Vaccine Therapy Using Melanoma Peptides for Cytotoxic T Cells and Helper T Cells in Treating Patients With Metastatic Melanoma

• Sponsor: Eastern Cooperative Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00071981
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 175
• Locations: 65
• Arms: 4
• Duration (Months): 106.1
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Vaccines made from peptides may make the body build an immune response to kill tumor cells.

PURPOSE: This randomized phase II trial is studying four different vaccines using melanoma peptides from cytotoxic T cells and helper T cells to see how well they work in treating patients with metastatic melanoma.

Condition or Disease	Intervention/Treatment	Phase
Melanoma (Skin)	Biological: incomplete Freund's adjuvant; Biological: melanoma helper peptide vaccine; Biological: multi-epitope melanoma peptide vaccine; Biological: sargramostim; Biological: tetanus peptide melanoma vaccine	Phase 2

Detailed Description

OBJECTIVES:

• Compare the cytotoxic T-cell response to each of 12 melanoma peptides restricted by Human Leukocyte Antigen (HLA)-A1, -A2, or -A3 in patients with metastatic melanoma vaccinated with or without these 12 melanoma peptides and with or without helper peptides.

• Compare the helper T-cell response to each of 6 melanoma helper peptides restricted by HLA-DR molecules in patients treated with these vaccinations.

• Determine whether the addition of 6 melanoma helper peptides to a vaccine containing multiple class I Major histocompatibility complex (MHC)-restricted peptides augments T-cell responses to the class I restricted peptides in these patients.

• Determine, preliminarily, whether booster vaccination maintains immune response in patients treated with these vaccinations.

• Compare the rates of clinical response and survival in patients treated with these vaccinations.

• Determine, preliminarily, whether cellular immune response correlates with clinical response and survival rates in patients treated with these vaccinations.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to HLA type (HLA-A1 vs HLA-A2 vs HLA-A1 and -A2 vs HLA-A3) and planned sentinel immunized node biopsy (yes vs no). Patients are randomized to 1 of 4 treatment arms.

• Arm I: Patients receive 2 injections of multi-epitope peptide vaccine comprising 12 melanoma peptides restricted by Class I MHC (12MP) emulsified with sargramostim (Granulocyte-macrophage colony-stimulating factor, GM-CSF) and Montanide ISA-51 or Montanide ISA-51 VG (ISA-51) intradermally (ID) and subcutaneously (SC) on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.

• Arm II: Patients receive 2 injections of multi-epitope peptide vaccine comprising 12MP and 1 tetanus helper peptide emulsified with GM-CSF and ISA-51 ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.

• Arm III (closed to accrual as of 5/19/08): Patients receive 2 injections of multi-epitope peptide vaccine comprising 12MP and 6 melanoma helper peptides (6HP) emulsified with GM-CSF and ISA-51 ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.

• Arm IV: Patients receive 2 injections of multi-epitope peptide vaccine comprising 6HP emulsified with GM-CSF and ISA-51 ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.

In all arms, patients continue therapy in the absence of unacceptable toxicity or disease progression necessitating other urgent therapy.

Patients are evaluated at 8 and 12 weeks. Beginning 2-3 weeks after the week-12 evaluation, patients with no evidence of disease progression may receive booster vaccinations according to their randomized treatment arm. Patients receive booster vaccination ID and SC once weekly for 3 weeks. Treatment repeats every 9 weeks for 1 course, every 12 weeks for 2 courses, and then every 24 weeks for 2 courses OR for up to 2 years (whichever comes first) provided the patient does not require an urgent change in therapy.

After completion of study treatment, patients are followed every 6 months for 2 years and then for survival for 5 years from study randomization.

ACTUAL ACCRUAL: A total of 175 patients were accrued for this study during March 2005 and January 2009.

Study Design

• Study Type: Interventional
• Actual Enrollment: 175 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Trial of Multi-Epitope Vaccination With Melanoma Peptides For Cytotoxic T Cells And Helper T Cells For Patients With Metastatic Melanoma
• Study Start Date: Mar 1, 2005
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: Jan 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (12MP) Patients receive 2 injections of multi-epitope peptide vaccine comprising 12 melanoma peptides restricted by Class I MHC (12MP) emulsified with sargramostim (GM-CSF) and Montanide ISA-51 (incomplete Freund's adjuvant) or Montanide ISA-51 VG (ISA-51) intradermally (ID) and subcutaneously (SC) on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.	Biological: incomplete Freund's adjuvant; Given by injection; Other Names: Montanide ISA-51 ; Biological: multi-epitope melanoma peptide vaccine; Given by injection; Other Names: 12 Melanoma peptides from melanocyte differentiation protein (MDP) and cancer testis antigen (CTA), 12 melanoma peptides restricted by class I MHC molecules,restricted by HLA-A1, A2, or A3 molecules ; Biological: sargramostim; Given by injection; Other Names: rhu GM-CSF, Leukine, Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF)
Experimental: Arm II (12MP/Tet) Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 1 tetanus peptide melanoma vaccine emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.	Biological: incomplete Freund's adjuvant; Given by injection; Other Names: Montanide ISA-51 ; Biological: multi-epitope melanoma peptide vaccine; Given by injection; Other Names: 12 Melanoma peptides from melanocyte differentiation protein (MDP) and cancer testis antigen (CTA), 12 melanoma peptides restricted by class I MHC molecules,restricted by HLA-A1, A2, or A3 molecules ; Biological: sargramostim; Given by injection; Other Names: rhu GM-CSF, Leukine, Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) ; Biological: tetanus peptide melanoma vaccine; Given by injection; Other Names: Modified Tetanus p2 peptide restricted by class II MHC molecules, Peptide-Tet
Experimental: Arm III (12MP/6MHP) Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 6 melanoma helper peptides (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.	Biological: incomplete Freund's adjuvant; Given by injection; Other Names: Montanide ISA-51 ; Biological: melanoma helper peptide vaccine; Given by injection; Other Names: 6 melanoma helper peptides restricted by class II MHC molecules, restricted by HLADR molecules, 6 class II MHC-Restricted Melanoma-Associated Peptides ; Biological: multi-epitope melanoma peptide vaccine; Given by injection; Other Names: 12 Melanoma peptides from melanocyte differentiation protein (MDP) and cancer testis antigen (CTA), 12 melanoma peptides restricted by class I MHC molecules,restricted by HLA-A1, A2, or A3 molecules ; Biological: sargramostim; Given by injection; Other Names: rhu GM-CSF, Leukine, Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF)
Experimental: Arm IV (6MHP) Patients receive 2 injections of multi-epitope peptide vaccine comprising melanoma helper peptide vaccine (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7.	Biological: incomplete Freund's adjuvant; Given by injection; Other Names: Montanide ISA-51 ; Biological: melanoma helper peptide vaccine; Given by injection; Other Names: 6 melanoma helper peptides restricted by class II MHC molecules, restricted by HLADR molecules, 6 class II MHC-Restricted Melanoma-Associated Peptides ; Biological: sargramostim; Given by injection; Other Names: rhu GM-CSF, Leukine, Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF)

Outcome Measures

Primary Outcome Measures

1. Cytotoxic T-cell Lymphocytes (CTL) Response Rate [Immune response was assessed at pre-registrtion, in weeks 1, 3, 5, 7, 8]

   Assessment of CTL response was based on a fold-increase in T cell response measure by interferon-gamma ELIspot assay.

Secondary Outcome Measures

1. Helper T-cells Response to 6MHP [Immune response was assessed at pre-registration, in weeks 1,3,5,7,8]

   Helper T cell response was evaluated by tritiated thymidine proliferation assay with fresh/cryopreserved PBL in the presence of each of the helper peptides.

2. Helper T Cell Response to Tetanus [Immune response was assessed at pre-registration, in weeks 1,3,5,7,8]

   Helper T cell response was evaluated by tritiated thymidine proliferation assay with fresh/cryopreserved PBL in the presence of each of the helper peptides.

3. Objective Response Rate [Tumor response was assessed in weeks 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, and 6 months after last vaccination]

   Tumor response was assessed via Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Objective response rate is calculated as the number of patients with complete response (disappearance of all lesions) or partial response () divided by total number of evaluable patients.

4. Median Overall Survival (OS) [assessed every 3 month within 2 years and every 6 months betwen 2 and 5 years]

   OS was defined as the time from registration to death from any cause.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically confirmed stage IV melanoma

• Multiple primary melanomas allowed

• Metastasis may be from a cutaneous, mucosal, ocular, or unknown primary site

• Measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST criteria)

• Must have 2 extremities uninvolved with tumor

• Must have at least 2 intact (undissected) axillary and/or inguinal lymph node basins

• Prior sentinel node biopsy may not have violated the integrity of a nodal basin

• This extremity may still be considered for vaccination

• Human Lymphocyte Antigen (HLA)-A1, -A2, or -A3 positive

• Prior brain metastases allowed provided all of the following are true:

• Surgically resected or treated with gamma-knife or stereotactic radiosurgery

• No disease progression in the brain for the past 3 months

• More than 30 days since prior steroids for the management of brain metastases

• Age: 18 and over

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

• Adequate organ function measured within 4 weeks before randomization:

• White blood cell (WBC) at least 4,000/mm^3

• Platelet count at least 100,000/mm^3

• Lymphocyte count at least 700/mm^3

• Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) no greater than 2 times upper limit of normal (ULN)

• Bilirubin no greater than 2 times ULN

• Alkaline phosphatase no greater than 2 times ULN

• Lactic dehydrogenase no greater than 2 times ULN

• Creatinine no greater than 1.8 mg/dL

• Negative pregnancy test

• Fertile patients must use effective contraception

• No other malignancy within the past 5 years except nonmetastatic squamous cell or basal cell skin cancer, ductal or lobular carcinoma in situ of the breast, or carcinoma in situ of the cervix

• At least 4 weeks since prior sargramostim (GM-CSF), interferon alfa-2b, or interleukin-2

• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)

• More than 30 days since prior systemic corticosteroids, including any of the following:

• Therapeutic doses of oral steroids (e.g., prednisone or dexamethasone)

• Steroid inhalers (e.g., Advair)

• Topical steroids and nasal steroids with low systemic absorption (e.g., fluticasone) or steroids with low systemic absorption (e.g., triamcinolone hexacetonide) injected into a joint space allowed

• At least 4 weeks since prior local control or palliative radiotherapy and recovered

• Recovered from prior major surgery

Exclusion criteria:

• More than 3 brain metastases

• Metastatic lesions greater than 2 cm

• Concurrent radiotherapy

• Prior radiotherapy to measurable disease

• Concurrent surgery

• Concurrent corticosteroids

• Concurrent topical or systemic steroids

• Concurrent chemotherapy

• Prior vaccination with any of the study peptides

• Recent (within the past year) or concurrent addiction to alcohol or illicit drugs

• Pregnant or nursing

• Known or suspected major allergy to any components of the study vaccine

• Significant detectable infection

• Immunosuppression conditions

• Prior or active autoimmune disorder requiring cytotoxic or mmunosuppressive therapy, except for any of the following:

• Presence of laboratory evidence of autoimmune disease (e.g., positive antinuclear antibody (ANA) titer) without symptoms

• Clinical evidence of vitiligo or other forms of depigmenting illness

• Mild arthritis requiring nonsteroidal anti-inflammatory medication

• Autoimmune disorder with visceral involvement

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Veterans Affairs Medical Center - Palo Alto	Palo Alto	California	United States	94304
2	Stanford Cancer Center	Stanford	California	United States	94305-5824
3	Tunnell Cancer Center at Beebe Medical Center	Lewes	Delaware	United States	19958
4	CCOP - Christiana Care Health Services	Newark	Delaware	United States	19713
5	Mayo Clinic - Jacksonville	Jacksonville	Florida	United States	32224
6	University of Miami Sylvester Comprehensive Cancer Center - Miami	Miami	Florida	United States	33136
7	Rush-Copley Cancer Care Center	Aurora	Illinois	United States	60504
8	Robert H. Lurie Comprehensive Cancer Center at Northwestern University	Chicago	Illinois	United States	60611-3013
9	Hematology and Oncology Associates	Chicago	Illinois	United States	60611
10	Midwest Center for Hematology/Oncology	Joliet	Illinois	United States	60432
11	Joliet Oncology-Hematology Associates, Limited - West	Joliet	Illinois	United States	60435
12	North Shore Oncology and Hematology Associates, Limited - Libertyville	Libertyville	Illinois	United States	60048
13	Cancer Care and Hematology Specialists of Chicagoland - Niles	Niles	Illinois	United States	60714
14	Hematology Oncology Associates - Skokie	Skokie	Illinois	United States	60076
15	Carle Cancer Center at Carle Foundation Hospital	Urbana	Illinois	United States	61801
16	CCOP - Carle Cancer Center	Urbana	Illinois	United States	61801
17	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202-5289
18	William N. Wishard Memorial Hospital	Indianapolis	Indiana	United States	46202
19	Saint Anthony Memorial Health Centers	Michigan City	Indiana	United States	46360
20	McCreery Cancer Center at Ottumwa Regional	Ottumwa	Iowa	United States	52501
21	Greater Baltimore Medical Center Cancer Center	Baltimore	Maryland	United States	21204
22	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21231-2410
23	Union Hospital Cancer Program at Union Hospital	Elkton MD	Maryland	United States	21921
24	Borgess Medical Center	Kalamazoo	Michigan	United States	49001
25	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007-3731
26	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
27	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
28	Mercy and Unity Cancer Center at Mercy Hospital	Coon Rapids	Minnesota	United States	55433
29	Fairview Southdale Hospital	Edina	Minnesota	United States	55435
30	Mercy and Unity Cancer Center at Unity Hospital	Fridley	Minnesota	United States	55432
31	Minnesota Oncology Hematology, PA - Maplewood	Maplewood	Minnesota	United States	55109
32	Virginia Piper Cancer Institute at Abbott - Northwestern Hospital	Minneapolis	Minnesota	United States	55407
33	Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center	Robbinsdale	Minnesota	United States	55422-2900
34	Mayo Clinic Cancer Center	Rochester	Minnesota	United States	55905
35	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota	United States	55416
36	Park Nicollet Cancer Center	Saint Louis Park	Minnesota	United States	55416
37	United Hospital	Saint Paul	Minnesota	United States	55102
38	St. Francis Cancer Center at St. Francis Medical Center	Shakopee	Minnesota	United States	55379
39	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
40	Minnesota Oncology Hematology, PA - Woodbury	Woodbury	Minnesota	United States	55125
41	CCOP - Northern New Jersey	Hackensack	New Jersey	United States	07601
42	Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School	New Brunswick	New Jersey	United States	08903
43	Cancer Institute of New Jersey at Cooper - Voorhees	Voorhees	New Jersey	United States	08043
44	Christ Hospital Cancer Center	Cincinnati	Ohio	United States	45219
45	Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44106-5065
46	Morgan Cancer Center at Lehigh Valley Hospital - Cedar Crest	Allentown	Pennsylvania	United States	18105
47	St. Mary Regional Cancer Center	Langhorne	Pennsylvania	United States	19047
48	Fox Chase Cancer Center - Philadelphia	Philadelphia	Pennsylvania	United States	19111-2497
49	UPMC Cancer Centers	Pittsburgh	Pennsylvania	United States	15232
50	Avera Cancer Institute	Sioux Falls	South Dakota	United States	57105
51	Medical X-Ray Center, PC	Sioux Falls	South Dakota	United States	57105
52	Sanford Cancer Center at Sanford USD Medical Center	Sioux Falls	South Dakota	United States	57117-5039
53	Center for Cancer Treatment & Prevention at Sacred Heart Hospital	Eau Claire	Wisconsin	United States	54701
54	Marshfield Clinic Cancer Care at Regional Cancer Center	Eau Claire	Wisconsin	United States	54701
55	Gundersen Lutheran Center for Cancer and Blood	La Crosse	Wisconsin	United States	54601
56	University of Wisconsin Paul P. Carbone Comprehensive Cancer Center	Madison	Wisconsin	United States	53792-6164
57	Marshfield Clinic - Marshfield Center	Marshfield	Wisconsin	United States	54449
58	Saint Joseph's Hospital	Marshfield	Wisconsin	United States	54449
59	Marshfield Clinic - Lakeland Center	Minocqua	Wisconsin	United States	54548
60	Ministry Medical Group at Saint Mary's Hospital	Rhinelander	Wisconsin	United States	54501
61	Marshfield Clinic - Indianhead Center	Rice Lake	Wisconsin	United States	54868
62	Saint Michael's Hospital Cancer Center	Stevens Point	Wisconsin	United States	54481
63	Marshfield Clinic - Wausau Center	Wausau	Wisconsin	United States	54401
64	Marshfield Clinic - Weston Center	Weston	Wisconsin	United States	54476
65	Marshfield Clinic - Wisconsin Rapids Center	Wisconsin Rapids	Wisconsin	United States	54494

Sponsors and Collaborators

• Eastern Cooperative Oncology Group
• National Cancer Institute (NCI)

Investigators

• Study Chair: Craig L. Slingluff, MD, University of Virginia

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eastern Cooperative Oncology Group
• ClinicalTrials.gov Identifier: NCT00071981
• Other Study ID Numbers: CDR0000335055; U10CA021115; E1602; NCT00464152
• First Posted: Nov 6, 2003
• Last Update Posted: Oct 28, 2015
• Last Verified: Oct 1, 2015

• Keywords provided by Eastern Cooperative Oncology Group: stage IV melanoma; recurrent melanoma
• Additional relevant MeSH terms: Melanoma; Molgramostim; Vaccines; Sargramostim; Freund's Adjuvant

Study Results

Participant Flow

Recruitment Details	This study was activated on March 21, 2005, and terminated on January 12, 2009 with the final accrual of 175 patients.22 ECOG institutions participated in the study.
Pre-assignment Detail	This study involved a pre-registration before randomization. For patients with locally-typed HLA status, randomization immediately followed pre-registration. For central evaluation of HLA status, samples were submitted after pre-registration, and results of the evaluation must have been received from the central laboratory prior to randomization

Arm/Group Title	Arm I (12MP)	Arm II (12MP/Tet)	Arm III (12MP/6MHP)	Arm IV (6MHP)
Arm/Group Description	Patients receive 2 injections of multi-epitope peptide vaccine comprising 12 melanoma peptides restricted by Class I MHC (12MP) emulsified with sargramostim (GM-CSF) and Montanide ISA-51 (incomplete Freund's adjuvant) or Montanide ISA-51 VG (ISA-51) intradermally (ID) and subcutaneously (SC) on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection	Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 1 tetanus peptide melanoma vaccine emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection tetanus peptide melanoma vaccine : Given by injection	Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 6 melanoma helper peptides (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection melanoma helper peptide vaccine : Given by injection	Patients receive 2 injections of multi-epitope peptide vaccine comprising melanoma helper peptide vaccine (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection melanoma helper peptide vaccine : Given by injection
Period Title: Overall Study
STARTED	47	43	37	48
Eligible	43	36	33	42
Treated	45	38	36	48
Eligible and Treated	41	33	32	42
Have CTL Response Data	40	30	29	41
Have Helper T Cell Response Data	37	27	25	39
COMPLETED	1	2	0	3
NOT COMPLETED	46	41	37	45

Baseline Characteristics

Arm/Group Title	Arm I (12MP)	Arm II (12MP/Tet)	Arm III (12MP/6MHP)	Arm IV (6MHP)	Total
Arm/Group Description	Patients receive 2 injections of multi-epitope peptide vaccine comprising 12 melanoma peptides restricted by Class I MHC (12MP) emulsified with sargramostim (GM-CSF) and Montanide ISA-51 (incomplete Freund's adjuvant) or Montanide ISA-51 VG (ISA-51) intradermally (ID) and subcutaneously (SC) on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection	Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 1 tetanus peptide melanoma vaccine emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection tetanus peptide melanoma vaccine : Given by injection	Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 6 melanoma helper peptides (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection melanoma helper peptide vaccine : Given by injection	Patients receive 2 injections of multi-epitope peptide vaccine comprising melanoma helper peptide vaccine (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection melanoma helper peptide vaccine : Given by injection	Total of all reporting groups
Overall Participants	41	33	32	42	148
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	65	69	66	64	66
Sex: Female, Male (Count of Participants)
Female	18 43.9%	14 42.4%	11 34.4%	17 40.5%	60 40.5%
Male	23 56.1%	19 57.6%	21 65.6%	25 59.5%	88 59.5%
Region of Enrollment (participants) [Number]
United States	41 100%	33 100%	32 100%	42 100%	148 100%

Outcome Measures

1. Primary Outcome

Title	Cytotoxic T-cell Lymphocytes (CTL) Response Rate
Description	Assessment of CTL response was based on a fold-increase in T cell response measure by interferon-gamma ELIspot assay.
Time Frame	Immune response was assessed at pre-registrtion, in weeks 1, 3, 5, 7, 8

Outcome Measure Data

Analysis Population Description

140 eligible and treated patients who had CTL response data were included in the analysis

Arm/Group Title	Arm I (12MP)	Arm II (12MP/Tet)	Arm III (12MP/6MHP)	Arm IV (6MHP)
Arm/Group Description	Patients receive 2 injections of multi-epitope peptide vaccine comprising 12 melanoma peptides restricted by Class I MHC (12MP) emulsified with sargramostim (GM-CSF) and Montanide ISA-51 (incomplete Freund's adjuvant) or Montanide ISA-51 VG (ISA-51) intradermally (ID) and subcutaneously (SC) on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection	Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 1 tetanus peptide melanoma vaccine emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection tetanus peptide melanoma vaccine : Given by injection	Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 6 melanoma helper peptides (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection melanoma helper peptide vaccine : Given by injection	Patients receive 2 injections of multi-epitope peptide vaccine comprising melanoma helper peptide vaccine (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection melanoma helper peptide vaccine : Given by injection
Measure Participants	40	30	29	41
Number (95% Confidence Interval) [percentage of participants]	43 104.9%	47 142.4%	28 87.5%	5 11.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (12MP), Arm II (12MP/Tet), Arm III (12MP/6MHP), Arm IV (6MHP)
	Comments	Compare CTL response rate among four arms. The null hypothesis is that CTL response is same in all four arms. Alternative hypothesis is that CTL response rate is different in at least one arm compared to other arms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments

2. Secondary Outcome

Title	Helper T-cells Response to 6MHP
Description	Helper T cell response was evaluated by tritiated thymidine proliferation assay with fresh/cryopreserved PBL in the presence of each of the helper peptides.
Time Frame	Immune response was assessed at pre-registration, in weeks 1,3,5,7,8

Outcome Measure Data

Analysis Population Description

128 eligible and treated patients who had data about helper T cell response were included in the analysis

Arm/Group Title	Arm I (12MP)	Arm II (12MP/Tet)	Arm III (12MP/6MHP)	Arm IV (6MHP)
Arm/Group Description	Patients receive 2 injections of multi-epitope peptide vaccine comprising 12 melanoma peptides restricted by Class I MHC (12MP) emulsified with sargramostim (GM-CSF) and Montanide ISA-51 (incomplete Freund's adjuvant) or Montanide ISA-51 VG (ISA-51) intradermally (ID) and subcutaneously (SC) on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection	Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 1 tetanus peptide melanoma vaccine emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection tetanus peptide melanoma vaccine : Given by injection	Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 6 melanoma helper peptides (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection melanoma helper peptide vaccine : Given by injection	Patients receive 2 injections of multi-epitope peptide vaccine comprising melanoma helper peptide vaccine (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection melanoma helper peptide vaccine : Given by injection
Measure Participants	37	27	25	39
Number (95% Confidence Interval) [percentage of participants]	3 7.3%	0 0%	40 125%	41 97.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (12MP), Arm II (12MP/Tet), Arm III (12MP/6MHP), Arm IV (6MHP)
	Comments	Compare HTL response rate to 6MHP among four arms. The null hypothesis is that HTL response is same in all four arms. Alternative hypothesis is that HTL response rate is different in at least one arm compared to other arms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments

3. Secondary Outcome

Title	Helper T Cell Response to Tetanus
Description	Helper T cell response was evaluated by tritiated thymidine proliferation assay with fresh/cryopreserved PBL in the presence of each of the helper peptides.
Time Frame	Immune response was assessed at pre-registration, in weeks 1,3,5,7,8

Outcome Measure Data

Analysis Population Description

128 eligible and treated patients who had data about HTL response to tetanus peptide were included in the analysis

Arm/Group Title	Arm I (12MP)	Arm II (12MP/Tet)	Arm III (12MP/6MHP)	Arm IV (6MHP)
Arm/Group Description	Patients receive 2 injections of multi-epitope peptide vaccine comprising 12 melanoma peptides restricted by Class I MHC (12MP) emulsified with sargramostim (GM-CSF) and Montanide ISA-51 (incomplete Freund's adjuvant) or Montanide ISA-51 VG (ISA-51) intradermally (ID) and subcutaneously (SC) on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection	Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 1 tetanus peptide melanoma vaccine emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection tetanus peptide melanoma vaccine : Given by injection	Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 6 melanoma helper peptides (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection melanoma helper peptide vaccine : Given by injection	Patients receive 2 injections of multi-epitope peptide vaccine comprising melanoma helper peptide vaccine (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection melanoma helper peptide vaccine : Given by injection
Measure Participants	37	27	25	39
Number (95% Confidence Interval) [percentage of participants]	11 26.8%	59 178.8%	4 12.5%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (12MP), Arm II (12MP/Tet), Arm III (12MP/6MHP), Arm IV (6MHP)
	Comments	Compare HTL response rate to tetanus peptide among four arms. The null hypothesis is that HTL response is same in all four arms. Alternative hypothesis is that HTL response rate is different in at least one arm compared to other arms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments

4. Secondary Outcome

Title	Objective Response Rate
Description	Tumor response was assessed via Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Objective response rate is calculated as the number of patients with complete response (disappearance of all lesions) or partial response () divided by total number of evaluable patients.
Time Frame	Tumor response was assessed in weeks 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, and 6 months after last vaccination

Outcome Measure Data

Analysis Population Description

148 eligible and treated patients were included in the analysis

Arm/Group Title	Arm I (12MP)	Arm II (12MP/Tet)	Arm III (12MP/6MHP)	Arm IV (6MHP)
Arm/Group Description	Patients receive 2 injections of multi-epitope peptide vaccine comprising 12 melanoma peptides restricted by Class I MHC (12MP) emulsified with sargramostim (GM-CSF) and Montanide ISA-51 (incomplete Freund's adjuvant) or Montanide ISA-51 VG (ISA-51) intradermally (ID) and subcutaneously (SC) on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection	Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 1 tetanus peptide melanoma vaccine emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection tetanus peptide melanoma vaccine : Given by injection	Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 6 melanoma helper peptides (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection melanoma helper peptide vaccine : Given by injection	Patients receive 2 injections of multi-epitope peptide vaccine comprising melanoma helper peptide vaccine (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection melanoma helper peptide vaccine : Given by injection
Measure Participants	41	33	32	42
Number (95% Confidence Interval) [percentage of participants]	2.4 5.9%	3.0 9.1%	6.3 19.7%	7.1 16.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (12MP), Arm II (12MP/Tet), Arm III (12MP/6MHP), Arm IV (6MHP)
	Comments	Compare objective response rate among four arms. The null hypothesis is that objective response rate is same in all four arms. Alternative hypothesis is that objective response rate is different in at least one arm compared to other arms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.741
	Comments
	Method	Fisher Exact
	Comments

5. Secondary Outcome

Title	Median Overall Survival (OS)
Description	OS was defined as the time from registration to death from any cause.
Time Frame	assessed every 3 month within 2 years and every 6 months betwen 2 and 5 years

Outcome Measure Data

Analysis Population Description

148 eligible and treated patients were included in the analysis

Arm/Group Title	Arm I (12MP)	Arm II (12MP/Tet)	Arm III (12MP/6MHP)	Arm IV (6MHP)
Arm/Group Description	Patients receive 2 injections of multi-epitope peptide vaccine comprising 12 melanoma peptides restricted by Class I MHC (12MP) emulsified with sargramostim (GM-CSF) and Montanide ISA-51 (incomplete Freund's adjuvant) or Montanide ISA-51 VG (ISA-51) intradermally (ID) and subcutaneously (SC) on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection	Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 1 tetanus peptide melanoma vaccine emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection tetanus peptide melanoma vaccine : Given by injection	Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 6 melanoma helper peptides (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection melanoma helper peptide vaccine : Given by injection	Patients receive 2 injections of multi-epitope peptide vaccine comprising melanoma helper peptide vaccine (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection melanoma helper peptide vaccine : Given by injection
Measure Participants	41	33	32	42
Median (95% Confidence Interval) [months]	14.9	10.2	12.4	11.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (12MP), Arm II (12MP/Tet), Arm III (12MP/6MHP), Arm IV (6MHP)
	Comments	Compare overall survival curves among four arms.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.532
	Comments
	Method	Log Rank
	Comments

Adverse Events

Time Frame	Assessed at the end of each cycle while on treatment and at 30 days following the last dose of treatment. Reported every 3 months within 2 years of study entry, and every 6 months between 2-5 years of study entry
Adverse Event Reporting Description	All patients who received protocol therapy were evaluated for toxicity, regardless of eligibility.
Arm/Group Title	Arm I (12MP)		Arm II (12MP/Tet)		Arm III (12MP/6MHP)		Arm IV (6MHP)
Arm/Group Description	Patients receive 2 injections of multi-epitope peptide vaccine comprising 12 melanoma peptides restricted by Class I MHC (12MP) emulsified with sargramostim (GM-CSF) and Montanide ISA-51 (incomplete Freund's adjuvant) or Montanide ISA-51 VG (ISA-51) intradermally (ID) and subcutaneously (SC) on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection		Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 1 tetanus peptide melanoma vaccine emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection tetanus peptide melanoma vaccine : Given by injection		Patients receive 2 injections of multi-epitope peptide vaccine comprising multi-epitope melanoma peptide vaccine (12MP) and 6 melanoma helper peptides (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. multi-epitope melanoma peptide vaccine : Given by injection incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection melanoma helper peptide vaccine : Given by injection		Patients receive 2 injections of multi-epitope peptide vaccine comprising melanoma helper peptide vaccine (6HP) emulsified with GM-CSF and ISA-51 (incomplete Freund's adjuvant) ID and SC on day 1 of weeks 1-3 and 1 injection at the primary site only on day 1 of weeks 5-7. incomplete Freund's adjuvant : Given by injection sargramostim : Given by injection melanoma helper peptide vaccine : Given by injection
All Cause Mortality
	Arm I (12MP)		Arm II (12MP/Tet)		Arm III (12MP/6MHP)		Arm IV (6MHP)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm I (12MP)		Arm II (12MP/Tet)		Arm III (12MP/6MHP)		Arm IV (6MHP)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/45 (13.3%)		9/38 (23.7%)		6/36 (16.7%)		4/48 (8.3%)
Blood and lymphatic system disorders
Anemia	0/45 (0%)		0/38 (0%)		0/36 (0%)		1/48 (2.1%)
Ear and labyrinth disorders
Tinnitus	0/45 (0%)		0/38 (0%)		1/36 (2.8%)		0/48 (0%)
Gastrointestinal disorders
Nausea	0/45 (0%)		0/38 (0%)		1/36 (2.8%)		0/48 (0%)
Vomiting	0/45 (0%)		0/38 (0%)		1/36 (2.8%)		0/48 (0%)
Abdomen, pain	0/45 (0%)		0/38 (0%)		1/36 (2.8%)		0/48 (0%)
General disorders
Fatigue	0/45 (0%)		4/38 (10.5%)		5/36 (13.9%)		1/48 (2.1%)
Injection site reaction	2/45 (4.4%)		3/38 (7.9%)		0/36 (0%)		2/48 (4.2%)
Immune system disorders
Allergic reaction	0/45 (0%)		1/38 (2.6%)		0/36 (0%)		0/48 (0%)
Infections and infestations
Infection Gr0-2 neut, lung	1/45 (2.2%)		0/38 (0%)		0/36 (0%)		0/48 (0%)
Infection Gr0-2 neut, skin	1/45 (2.2%)		0/38 (0%)		0/36 (0%)		0/48 (0%)
Investigations
Leukopenia (Leukocytes decreased)	1/45 (2.2%)		1/38 (2.6%)		0/36 (0%)		0/48 (0%)
Lymphopenia	1/45 (2.2%)		1/38 (2.6%)		1/36 (2.8%)		0/48 (0%)
Neutropenia (Neutrophils decreased)	1/45 (2.2%)		0/38 (0%)		0/36 (0%)		0/48 (0%)
Cardiac troponin I (cTnI)	1/45 (2.2%)		0/38 (0%)		0/36 (0%)		0/48 (0%)
Alanine aminotransferase (ALT, SGPT)	0/45 (0%)		0/38 (0%)		2/36 (5.6%)		0/48 (0%)
