PRIMARY OBJECTIVES:

I. To compare overall survival and recurrence-free survival of patients with completely resected stage IV melanoma or stage III melanoma with gross extranodal extension, satellites, and/or intransit lesions, treated with granulocyte macrophage colony-stimulating factor (GM-CSF) (sargramostim) vs. no GM-CSF, or other high risk patients listed in the eligibility section.

SECONDARY OBJECTIVES:

I. To compare, using a 2 x 2 factorial design, overall survival and recurrence-free survival of human leukocyte antigen (HLA)-A2 positive patients treated with peptide vaccination vs. no peptide vaccination.

II. The following descriptive evaluations of survival and recurrence-free survival are planned for the HLA-A2 positive patients: (1) GM-CSF plus peptide vaccination vs. peptide vaccination alone; (2) GM-CSF plus peptide vaccination vs. GM-CSF alone; (3) GM-CSF plus peptide vaccination vs. placebo.

III. Survival and recurrence-free survival of HLA-A2 positive patients not receiving peptide vaccination will be compared to that of HLA-A2 negative patients not receiving peptide vaccination.

IV. To determine the influence of GM-CSF on circulating dendritic cell numbers and subpopulations in peripheral blood of patients receiving and not receiving GM-CSF.

V. To determine, in HLA-A2 positive patients, whether immunization with peptides with or without GM-CSF elicits a measurable T-cell response as assessed by enzyme-linked immunosorbent spot (ELISPOT) and the major histocompatibility complex (MHC) tetramer assay, and to determine the functionality of these cells by intracellular cytokine staining.

OUTLINE: After patients are screened for HLA-A2 positivity, patients would be categorized into two groups: HLA-A2 positive patients and HLA-A2 negative patients. HLA-A2 positive patients are randomized to 1 of 4 treatment regimens (Arms I-IV). HLA-A2 negative patients are randomized to 1 of 2 treatment arms (Arms V-VI).

ARM I: Patients receive sargramostim subcutaneously (SC) on days 1-14 and peptide vaccine comprising tyrosinase, gp100 antigen, and melanoma antigen recognized by T-cells 1 (MART-1) mixed with either incomplete Freund's adjuvant or Montanide ISA-51 VG subcutaneously on days 1 and 15 (course 1) and day 1 (course 2 and subsequent courses).

ARM II: Patients receive sargramostim placebo SC on days 1-14 and peptide vaccine comprising tyrosinase, gp100 antigen, and MART-1 antigen mixed with either incomplete Freund's adjuvant or Montanide ISA-51 VG subcutaneously on days 1 and 15 (course 1) and day 1 (course 2 and subsequent courses).

ARM III: Patients receive sargramostim SC on days 1-14 and peptide placebo mixed with either incomplete Freund's adjuvant or Montanide ISA-51 VG subcutaneously on days 1 and 15 (course 1) and day 1 (course 2 and subsequent courses).

ARM IV: Patients receive sargramostim placebo SC on days 1-14 and peptide placebo mixed with either incomplete Freund's adjuvant or Montanide ISA-51 VG subcutaneously on days 1 and 15 (course 1) and day 1 (course 2 and subsequent courses).

ARM V: Patients receive sargramostim SC on days 1-14.

ARM VI: Patients receive sargramostim placebo SC on days 1-14.

In all arms, treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity.

In the event of recurrence, patients who undergo complete resection of the recurrence may continue treatment for 6 courses or until completion of 1 year of therapy (whichever is longer). For patients with recurrence that is not surgically resectable or experiencing second recurrence, treatment will be discontinued.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then every 12 months for 15 years.

PROJECTED ACCRUAL: 800 patients

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Prevention
  • Local Recurrence of Malignant Melanoma of Skin
  • Stage IV Melanoma
  • Biological: sargramostim
    Given SC
    Other Names:
    • GM-CSF
    • Leukine
    • Prokine
  • Biological: peptide vaccine
    Given SC
    Other Names:
    • TYRP
    • tyrosinase peptide
  • Other: GM-CSF placebo
    Given SC
    Other Name: PLCB
  • Other: peptide placebo
    Given SC
    Other Name: PLCB
  • Experimental: Arm I (GM-CSF, peptide vaccine)
    Patients receive GM-CSF (sargramostim) SC on days 1-14 and peptide vaccine comprising tyrosinase, gp100 antigen, and MART-1 antigen mixed with either incomplete Freund's adjuvant or Montanide ISA-51 VG SC on days 1 and 15 (course 1) and day 1 (course 2 and subsequent courses).
    Interventions:
    • Biological: sargramostim
    • Biological: peptide vaccine
  • Experimental: Arm II (GM-CSF placebo, peptide vaccine)
    Patients receive GM-CSF (sargramostim) placebo SC on days 1-14 and peptide vaccine comprising tyrosinase, gp100 antigen, and MART-1 antigen mixed with either incomplete Freund's adjuvant or Montanide ISA-51 VG SC on days 1 and 15 (course 1) and day 1 (course 2 and subsequent courses).
    Interventions:
    • Biological: peptide vaccine
    • Other: GM-CSF placebo
  • Experimental: Arm III (GM-CSF, peptide placebo)
    Patients receive GM-CSF (sargramostim) SC on days 1-14 and peptide placebo mixed with either incomplete Freund's adjuvant or Montanide ISA-51 VG SC on days 1 and 15 (course 1) and day 1 (course 2 and subsequent courses).
    Interventions:
    • Biological: sargramostim
    • Other: peptide placebo
  • Placebo Comparator: Arm IV (GM-CSF placebo, peptide placebo)
    Patients receive GM-CSF placebo SC on days 1-14 and peptide placebo on days 1 and 15 (course 1) and day 1 (course 2 and subsequent courses).
    Interventions:
    • Other: GM-CSF placebo
    • Other: peptide placebo
  • Experimental: Arm V (GM-CSF)
    Patients receive GM-CSF (sargramostim) SC on days 1-14.
    Intervention: Biological: sargramostim
  • Placebo Comparator: Arm VI (GM-CSF placebo)
    Patients receive GM-CSF (sargramostim) placebo SC on days 1-14.
    Intervention: Other: GM-CSF placebo
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
815
January 2013
January 2013   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Patients must have HLA-A2 status known prior to randomization; typing may be obtained through a local laboratory facility or through a reference lab utilized by the initiating institution; if typing is not available through these means, it may be obtained from the University of Pittsburgh
  • All patients must have disease completely resected with one of the following in order to be eligible:

