Sargramostim, Vaccine Therapy, or Sargramostim and Vaccine Therapy in Preventing Disease Recurrence in Patients With Melanoma That Has Been Removed By Surgery

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Brief Title

Sargramostim, Vaccine Therapy, or Sargramostim and Vaccine Therapy in Preventing Disease Recurrence in Patients With Melanoma That Has Been Removed By Surgery

Official Title

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

Brief Summary

      This randomized phase III trial studies sargramostim or vaccine therapy alone to see how well
      they work compared to sargramostim and vaccine therapy together in preventing disease
      recurrence in patients with 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.
    

Detailed Description

      PRIMARY OBJECTIVES:

      I. To compare overall survival and disease-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 disease-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 disease-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 disease-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: 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 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).

      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 SC 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 SC 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 SC 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 10 years.
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

Overall Survival

Secondary Outcome

 Overall Survival in Human Leukocyte Antigens-A2 (HLA-A2) Positive Patients

Condition

Iris Melanoma

Intervention

Laboratory Biomarker Analysis

Study Arms / Comparison Groups

 Arm I (sargramostim, peptide vaccine)
Description:  Patients receive 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).

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Other

Estimated Enrollment

815

Start Date

February 23, 2000

Completion Date

January 31, 2013

Primary Completion Date

October 8, 2012

Eligibility Criteria

        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

          -  Prior treatment with GM-CSF or any peptides used in this protocol, is not allowed

          -  Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

          -  Patients must not have an active infection requiring treatment with parenteral
             antibiotics

          -  Patients must not 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 must not 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

          -  Patients must be able to self-administer or arrange for administration of subcutaneous
             injections

          -  Patients who have other current malignancies are not eligible

          -  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/mm?

          -  Platelet count >= 100,000/mm?

          -  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
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

David H Lawson, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01989572

Organization ID

NCI-2013-02101

Secondary IDs

NCI-2013-02101

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

David H Lawson, Principal Investigator, Eastern Cooperative Oncology Group


Verification Date

June 2020