Mel62; 6PAC: A Phase I/II Trial to Evaluate a Peptide Vaccine Plus Ipilimumab in Patients With Melanoma

• Sponsor: Craig L Slingluff, Jr (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02385669
• Collaborator: (none)
• Enrollment: 3
• Location: 1
• Arm: 1
• Actual Duration (Months): 53.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study evaluates whether it is safe to administer a peptide vaccine with ipilimumab. This study will also evaluate the effects of the combination of the peptide vaccine and ipilimumab on the immune system. The investigators will monitor these effects by performing tests in the laboratory on participants' blood, a lymph node, and tumor samples.

Condition or Disease	Intervention/Treatment	Phase
Melanoma	Drug: Ipilimumab; Biological: 6MHP	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Trial to Evaluate the Safety and Immunogenicity of a Helper Peptide Vaccine Plus CTLA-4 Blockade in Melanoma Patients (Mel62; 6PAC)
• Actual Study Start Date: Apr 1, 2015
• Actual Primary Completion Date: Sep 18, 2019
• Actual Study Completion Date: Sep 18, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: 6MHP and ipilimumab The vaccine drug product, 6MHP, consists of 6 class II MHC-restricted peptides derived from melanoma proteins. Each vaccine consists of 200 mcg of each of the six peptides. An aqueous solution of vaccine is mixed 1/1 with Montanide ISA-51 to form water-in-oil emulsions. Vaccines are administered days 1, 8, 15, 43, 64, and 85. All peptide vaccines are administered intradermally and subcutaneously. Ipilimumab will be administered in accord with the official prescribing information: 3 mg/kg intravenously once every 3 weeks, for 4 doses. Ipilimumab will be administered on days 1, 22, 43, and 64.

Drug: Ipilimumab; Checkpoint blockade inhibitor; Other Names: Yervoy ; Biological: 6MHP; 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides; Other Names: 6 melanoma helper peptide vaccine

Outcome Measures

Primary Outcome Measures

1. Safety (Adverse Event Profile) [30 days after the last vaccination]

   Adverse event profile for the combination of ipilimumab and 6MHP

2. CD4+ T Cell Responses in the Blood and in the Sentinel Immunized Node [through day 92]

   CD4+ T cell responses to the peptide vaccine, defined as: any CD4+ T cell response to 6 melanoma helper peptides (6MHP) in peripheral blood mononuclear cells (PBMC) with a 10 fold (or greater) increase in response over background (high response) by ex vivo ELIspot assay. CD4+ T cell high responses to 6MHP in PBMC at at least 2 consecutive time points having peripheral blood mononuclear cells (PBMC) with a 10 fold (or greater) increase in response over background by ex vivo ELIspot assay. CD4+ T cell high response to 6MHP in sentinel immunized lymph node (SIN).

Secondary Outcome Measures

1. Epitope Spreading (Epitope-spreading for CD8+ T Cells in the Blood and the Sentinel Immunized Node) [through day 92]

   An evaluation of epitope-spreading for CD8+ T cells in the blood and the sentinel immunized node that are reactive to a panel of defined melanoma antigens.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Participants with stage IIA (with class 2 DecisionDx Score) through IV melanoma in cohorts defined below. These participants may have had cutaneous, uveal, mucosal primary melanoma, or an unknown primary melanoma. The diagnosis of melanoma must be confirmed by cytological or histological examination. Staging of cutaneous melanoma will be based on the revised AJCC staging system. Participants must be eligible to be treated with ipilimumab based on clinician judgment within standard of care.

• Cohort 1 (Advanced Patients): unresectable stage III or IV melanoma that have clinical or radiographic evidence of disease.

• Cohort 2 (Neoadjuvant therapy): primary melanoma with clinically apparent lymph node or in transit/satellite lesions with or without lymph node involvement, in transit recurrence or metastatic recurrence amenable to complete resection to no evidence of disease

• Cohort 3 (Adjuvant therapy): Stage IIA (with class 2 DecisionDx Score), IIB-IV melanoma resected to no evidence of disease.

• Participants will be required to have radiological studies to define radiologically evident disease. Required studies include:

• Chest CT scan,

• Abdominal and pelvic CT scan, and

• Head CT scan or MRI PET/CT fusion scan may replace scans of the chest, abdomen, and pelvis.

• Participants who have melanoma available for biopsy pre-treatment and on day 22 must consent to having those biopsies. Melanoma lesions may be in nodes, skin, soft tissue, liver, or other sites that can be accessed by core needle biopsy, or incisional or excisional biopsy, with or without image guidance.

• Participants who have had brain metastases will be eligible if all of the following are true:

• Each brain metastasis must have been treated by surgical removal, stereotactic radiosurgery or managed to complete resolution with immunotherapy. Patients with brain lesions managed by immunotherapy without excision or radiosurgery are included provided that the brain metastases have completely resolved after systemic therapy and there are no neurologic symptoms or need for systemic therapy to control CNS-disease related symptoms.

• There has been no evident growth of any brain metastasis since the most recent treatment. If a patient has been managed by immunotherapy alone, the prior lesions must be completely resolved.

• No brain metastasis is > 2 cm in diameter at the time of registration

• The most recent surgical resections or gamma-knife therapy for malignant melanoma must have been completed ≥ 1 week prior to registration.

• ECOG performance status of 0 or 1

• Ability and willingness to give informed consent

• Adequate lab function tests Age 18 years or older at registration.

• Participants must have at least two intact (undissected) axillary and/or inguinal lymph node basins

Exclusion Criteria:

• Participants who have received the following medications or treatments at any time within 4 weeks of registration:

• Chemotherapy

• Interferon (e.g. Intron-A®)

• Radiation therapy (Stereotactic radiotherapy, such as gamma knife, can be used ≥ 1 week prior to registration)

• Allergy desensitization injections

• High doses of systemic corticosteroids, with the following qualifications and exceptions:

• Daily doses of 10 mg predisone (or equivalent) per day administered parenterally or orally are not allowed in patients with normal adrenal and pituitary function.

• In patients with adrenal or pituitary insufficiency replacement steroid doses are allowed.

• Inhaled steroids (e.g.: Advair®, Flovent®, Azmacort®) are permitted at low doses (less than 500 mcg fluticasone per day, or equivalent).

• Topical and nasal corticosteroids are acceptable.

• Growth factors (e.g. Procrit®, Aranesp®, Neulasta®)

• Interleukins (e.g. Proleukin®)

• Any investigational medication

• Targeted therapies specific for mutated BRAF or for MEK

• HIV positivity or evidence of active Hepatitis C virus (testing to be done within 6 months of study entry).

• Participants who are currently receiving nitrosoureas or who have received this therapy within the preceding 6 weeks

• Participants who are currently receiving a checkpoint molecule blockade therapy, or who have received this therapy within the preceding 6 weeks, with the following exceptions:

• Participants who have received a PD-1 blocking antibody (eg: pembrolizumab or nivolumab) may be enrolled 3 weeks after receiving the last dose of that antibody.

• Participants who have been treated previously with a CTLA-4 blocking antibody either as monotherapy or as part of combination CTLA-4/PD-1 blockade will be ineligible if CTLA-4 therapy:

1. was discontinued early for toxicity, or

2. did not induce stable disease or objective clinical response (by RECIST or irRC criteria) lasting 6 months or more.

Note: Patients may be eligible if they have experienced progression after a period of stable disease (6 months or more) or an objective clinical response (by irRC or RECIST) (6 months or more) induced by CTLA-4 blockade or combination CTLA-4/PD-1 blockade.

Note: Similar guidelines will apply for tremelimumab or other CTLA-4 blocking antibodies.

• Participants with known or suspected allergies to any component of the vaccine.

• Participants may not have been vaccinated previously with any of the synthetic peptides included in this protocol. Participants who have received vaccinations containing agents other than the synthetic peptides included in this protocol and have recurred during or after administration of the vaccine will be eligible to enroll 12 weeks following their last vaccination.

• Pregnancy.

• Female participants must not be breastfeeding

• Participants in whom there is a medical contraindication or potential problem in complying with the requirements of the protocol in the opinion of the investigator.

• Participants classified according to the New York Heart Association classification as having Class III or IV heart disease.

Participants with uncontrolled diabetes, defined as having a HGB-A1C> 7.5%.

• Participants must not have had prior autoimmune disorders requiring cytotoxic or immunosuppressive therapy, or autoimmune disorders with visceral involvement. Participants with an active autoimmune disorder requiring these therapies are also excluded. The following will not be exclusionary:

• The presence of laboratory evidence of autoimmune disease (e.g. positive ANA titer) without symptoms

• Clinical evidence of vitiligo

• Other forms of depigmenting illness

• Mild arthritis requiring NSAID medications

• A history of immune-related adverse events with immune therapy, if they have resolved completely.

• Participants who have another cancer diagnosis, except that the following diagnoses will be allowed:

• squamous cell cancer of the skin without known metastasis

• basal cell cancer of the skin without known metastasis

• carcinoma in situ of the breast (DCIS or LCIS)

• carcinoma in situ of the cervix

• any cancer without distant metastasis that has been treated successfully, without evidence of recurrence or metastasis for over 2 years

• Participants with known addiction to alcohol or drugs who are actively taking those agents, or participants with recent (within 1 year) or ongoing illicit IV drug use.

• Body weight < 110 pounds at registration, due to the amount and frequency with which blood will be drawn.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cancer Center at the University of Virginia	Charlottesville	Virginia	United States	22908

Sponsors and Collaborators

• Craig L Slingluff, Jr

Investigators

• Principal Investigator: Elizabeth Gaughan, MD, University of Virginia
• Study Director: Craig L. Slingluff, Jr., MD, University of Virginia

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 10, 2017

More Information

Publications

None provided.

• Responsible Party: Craig L Slingluff, Jr, Director, Human Immune Therapy Center, University of Virginia
• ClinicalTrials.gov Identifier: NCT02385669
• Other Study ID Numbers: 17780
• First Posted: Mar 11, 2015
• Last Update Posted: May 5, 2020
• Last Verified: Apr 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Craig L Slingluff, Jr, Director, Human Immune Therapy Center, University of Virginia: vaccine; peptide; ipilimumab; Yervoy; Montanide ISA-51
• Additional relevant MeSH terms: Melanoma; Ipilimumab

Study Results

Participant Flow

Recruitment Details	Enrollment opened 4/29/15 Closed to enrollment December 2018. Enrollment has been slow due to changes in standard of care, especially the dominance of PD-1 blockade over CTLA-4 blockade. The study was closed to enrollment due to slow accrual, despite multiple revisions in the protocol to enhance enrollment.

Arm/Group Title	6MHP and Ipilimumab
Arm/Group Description	The vaccine drug product, 6MHP, consists of 6 class II MHC-restricted peptides derived from melanoma proteins. Each vaccine consists of 200 mcg of each of the six peptides. An aqueous solution of vaccine is mixed 1/1 with Montanide ISA-51 to form water-in-oil emulsions. Vaccines are administered days 1, 8, 15, 43, 64, and 85. All peptide vaccines are administered intradermally and subcutaneously. Ipilimumab will be administered in accord with the official prescribing information: 3 mg/kg intravenously once every 3 weeks, for 4 doses. Ipilimumab will be administered on days 1, 22, 43, and 64. Ipilimumab: Checkpoint blockade inhibitor 6MHP: 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides
Period Title: Overall Study
STARTED	3
COMPLETED	1
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	6MHP and Ipilimumab
Arm/Group Description	The vaccine drug product, 6MHP, consists of 6 class II MHC-restricted peptides derived from melanoma proteins. Each vaccine consists of 200 mcg of each of the six peptides. An aqueous solution of vaccine is mixed 1/1 with Montanide ISA-51 to form water-in-oil emulsions. Vaccines are administered days 1, 8, 15, 43, 64, and 85. All peptide vaccines are administered intradermally and subcutaneously. Ipilimumab will be administered in accord with the official prescribing information: 3 mg/kg intravenously once every 3 weeks, for 4 doses. Ipilimumab will be administered on days 1, 22, 43, and 64. Ipilimumab: Checkpoint blockade inhibitor 6MHP: 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides
Overall Participants	3
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	2 66.7%
>=65 years	1 33.3%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	54
Sex: Female, Male (Count of Participants)
Female	1 33.3%
Male	2 66.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	3 100%
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	3 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	3 100%

Outcome Measures

1. Primary Outcome

Title	Safety (Adverse Event Profile)
Description	Adverse event profile for the combination of ipilimumab and 6MHP
Time Frame	30 days after the last vaccination

Outcome Measure Data

Analysis Population Description

All eligible enrolled and treated patients. Partiipants analyzed for any adverse event (AE) and for dose limiting toxicities (DLT).

Arm/Group Title	6MHP and Ipilimumab
Arm/Group Description	The vaccine drug product, 6MHP, consists of 6 class II MHC-restricted peptides derived from melanoma proteins. Each vaccine consists of 200 mcg of each of the six peptides. An aqueous solution of vaccine is mixed 1/1 with Montanide ISA-51 to form water-in-oil emulsions. Vaccines are administered days 1, 8, 15, 43, 64, and 85. All peptide vaccines are administered intradermally and subcutaneously. Ipilimumab will be administered in accord with the official prescribing information: 3 mg/kg intravenously once every 3 weeks, for 4 doses. Ipilimumab will be administered on days 1, 22, 43, and 64. Ipilimumab: Checkpoint blockade inhibitor 6MHP: 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides
Measure Participants	3
Number of participants with DLTs	2 66.7%
Participants with any treatment-related AEs	3 100%

2. Primary Outcome

Title	CD4+ T Cell Responses in the Blood and in the Sentinel Immunized Node
Description	CD4+ T cell responses to the peptide vaccine, defined as: any CD4+ T cell response to 6 melanoma helper peptides (6MHP) in peripheral blood mononuclear cells (PBMC) with a 10 fold (or greater) increase in response over background (high response) by ex vivo ELIspot assay. CD4+ T cell high responses to 6MHP in PBMC at at least 2 consecutive time points having peripheral blood mononuclear cells (PBMC) with a 10 fold (or greater) increase in response over background by ex vivo ELIspot assay. CD4+ T cell high response to 6MHP in sentinel immunized lymph node (SIN).
Time Frame	through day 92

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	6MHP and Ipilimumab
Arm/Group Description	The vaccine drug product, 6MHP, consists of 6 class II MHC-restricted peptides derived from melanoma proteins. Each vaccine consists of 200 mcg of each of the six peptides. An aqueous solution of vaccine is mixed 1/1 with Montanide ISA-51 to form water-in-oil emulsions. Vaccines are administered days 1, 8, 15, 43, 64, and 85. All peptide vaccines are administered intradermally and subcutaneously. Ipilimumab will be administered in accord with the official prescribing information: 3 mg/kg intravenously once every 3 weeks, for 4 doses. Ipilimumab will be administered on days 1, 22, 43, and 64. Ipilimumab: Checkpoint blockade inhibitor 6MHP: 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides
Measure Participants	3
Number with T cell response to 6MHP in PBMC	2 66.7%
Number with T cell response at 2 consecutive times	0 0%
T cell reactivity to 6MHP in SIN	1 33.3%

3. Secondary Outcome

Title	Epitope Spreading (Epitope-spreading for CD8+ T Cells in the Blood and the Sentinel Immunized Node)
Description	An evaluation of epitope-spreading for CD8+ T cells in the blood and the sentinel immunized node that are reactive to a panel of defined melanoma antigens.
Time Frame	through day 92

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	3 months
Arm/Group Title	6MHP and Ipilimumab
Arm/Group Description	The vaccine drug product, 6MHP, consists of 6 class II MHC-restricted peptides derived from melanoma proteins. Each vaccine consists of 200 mcg of each of the six peptides. An aqueous solution of vaccine is mixed 1/1 with Montanide ISA-51 to form water-in-oil emulsions. Vaccines are administered days 1, 8, 15, 43, 64, and 85. All peptide vaccines are administered intradermally and subcutaneously. Ipilimumab will be administered in accord with the official prescribing information: 3 mg/kg intravenously once every 3 weeks, for 4 doses. Ipilimumab will be administered on days 1, 22, 43, and 64. Ipilimumab: Checkpoint blockade inhibitor 6MHP: 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides
All Cause Mortality
	6MHP and Ipilimumab
	Affected / at Risk (%)	# Events
Total	0/3 (0%)
Serious Adverse Events
	6MHP and Ipilimumab
	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)
Eye disorders
uveitis	1/3 (33.3%)	1
Other (Not Including Serious) Adverse Events
	6MHP and Ipilimumab
	Affected / at Risk (%)	# Events
Total	3/3 (100%)
Endocrine disorders
adrenal insufficiency	1/3 (33.3%)	1
Eye disorders
blurred vision	1/3 (33.3%)
Other	1/3 (33.3%)
Gastrointestinal disorders
Diarrhea	1/3 (33.3%)
Nausea	2/3 (66.7%)
Vomiting	2/3 (66.7%)
General disorders
Chills	1/3 (33.3%)
Edema limbs	1/3 (33.3%)
Fatigue	2/3 (66.7%)
Fever	1/3 (33.3%)
Flu like symptoms	1/3 (33.3%)
Injection site reaction	2/3 (66.7%)
Investigations
alanine aminotransferase increased	1/3 (33.3%)
aspartate aminotransferase increased	1/3 (33.3%)
weight loss	1/3 (33.3%)
Metabolism and nutrition disorders
anorexia	1/3 (33.3%)
dehydration	1/3 (33.3%)
Musculoskeletal and connective tissue disorders
myalgia	1/3 (33.3%)
Nervous system disorders
headache	1/3 (33.3%)
Skin and subcutaneous tissue disorders
Pruritis	2/3 (66.7%)
skin hypopigmentation	2/3 (66.7%)
skin induration	3/3 (100%)
skin ulceration	1/3 (33.3%)

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.