Aspartate aminotransferase (AST, SGOT)	0/45 (0%)		0/38 (0%)		1/36 (2.8%)		0/48 (0%)
Blood bilirubin increased	0/45 (0%)		0/38 (0%)		1/36 (2.8%)		0/48 (0%)
Metabolic/Laboratory-other	0/45 (0%)		0/38 (0%)		1/36 (2.8%)		0/48 (0%)
Metabolism and nutrition disorders
Hyponatremia	1/45 (2.2%)		0/38 (0%)		0/36 (0%)		0/48 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	0/45 (0%)		0/38 (0%)		1/36 (2.8%)		0/48 (0%)
Nervous system disorders
Central nervous system (CNS) cerebrovascular ischemia	0/45 (0%)		1/38 (2.6%)		0/36 (0%)		0/48 (0%)
Head/headache	0/45 (0%)		1/38 (2.6%)		0/36 (0%)		1/48 (2.1%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/45 (0%)		0/38 (0%)		1/36 (2.8%)		0/48 (0%)
Pneumonitis/pulmonary infiltrates	1/45 (2.2%)		0/38 (0%)		0/36 (0%)		0/48 (0%)
Skin and subcutaneous tissue disorders
Ulceration	0/45 (0%)		1/38 (2.6%)		1/36 (2.8%)		0/48 (0%)
Other (Not Including Serious) Adverse Events
	Arm I (12MP)		Arm II (12MP/Tet)		Arm III (12MP/6MHP)		Arm IV (6MHP)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	36/45 (80%)		28/38 (73.7%)		28/36 (77.8%)		33/48 (68.8%)
Gastrointestinal disorders
Constipation	0/45 (0%)		1/38 (2.6%)		2/36 (5.6%)		1/48 (2.1%)
Diarrhea w/o prior colostomy	3/45 (6.7%)		2/38 (5.3%)		1/36 (2.8%)		3/48 (6.3%)
Nausea	1/45 (2.2%)		6/38 (15.8%)		3/36 (8.3%)		2/48 (4.2%)
Vomiting	0/45 (0%)		2/38 (5.3%)		1/36 (2.8%)		1/48 (2.1%)
General disorders
Fatigue	9/45 (20%)		11/38 (28.9%)		10/36 (27.8%)		7/48 (14.6%)
Fever w/o neutropenia	1/45 (2.2%)		4/38 (10.5%)		2/36 (5.6%)		0/48 (0%)
Rigors/chills	1/45 (2.2%)		5/38 (13.2%)		4/36 (11.1%)		2/48 (4.2%)
Injection site reaction	28/45 (62.2%)		20/38 (52.6%)		18/36 (50%)		18/48 (37.5%)
Investigations
Leukopenia (Leukocytes decreased)	3/45 (6.7%)		5/38 (13.2%)		1/36 (2.8%)		0/48 (0%)
Lymphopenia	2/45 (4.4%)		8/38 (21.1%)		6/36 (16.7%)		4/48 (8.3%)
Neutropenia (Neutrophils decreased)	0/45 (0%)		2/38 (5.3%)		0/36 (0%)		1/48 (2.1%)
Thrombocytopenia (Platelets decreased)	2/45 (4.4%)		3/38 (7.9%)		2/36 (5.6%)		1/48 (2.1%)
Alkaline phosphatase increased	4/45 (8.9%)		3/38 (7.9%)		2/36 (5.6%)		4/48 (8.3%)
Aspartate aminotransferase increased (AST, SGOT)	3/45 (6.7%)		5/38 (13.2%)		2/36 (5.6%)		1/48 (2.1%)
Blood bilirubin increased	1/45 (2.2%)		2/38 (5.3%)		2/36 (5.6%)		0/48 (0%)
Creatinine increased	2/45 (4.4%)		3/38 (7.9%)		1/36 (2.8%)		5/48 (10.4%)
Metabolic/Laboratory-other	2/45 (4.4%)		2/38 (5.3%)		5/36 (13.9%)		3/48 (6.3%)
Alanine aminotransferase increased (ALT, SGPT)	2/45 (4.4%)		1/38 (2.6%)		2/36 (5.6%)		1/48 (2.1%)
Metabolism and nutrition disorders
Anorexia	1/45 (2.2%)		3/38 (7.9%)		3/36 (8.3%)		2/48 (4.2%)
Hyponatremia	0/45 (0%)		0/38 (0%)		2/36 (5.6%)		1/48 (2.1%)
Musculoskeletal and connective tissue disorders
Joint, pain	2/45 (4.4%)		1/38 (2.6%)		1/36 (2.8%)		3/48 (6.3%)
Muscle, pain	6/45 (13.3%)		1/38 (2.6%)		2/36 (5.6%)		1/48 (2.1%)
Nervous system disorders
Dizziness	0/45 (0%)		2/38 (5.3%)		1/36 (2.8%)		0/48 (0%)
Head/headache	5/45 (11.1%)		5/38 (13.2%)		3/36 (8.3%)		2/48 (4.2%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/45 (2.2%)		1/38 (2.6%)		2/36 (5.6%)		1/48 (2.1%)
Skin and subcutaneous tissue disorders
Sweating	0/45 (0%)		3/38 (7.9%)		2/36 (5.6%)		1/48 (2.1%)
Pruritus/itching	4/45 (8.9%)		2/38 (5.3%)		2/36 (5.6%)		2/48 (4.2%)
Rash/desquamation	1/45 (2.2%)		2/38 (5.3%)		5/36 (13.9%)		1/48 (2.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.