NY-ESO-1 Protein Vaccine With Imiquimod in Melanoma (Adjuvant Setting)

• Sponsor: Ludwig Institute for Cancer Research (Other)
• Overall Status: Completed
• CT.gov ID: NCT00142454
• Collaborator: Cancer Research Institute (CRI) (Other)
• Enrollment: 9
• Location: 1
• Arm: 1
• Actual Duration (Months): 8
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

This was a Phase 1, single-arm, open-label, pilot study of NY-ESO-1 protein vaccination with imiquimod as an adjuvant in patients with resected Stage IIB, IIC, and III malignant melanoma. The primary study objective was to determine the safety of NY-ESO-1 protein/imiquimod treatment, and the secondary objective was to evaluate the immunogenicity of treatment.

Condition or Disease	Intervention/Treatment	Phase
Malignant Melanoma	Drug: Imiquimod; Biological: NY-ESO-1 protein	Phase 1

Detailed Description

Patients applied imiquimod (250 mg) topically to a designated area of healthy skin on the upper inner arm or inner thigh (the cream remained on the skin overnight for 6-10 hours) every day for 5 consecutive days (i.e., for the first 5 days of Cycles 1-3 and for the first 4 days of Cycle 4). The NY-ESO-1 protein (100 μg) was injected intradermally into the imiquimod-pretreated area on Day 3 of each cycle for 4 consecutive 21-day cycles.

Safety was monitored continuously. Immunization was assessed by the generation of NY-ESO-1-specific cluster of differentiation (CD)4+ and CD8+ T cell responses in enzyme-linked immunosorbent spot (ELISPOT) assays and by the development or augmentation of NY-ESO-1-specific antibody titers, assessed by enzyme-linked immunosorbent assay (ELISA).

Blood samples were obtained for the assessment of clinical biochemistry and hematology, and physical examinations were performed at baseline, on Day 1 of each cycle, and at a follow-up visit at Week 13.

Skin biopsies of the vaccinated area were obtained 48 hours after the last injection (Day 5 of Cycle 4). To avoid irritation, imiquimod was not applied after the biopsies.

Study Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: NY-ESO-1 Protein Vaccination in Malignant Melanoma Administered With Imiquimod as Adjuvant
• Actual Study Start Date: Aug 24, 2005
• Actual Primary Completion Date: Apr 25, 2006
• Actual Study Completion Date: Apr 25, 2006

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Imiquimod + NY-ESO-1 Patients applied topical imiquimod followed by vaccination with intradermal injections of the NY-ESO-1 protein.

Drug: Imiquimod; Patients applied imiquimod cream at bedtime every day for 5 consecutive days (for the first 5 days of Cycles 1-3 and for the first 4 days of Cycle 4) at a dose of 250 mg as supplied in single-use packets to a 4 x 5 cm area of healthy skin, alternating among the extremities (upper inner arms and inner thighs) in each cycle. The cream was to be rubbed into the skin until it was no longer visible. Patients were encouraged to wash their hands before and after applying cream. The application site was not occluded. The next morning, 6 to 10 hours after initial application, the treated area was washed with mild soap and water to remove any residual cream.; Other Names: Aldara ; Biological: NY-ESO-1 protein; NY-ESO-1 protein was injected intradermally by a study physician or nurse at a dose of 100 μg into the imiquimod-pretreated area on Day 3 of each cycle for 4 consecutive 21-day cycles.

Outcome Measures

Primary Outcome Measures

1. Number of Patients With Treatment-emergent Adverse Events (TEAEs) [Up to 4 months]

   Toxicity was graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, as follows: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), and Grade 5 (fatal). Adverse events (AEs) were reported based on clinical laboratory tests, vital sign and weight measurements, physical examinations, performance status evaluations, and any other medically indicated assessments, including patient interviews, from the time informed consent was signed through the last follow-up visit. AEs were considered to be treatment emergent (TEAE) if they occurred or worsened in severity after the first dose of study treatment.

Secondary Outcome Measures

1. Number of Patients With Cellular Antibody Response to NY-ESO-1 at Two or More Post-vaccination Time Points [Up to 4 months]

   Assays to assess cluster of differentiation (CD)8+ and CD4+ antigen-specific responses were performed at baseline (Cycle 1 Day 1), throughout the vaccination period (Day 1 of Cycles 2 through 4 and Day 10 of each cycle), and at the 2 post-treatment follow-up visits (Weeks 13 and 16) by enzyme-linked immune absorbent spot (ELISPOT) assay following prior in vitro sensitization. A 3-fold increase in spot-forming cells over baseline defined a positive response. Suitable antigens may have included recombinant viral vectors encoding NY-ESO-1, or NY-ESO-1 overlapping peptides, depending upon availability.

2. Number of Patients With Humoral Antibody Response to NY-ESO-1 [Up to 4 months]

   Assays to assess NY-ESO-1 specific antibodies were performed at baseline (Cycle 1 Day 1), throughout the vaccination period (Day 1 of Cycles 2 through 4 and Day 10 of each cycle), and at the 2 post-treatment follow-up visits (Weeks 13 and 16) by enzyme-linked immunosorbent assay (ELISA). Samples were diluted serially. The induction and augmentation of immunity were defined as an increase in antibody titer of ≥ 3× over buffer alone or ≥ 4× the pre-vaccination titer, respectively. Sera from the responding patients were tested a second time against a pool of NY-ESO-1 overlapping peptides to confirm NY-ESO-1 specificity; the number of patients in the table reflect the patients with confirmed NY-ESO-1 specificity.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Had histologically confirmed, resected American Joint Committee on Cancer Stage IIB, IIC or III malignant melanoma

• Fully recovered from surgery

• Age ≥ 18 years; children were excluded from this study, as the safety of imiquimod had not been established in patients below the age of 18

• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

• Adequate organ and marrow function as defined below:

• absolute neutrophil count: ≥ 1500/μL

• hemoglobin: ≥ 9 g/dL

• platelets: ≥ 100,000/μL

• total bilirubin: ≤ 1.5 × institutional upper limit of normal (ULN)

• aspartate aminotransferase/alanine aminotransferase (AST/ALT): ≤ 2.5 × institutional ULN

• creatinine: ≤ 1.5 × institutional ULN

• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Received chemotherapy, immunotherapy (including interferon), or radiotherapy within 4 weeks prior to first dosing of study agent

• Prior treatment with NY-ESO-1 vaccines

• Known human immunodeficiency virus infection or autoimmune disease (rheumatoid arthritis, systemic lupus erythematosus), as these conditions could have interfered with the evaluation of the induced immune response; patients with vitiligo or melanoma-associated hypopigmentation were not excluded

• History of allergic reactions attributed to compounds of similar chemical or biologic composition to imiquimod or other agents used in the study

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection,symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would have limited compliance with study requirements

• Pregnancy or lactation

• Women of childbearing potential not using a medically acceptable means of contraception

• Known history of inflammatory skin disorders, as imiquimod might have exacerbated these conditions

• Chronic corticosteroid or immunosuppressive therapies, as these might have interfered with the evaluation of the induced immune response

• Lack of availability for immunological and clinical follow-up assessments

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	NYU Cancer Institute	New York	New York	United States	10016

Sponsors and Collaborators

• Ludwig Institute for Cancer Research
• Cancer Research Institute (CRI)

Investigators

• Principal Investigator: Nina Bhardwaj, MD, PhD, NYU Langone Health
• Study Director: Sylvia Adams, MD, NYU Langone Health

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ludwig Institute for Cancer Research
• ClinicalTrials.gov Identifier: NCT00142454
• Other Study ID Numbers: LUD2004-006; NYU 04-53
• First Posted: Sep 2, 2005
• Last Update Posted: Oct 22, 2020
• Last Verified: Sep 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Ludwig Institute for Cancer Research: Malignant melanoma; Stages IIB-III
• Additional relevant MeSH terms: Melanoma; Imiquimod