    • Completely resected disease
    • Any locoregional recurrence after prior adjuvant interferon or failure on S008
    • Any local recurrence of disease after adequate surgical excision of the original primary
    • Mucosal melanoma
    • Stage IV melanoma (cutaneous, ocular, mucosal, or unknown primary)
  • The following groups of patients may be entered onto this trial only if they are ineligible for S0008 or are, in the opinion of the managing physician, medically unfit to receive standard high-dose interferon:

    • Any clinically evident satellite or in-transit disease
    • Stage II disease with gross extracapsular extension
    • Recurrence in a previously resected nodal basin
    • Four or more involved lymph nodes or matted lymph nodes
    • Ulcerated primary melanoma and any involved lymph nodes

      • NOTE: Patients who are eligible for S0008 will be strongly encouraged to participate in that study in preference to this one
  • Patients must have been surgically rendered free of disease with negative margins on resected specimens; patients rendered free of disease by non-surgical means are not eligible
  • Patients must be randomized within 112 days (16 weeks) of surgical resection; if more than one surgical procedure is required to render the patient disease-free, all required surgeries must be accomplished within this 16 week time period
  • Patients must not have received any adjuvant treatment (chemotherapy, biotherapy, or limb perfusion) after the resection(s) that make(s) them eligible for this trial; one systemic treatment after a prior surgery is allowed, and must have been completed >= 8 weeks prior to randomization; (when chemotherapy and biotherapy are given together as one planned treatment [biochemotherapy], this counts as one regimen); NOTE: Previous radiation therapy, including after the resection, is allowed as long as 30 days elapse between the radiation and initiation of therapy
  • Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  • Patients must be able to self-administer or arrange for administration of subcutaneous injections
  • Patients with prior history at any time of any in situ cancer, lobular carcinoma of the breast in situ, cervical cancer in situ, atypical melanocytic hyperplasia or Clark I melanoma in situ are eligible; patients who meet this criteria must be disease-free at time of randomization
  • Patients with prior history of basal or squamous skin cancer are eligible; patients who meet this criteria must be disease-free at time of randomization
  • Patients who have had multiple primary melanomas are eligible
  • Patients with other malignancies are eligible if they have been continuously disease free for > 5 years prior to the time of randomization
  • Patients must not have autoimmune disorders, conditions of immunosuppression or treatment with systemic corticosteroids, including oral steroids (i.e., prednisone, dexamethasone), continuous use of topical steroid creams or ointments, or any steroid containing inhalers; 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, the patient is not likely to require these classes of drugs during the study
  • Women of childbearing potential must not be pregnant (negative beta human chorionic gonadotropin [bHCG] within 2 weeks prior to randomization) or breast-feeding
  • Women of childbearing potential and sexually active males must be counseled to use an accepted and effective method of contraception (including abstinence) while on treatment and for a period of 18 months after completing or discontinuing treatment
  • All patients must have brain computed tomography (CT) or magnetic resonance imaging (MRI), chest CT or chest x-ray (CXR), and abdominal (liver) CT or MRI within 4 weeks prior to randomization; positron emission tomography (PET) scans are also acceptable in place of CT, CXR and/or abdominal MRI if obtained within 4 weeks prior to randomization; patients with lesions on the lower extremity must also have pelvic imaging within this time period; this is also strongly recommended for patients with lesions on the lower trunk; PET scans are acceptable
  • Patients with resection of visceral disease must have imaging of the affected area/organ documenting disease-free status within 2 weeks prior to randomization
  • White blood cells (WBC) >= 3,000/mm³
  • Platelet count >= 100,000/mm³
  • Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2 x institutional upper limit (IUL) of normal
  • Bilirubin =< 2 x IUL of normal
  • Serum creatinine =< 1.8 mg/dl
  • Alkaline phosphatase and lactate dehydrogenase (LDH) must be performed within 4 weeks prior to randomization; LDH must be normal; patients with abnormal alkaline phosphatase which is =< 1.25 times the institutional upper limit of normal who have a negative CT or MRI of the liver and negative bone scan or a negative PET scan are eligible
  • Patients with bone pain must have a bone scan within 4 weeks prior to randomization to document the absence of tumor

Exclusion criteria:

  • Prior treatment with GM-CSF or any peptides used in this protocol
  • Patients who have other current malignancies are not eligible
  • Patients have an active infection requiring treatment with parenteral antibiotics
  • Patients have other significant medical, surgical, or psychiatric conditions or require any medication or treatment that may interfere with compliance on any of the E4697 treatment regimens
  • Patients have a diagnosis or evidence of organic brain syndrome or significant impairment of basal cognitive function or any psychiatric disorder that might preclude participation in the full protocol
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01989572
NCI-2013-02101, E4697, U10CA021115
Yes
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: David Lawson Medical Oncology, Emory University
National Cancer Institute (NCI)
March 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP