Mel66: Melanoma Vaccine Against Neoantigen and Shared Antigens by CD40 Activation and TLR Agonists In Patients With Melanoma (Including Ocular Melanoma)

Sponsor

Craig L Slingluff, Jr (Other)

Overall Status

Recruiting

CT.gov ID

NCT04364230

Collaborator

Celldex Therapeutics (Industry)

Enrollment

Locations

Arm

55.1

Anticipated Duration (Months)

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study evaluates whether it is safe to administer a peptide vaccine made of 6MHP and a mutated neoantigen peptide (BRAF585-614-V600E) combined with adjuvants. The adjuvants that will be used in this trial are a CD40 antibody (CDX-1140) and a toll-like receptor (TLR) 3 agonist (Poly-ICLC). The study will also investigate the effects of the vaccine and the adjuvants on the immune response. The investigators will monitor these effects by performing tests in the laboratory on participants' blood and skin tissue.

Condition or Disease	Intervention/Treatment	Phase
Melanoma Ocular Melanoma Uveal Melanoma	Drug: 6MHP Drug: NeoAg-mBRAF Drug: PolyICLC Drug: CDX-1140	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

44 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Enhanced Melanoma Vaccine Against Neoantigen and Shared Antigens by CD40 Activation and TLR Agonists in Patients With Melanoma

Actual Study Start Date :

Sep 28, 2020

Anticipated Primary Completion Date :

Sep 1, 2024

Anticipated Study Completion Date :

May 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: All Participants 6MHP (200mcg of each peptide) and 300mcg of NeoAg-mBRAF will be co-administered locally with 0.9mg of polyICLC and CDX-1140. There will be a dose escalation of CDX-1140 (50mcg, 200mcg, 800mcg, 3.0mg). A vaccine containing all of these components will be given on days 1, 22, 43, and 64. The vaccine will be given subcutaneously/intradermally.	Drug: 6MHP 6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides Other Names: 6 melanoma helper peptide vaccine Drug: NeoAg-mBRAF BRAF 586-614 (V600E) peptide to which a histidine has been added to the N-terminus, resulting in BRAF 585-614 (V600E). Other Names: BRAF 585-614 (V600E) Drug: PolyICLC polyICLC, local adjuvant Drug: CDX-1140 CDX-1140, local adjuvant

Arm

Intervention/Treatment

Experimental: All Participants

6MHP (200mcg of each peptide) and 300mcg of NeoAg-mBRAF will be co-administered locally with 0.9mg of polyICLC and CDX-1140. There will be a dose escalation of CDX-1140 (50mcg, 200mcg, 800mcg, 3.0mg). A vaccine containing all of these components will be given on days 1, 22, 43, and 64. The vaccine will be given subcutaneously/intradermally.

Drug: 6MHP

6 melanoma helper vaccine comprised of 6 class II MHC-restricted helper peptides

Other Names:

6 melanoma helper peptide vaccine

Drug: NeoAg-mBRAF

BRAF 586-614 (V600E) peptide to which a histidine has been added to the N-terminus, resulting in BRAF 585-614 (V600E).

Other Names:

BRAF 585-614 (V600E)

Drug: PolyICLC

polyICLC, local adjuvant

Drug: CDX-1140

CDX-1140, local adjuvant

Outcome Measures

Primary Outcome Measures

Safety of CDX-1140 + melanoma peptide vaccine (6MHP and NeoAg-mBRAF) + PolyICLC [30 days after receiving the last dose of study drug]
Number of participants with dose-limiting toxicities based on CTCAE v5.0
Immunogenicity: Estimate immune response rate to a melanoma vaccine combined with CDX-1140 [Day 85 and/or Day 176]
Number of participants with durable or persistent C4+ Th1 responses to the melanoma vaccine at either day 85 or day 176, or both

Secondary Outcome Measures

Immunogenicity: Impact of vaccine containing peptides plus CDX-1140 and polyICLC on regulatory T cells [Day 50]
Number of FoxP3+ CD4+ T cells per mm^2 in vaccine site biopsies
Immunogenicity: Impact of addition of CDX-1140 to melanoma vaccine on circulating regulatory T cells [Through Day 85]
Number of participants with circulating Tregs (CD4+ FoxP3+) as a proportion of circulating CD4 T cells
Immunogenicity: Impact of addition of CDX-1140 to melanoma vaccine on induction of CD4+ Th1 responses to vaccine antigens [Through Day 176]
Number of participants with CD4+ T cell response; maximum increase after vaccination at any time point.
Immunogenicity: Impact of addition of CDX-1140 to melanoma vaccine on CD4+ Th1 memory response to vaccine antigens [Day 176]
Number of participants with CD4+ T cell response to the melanoma peptides

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Main Inclusion Criteria:

1. For individuals with primary cutaneous, mucosal, or unknown melanoma, an individual must have stage IB ulcerated, II, III, or IV melanoma at original diagnosis or at restaging after recurrence, and be rendered clinically free of disease by surgery, other therapy, or spontaneous remission within 6 months prior to registration.

For patients with stage II, III, or IV uveal melanoma, patients must be rendered clinically free of disease by surgery, other therapy, or spontaneous remission within 6 months prior to registration.

An individual with small radiologic or clinical findings of an indeterminate nature may still be eligible
An individual may have had cutaneous, uveal, mucosal primary melanoma, or an unknown primary melanoma.
Biopsies of nevi are optional. Participants with at least 4-10 evaluable nevi at least 4 mm in diameter that are located on truncal or non-acral extremity sites and are accessible for biopsy and observation will be asked to participate in the optional nevi biopsies
Diagnosis of melanoma must be confirmed by cytological or histological examination except that patients with clinically localized primary uveal melanoma will not require pathologic review.
Individuals will be required to have radiological studies to rule out radiologically evident melanoma metastasis.
Individuals who have had brain metastases will be eligible if all of the following are true:

Each brain metastasis must have been completely removed by surgery or each unresected brain metastasis must have been treated with stereotactic radiosurgery.
No brain metastasis is > 2 cm in diameter at the time of registration.
Any neurologic symptoms attributable to brain metastases have returned to baseline.
There is no evidence of new or enlarging brain metastases.

The most recent surgical resections or gamma-knife therapy for malignant melanoma must have been completed ≥ 1 week and ≤ 6 months prior to registration.
ECOG performance status of 0 or 1 (Section 13.3).
Ability and willingness to give informed consent.
Adequate organ function as determined by laboratory parameters.
Male or female, age 18 years or older at registration.
Individuals must have at least one intact (undissected) axillary and/or inguinal lymph node basin.
For females and males of reproductive potential: agreement to use adequate contraception during study participation and for an additional 3 months after receiving the last dose of study drug.

Main Exclusion Criteria:

Individuals 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 and ≤ 6 months prior to registration)
Allergy desensitization injections
High doses of systemic corticosteroids, with some qualifications and exceptions
Growth factors (e.g. Procrit®, Aranesp®, Neulasta®)
Interleukins (e.g. Proleukin®)
Any investigational medication
Targeted therapies specific for mutated BRAF or for MEK

Individuals who are currently receiving nitrosoureas or who have received this therapy within 6 weeks of registration.
Individuals who are currently receiving a checkpoint molecule blockade therapy, or who have received this therapy within 12 weeks of registration.
Individuals with known or suspected allergies to any component of the vaccine.
Individuals who have received prior melanoma vaccinations with 6MHP plus the mutated BRAF peptide. However, participants who have received prior vaccinations will be eligible to enroll 12 weeks following their last vaccination if they have recurred during or after administration of the vaccine, and if their vaccines did not include all of the synthetic peptides included in this protocol.
Individuals who have previously received CDX-1140 or another CD40 agonistic antibody.
Pregnancy. Female individuals of childbearing potential must have a negative pregnancy test (urinary or serum beta-HCG) obtained within 2 weeks prior to registration.
HIV positivity or evidence of active Hepatitis C virus (testing to be done within 6 months of study entry).
Female individuals must not be breastfeeding.
Individuals in whom there is a medical contraindication or potential problem in complying with the requirements of the protocol in the opinion of the investigator.
Individuals classified according to the New York Heart Association classification as having Class III or IV heart disease (Section 13.4).
Individuals must not have had prior autoimmune disorders requiring systemic cytotoxic or immunosuppressive therapy, or autoimmune disorders with visceral involvement. Participants with an active autoimmune disorder requiring these therapies are also excluded. Some autoimmune disorders 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 non-steroidal anti-inflammatory drugs (NSAID) medications
Resolved childhood asthma/atopy
Endocrinopathies on stable hormone replacement therapy

Individuals 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.
Individuals with current pneumonitis. Individuals must not have had pneumonitis within 30 days of registration. Patients who have had complete resolution of prior pneumonitis will be eligible.
Individuals who have received a live vaccine within 30 days of registration.
Body weight < 110 pounds (50 kg) at registration