Study Results

Participant Flow

Arm/Group Title	Imiquimod + NY-ESO-1
Arm/Group Description	Patients applied topical imiquimod cream (250 mg) to a designated area of healthy skin on the upper inner arm or inner thigh (the cream remained on the skin overnight for 6-10 hours) every day for 5 consecutive days (i.e., for the first 5 days of Cycles 1-3 and for the first 4 days of Cycle 4). A vaccination with the NY-ESO-1 protein (100 μg) was injected intradermally into the imiquimod-pretreated area on Day 3 of each cycle for 4 consecutive 21-day cycles.
Period Title: Overall Study
STARTED	9
COMPLETED	9
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Imiquimod + NY-ESO-1
Arm/Group Description	Patients applied topical imiquimod cream (250 mg) to a designated area of healthy skin on the upper inner arm or inner thigh (the cream remained on the skin overnight for 6-10 hours) every day for 5 consecutive days (i.e., for the first 5 days of Cycles 1-3 and for the first 4 days of Cycle 4). A vaccination with the NY-ESO-1 protein (100 μg) was injected intradermally into the imiquimod-pretreated area on Day 3 of each cycle for 4 consecutive 21-day cycles.
Overall Participants	9
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	49
Sex: Female, Male (Count of Participants)
Female	7 77.8%
Male	2 22.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 11.1%
Not Hispanic or Latino	8 88.9%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	8 88.9%
More than one race	0 0%
Unknown or Not Reported	1 11.1%
Region of Enrollment (Count of Participants)
United States	9 100%
Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 (Count of Participants)
Count of Participants [Participants]	9 100%

Outcome Measures

1. Primary Outcome

Title	Number of Patients With Treatment-emergent Adverse Events (TEAEs)
Description	Toxicity was graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, as follows: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), and Grade 5 (fatal). Adverse events (AEs) were reported based on clinical laboratory tests, vital sign and weight measurements, physical examinations, performance status evaluations, and any other medically indicated assessments, including patient interviews, from the time informed consent was signed through the last follow-up visit. AEs were considered to be treatment emergent (TEAE) if they occurred or worsened in severity after the first dose of study treatment.
Time Frame	Up to 4 months

Outcome Measure Data

Analysis Population Description

The population comprises all patients who received any dose of study treatment.

Arm/Group Title	Imiquimod + NY-ESO-1
Arm/Group Description	Patients applied topical imiquimod cream (250 mg) to a designated area of healthy skin on the upper inner arm or inner thigh (the cream remained on the skin overnight for 6-10 hours) every day for 5 consecutive days (i.e., for the first 5 days of Cycles 1-3 and for the first 4 days of Cycle 4). A vaccination with the NY-ESO-1 protein (100 μg) was injected intradermally into the imiquimod-pretreated area on Day 3 of each cycle for 4 consecutive 21-day cycles.
Measure Participants	9
Any TEAE	8 88.9%
Maximum TEAE severity Grade 1	8 88.9%
Serious TEAE	0 0%
TEAE leading to discontinuation	0 0%

2. Secondary Outcome

Title	Number of Patients With Cellular Antibody Response to NY-ESO-1 at Two or More Post-vaccination Time Points
Description	Assays to assess cluster of differentiation (CD)8+ and CD4+ antigen-specific responses were performed at baseline (Cycle 1 Day 1), throughout the vaccination period (Day 1 of Cycles 2 through 4 and Day 10 of each cycle), and at the 2 post-treatment follow-up visits (Weeks 13 and 16) by enzyme-linked immune absorbent spot (ELISPOT) assay following prior in vitro sensitization. A 3-fold increase in spot-forming cells over baseline defined a positive response. Suitable antigens may have included recombinant viral vectors encoding NY-ESO-1, or NY-ESO-1 overlapping peptides, depending upon availability.
Time Frame	Up to 4 months

Outcome Measure Data

Analysis Population Description

The population comprises all patients who received any dose of study treatment.

Arm/Group Title	Imiquimod + NY-ESO-1
Arm/Group Description	Patients applied topical imiquimod cream (250 mg) to a designated area of healthy skin on the upper inner arm or inner thigh (the cream remained on the skin overnight for 6-10 hours) every day for 5 consecutive days (i.e., for the first 5 days of Cycles 1-3 and for the first 4 days of Cycle 4). A vaccination with the NY-ESO-1 protein (100 μg) was injected intradermally into the imiquimod-pretreated area on Day 3 of each cycle for 4 consecutive 21-day cycles.
Measure Participants	9
CD4+ T cell response	7 77.8%
CD8+ T cell response	0 0%

3. Secondary Outcome

Title	Number of Patients With Humoral Antibody Response to NY-ESO-1
Description	Assays to assess NY-ESO-1 specific antibodies were performed at baseline (Cycle 1 Day 1), throughout the vaccination period (Day 1 of Cycles 2 through 4 and Day 10 of each cycle), and at the 2 post-treatment follow-up visits (Weeks 13 and 16) by enzyme-linked immunosorbent assay (ELISA). Samples were diluted serially. The induction and augmentation of immunity were defined as an increase in antibody titer of ≥ 3× over buffer alone or ≥ 4× the pre-vaccination titer, respectively. Sera from the responding patients were tested a second time against a pool of NY-ESO-1 overlapping peptides to confirm NY-ESO-1 specificity; the number of patients in the table reflect the patients with confirmed NY-ESO-1 specificity.
Time Frame	Up to 4 months

Outcome Measure Data

Analysis Population Description

The population comprises all patients who received any dose of study treatment.

Arm/Group Title	Imiquimod + NY-ESO-1
Arm/Group Description	Patients applied topical imiquimod cream (250 mg) to a designated area of healthy skin on the upper inner arm or inner thigh (the cream remained on the skin overnight for 6-10 hours) every day for 5 consecutive days (i.e., for the first 5 days of Cycles 1-3 and for the first 4 days of Cycle 4). A vaccination with the NY-ESO-1 protein (100 μg) was injected intradermally into the imiquimod-pretreated area on Day 3 of each cycle for 4 consecutive 21-day cycles.
Measure Participants	9
Count of Participants [Participants]	4 44.4%

Adverse Events

Time Frame	All adverse events (AEs), regardless of causality to study drug, were documented from informed consent through the final follow-up visit, which was up to 4 months for each patient.
Adverse Event Reporting Description	AE documentation included onset/resolution dates, severity using the NCI CTCAE (version 3.0), frequency, seriousness, relationship to study drug, study drug action taken, treatment, and outcome. In summaries, preferred terms were counted only once per patient at the maximum reported grade.
Arm/Group Title	Imiquimod + NY-ESO-1
Arm/Group Description	Patients applied topical imiquimod cream (250 mg) to a designated area of healthy skin on the upper inner arm or inner thigh (the cream remained on the skin overnight for 6-10 hours) every day for 5 consecutive days (i.e., for the first 5 days of Cycles 1-3 and for the first 4 days of Cycle 4). A vaccination with the NY-ESO-1 protein (100 μg) was injected intradermally into the imiquimod-pretreated area on Day 3 of each cycle for 4 consecutive 21-day cycles.
All Cause Mortality
	Imiquimod + NY-ESO-1
	Affected / at Risk (%)	# Events
Total	0/9 (0%)
Serious Adverse Events
	Imiquimod + NY-ESO-1
	Affected / at Risk (%)	# Events
Total	0/9 (0%)
Other (Not Including Serious) Adverse Events
	Imiquimod + NY-ESO-1
	Affected / at Risk (%)	# Events
Total	8/9 (88.9%)
Cardiac disorders
Irregular heart rate	1/9 (11.1%)
General disorders
Redness at injection site	6/9 (66.7%)
Swelling at injection site	2/9 (22.2%)
Pain at injection site	1/9 (11.1%)
Splotchy at injection site	1/9 (11.1%)
Edema	1/9 (11.1%)
Fatigue	4/9 (44.4%)
Tenderness on heel	1/9 (11.1%)
Itching at injection site	1/9 (11.1%)
Burning in groin area	1/9 (11.1%)
Hardness at injection site	1/9 (11.1%)
Flu-like symptoms	2/9 (22.2%)
Injection site reaction	2/9 (22.2%)
Mouth sores	1/9 (11.1%)
Flu shot reaction	1/9 (11.1%)
Leg edema	1/9 (11.1%)
Fever	1/9 (11.1%)
Infections and infestations
Staph infection	1/9 (11.1%)
Urinary tract infection	1/9 (11.1%)
Respiration infection	1/9 (11.1%)
Musculoskeletal and connective tissue disorders
Shoulder pain	1/9 (11.1%)
Psychiatric disorders
Difficulty sleeping	1/9 (11.1%)
Skin and subcutaneous tissue disorders
Boils	1/9 (11.1%)
Pruritus	1/9 (11.1%)
Thigh pimple	1/9 (11.1%)
Rash	1/9 (11.1%)
Itching shoulder scar	1/9 (11.1%)
Redness on thigh	1/9 (11.1%)
Redness on arm	1/9 (11.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.