Clinical trial NCT01723813: Peptide Vaccinations Plus GM-CT-01 in Melanoma
Official title: Phase I/II Study of Peptide Vaccination Associated With GM-CT-01, a Galactomannan Oligomer That Inhibits Galectin-3, in Patients With Advanced Metastatic Melanoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Metastatic Melanoma
Keywords: Immunotherapy
Tumor-specific peptides
GM-CT-01
Lead sponsor: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
Sponsor class: OTHER
First posted: 2012-11-08
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether the intravenous and/or GM-CT-01 administration can correct Tumor Infiltrating Lymphocytes (TIL) anergy and induce a more efficient and long-lasting anti-tumoral immune response following peptide vaccination.

Detailed description: Human cancers express tumor antigens that can be targeted by cytolytic T lymphocytes (CTL). These antigens consist of a small peptide, derived from endogenous proteins, that is presented at the cancer cell's surface by an HLA class I molecule. Such antigenic peptides, including MAGE-3.A1 and NA17.A2, have been tested in experimental therapeutic vaccines to elicit CTL responses in cancer patients, mainly with metastatic melanoma. Up to now, only rare tumor responses have been observed.

Tumor resistance to CTL killing is the most likely explanation for the poor effectiveness of cancer vaccines. This resistance is probably acquired by the tumor during its development and selected by its repetitive challenge with spontaneous anti-tumoral immune responses. Recently, we have identified a novel mechanism causing anergy of tumor-associated T lymphocytes, and established new approaches to correct this anergy in vitro. Galectin-3, secreted by tumor cells, appears to inhibit CTL function the co-localization of the T cell receptor and the cluster of differentiation 8 coreceptor. Importantly, this functional defect is restored when anergic T cells are incubated with galectin-3 inhibitors such as the disaccharides lactose and N-acetyllactosamine, and the polysaccharide GM-CT-01. GM-CT-01 is a vegetal galactomannan oligomer, currently under clinical investigation in several types of solid malignancies for its capacity to inhibit galectins and to synergize with chemotherapy drugs.

Our observations suggest that treatment of cancer patients with GM-CT-01 could correct TIL anergy and induce a more efficient and long-lasting anti-tumoral immune response following peptide vaccination.

Eligibility criteria: Inclusion Criteria:

* Patients with histologically proven cutaneous melanoma at one of the following American Joint Committee on Cancer stages : Regional metastatic disease (any T; N2c or N3; M0), no amenable to curative treatment by surgery or isolated limb perfusion.Distant metastatic disease (any T; any N; M1a, M1b or M1c\*).\*except uncontrolled brain metastasis and except Lactate dehydrogenase \>1.5 upper normal value
* HLA-A1 or HLA-A2 (by serology or molecular biology)
* At least one of the two following conditions:

MAGE-3 gene expression by the tumor if patient is HLA-A1 NA17 gene expression by the tumor if patient is HLA-A2 (determined by reverse transcription and polymerase chain reaction amplification).

* Measurable Disease. Patients must have at least 1 measurable metastasis at study entry for all patients. In addition, patients candidates for enrollment in Group 2 who will receive peri-tumoral injections of GM-CT-01 must have at least 1 superficial metastasis (cutaneous, subcutaneous or superficial lymph node metastasis, with its largest diameter equal to or greater than 5, 5, or 10 mm, respectively) at study entry.
* Age ≥ 18 years.
* Karnofsky Performance status ≥70 or WHO performance status of 0 or 1
* Expected survival of at least 6 months.
* Laboratory values :

Platelet count ≥100x103/μL Leukocyte count ≥ 3x103/μL Hemoglobin ≥ 9 g/dL Aspartate transaminase and Alanine transaminase ≤ 2 times upper normal value Serum creatinine ≤1.5 times upper normal value Total bilirubin ≤ 1.5 times upper normal value Lactate dehydrogenase ≤ 1.5 times upper normal value

* Viral serology : negative antibodies for Hepatitis C Virus \& HIV; negative antigens for Hepatitis B Virus.
* Patient should agree to perform biopsies and blood collections for translational research.
* Signed informed consent from the patient must be obtained.

Exclusion Criteria:

* Uncontrolled brain or central nervous system metastasis.
* Previous treatment for the melanoma within 6 weeks from inclusion, with any reagent known to modulate the immune system such as a cancer vaccine, interferon-alpha, interleukins or anti-CTLA-4 antibodies.
* Previous chemotherapy, radiotherapy, corticotherapy, or other immune suppressive therapy within 4 weeks from inclusion.
* Clinically significant cardiovascular disease (including cardiac insufficiency New York Heart Association grade III and IV, unstable angina, arrythmia, myocardial infarction, symptomatic congestive heart failure) in the past 12 months before enrollment.
* Other serious acute or chronic illnesses, e.g. active infections requiring antibiotics, bleeding disorders or other conditions requiring concurrent medications not allowed during this study.
* Other malignancy within 3 years prior to entry in the study, except for treated non-melanoma skin cancer and in situ cervical carcinoma.
* Active immunodeficiency disease or autoimmune disease (vitiligo is not an exclusion criterion).
* Lack of availability for immunological and clinical follow-up assessments.
* Participation in any other clinical trial involving another investigational agent within 4 weeks prior to enrollment.
* Subject pregnant or breastfeeding, or planning to become pregnant within 6 months after the end of treatment.
* Subject (male or female) not willing to use highly effective methods of contraception (per institutional standard) during treatment and for 6 months after the end of treatment.

Primary outcomes:
measure: Number of participants with adverse events
timeFrame: 30 days after last administration of Study drugs
measure: Response rate in both arms
timeFrame: Change from baseline at week 7 and week 20
Secondary outcomes:
measure: Response rate in group 2 versus group 1
timeFrame: Change from baseline at week 7 and week 20
measure: Time to Progression
timeFrame: From date of inclusion until the date of first documented progression or date of death from any cause, which ever came first, assessed up to 100 weeks
measure: Overall Survival
timeFrame: From day of inclusion to date of death
measure: Immunogenicity of the treatment
timeFrame: Change from baseline at week 20
Other outcomes:
measure: Translational research
timeFrame: baseline and at progression
measure: Pharmacokinetics of GM-CT-01
timeFrame: Change from baseline at days 46 to 48
Locations:
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint Luc
Study officials:
affiliation: Cliniques univeristaires Saint-Luc
name: Jean-Francois BAURAIN, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: