Modified Melanoma Vaccine for High Risk or Low Residual Disease Patients

Allogeneic Vaccine Modified to Express HLA A2/4-1BB Ligand for High Risk or Low Residual Disease Melanoma Patients - Phase I/II Study.

This study is designed for patients who had malignant melanoma and, following tumor removal, are now free of disease, or have only very minor residual disease, and are at a very high risk of disease recurrence. These patients will be treated with the A2/4-1BBL melanoma vaccine, a compatible melanoma cell line that has been engineered to express a molecule termed 4-1BBL, which enhances the chances of the cell line to be recognized by the patient's immune system, and to induce its stimulation. The hypothesis that drives the study states that the immune response against the cell line will also be effective against the residual tumor that may still be present in the body.

Study Overview

• Status: Unknown
• Conditions: Malignant Melanoma
• Intervention / Treatment: Biological: A2/4-1BBL melanoma vaccine; Procedure: DNP sensititzation; Drug: Cyclophosphamide

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Israel
  • Jerusalem, Israel, 91120
    • Recruiting
    • Sharett Institute of Oncology, Hadassah Medical Organization
    • Contact: Hani Steinberg, RN; Email: hanis@hadassah.org.il

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients included in this protocol must carry one or more of the following tissue typing alleles: HLA-A2, -A24, -A33, -B35, -B49, -CW04/12(04/08). We estimate that 50% of melanoma patients will be eligible.
2. Cutaneous malignant melanoma AJCC stage IIb (>4 mm) or IIc (ulcerated melanoma >4mm).
3. Metastatic melanoma AJCC stage III (nodal involvement, N1-3a,b) post-surgical removal of lymph nodes.
4. Metastatic melanoma AJCC stage IV, completely resected.
5. Non-resectable metastatic melanoma of low burden disease and normal LDH who have undergone at least two treatment lines, including chemotherapy (DTIC, temodal, taxanes, platinum compounds), anti-CTLA-4 (ipilimumab) and B-RAF inhibitor if harboring the V600E BRAF mutation in their tumor.
6. Non cutaneous malignant melanoma of respective stages including uveal and mucosal melanoma.
7. Melanoma can be of either mutant or wild-type B-RAF.
8. Karnofsky performance status > 80 (Normal activity with effort).
9. No active cardio-respiratory disease.
10. Not pregnant or nursing. Women must take contraceptives during the treatment period.Hematocrit >25% and WBC >3000.
11. Informed consent of the patient.

Exclusion Criteria:

1. Administration of cytotoxic drugs or extensive radiotherapy less than 28 days prior to protocol administration.
2. Active brain metastases requiring corticosteroids.
3. Concurrent malignancy (other than skin cancer, carcinoma in situ of cervix and early stage prostate cancer).
4. Active serious infection.
5. Allergy to penicillin.
6. Patient's will to withdraw from the study at any stage.
7. HIV and chronic hepatitis B and C carrier

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: A2/4-1BBL melanoma vaccine; On days 1 and 2 patients will be sensitized to DNP by topically applying 0.1 ml of 2% DNP dissolved in acetone-corn oil (Sigma) to the inner aspect of the arm. On day 10, intravenous low dose cyclophosphamide, 300 mg/m2, will be administered at the day care unit. On day 14 the appropriate dose of irradiated M20/A2B cells will be injected into three adjacent sites on the upper arm or thigh, avoiding limbs where lymph node dissection had been previously performed. Four additional doses of the vaccine will be administered at intervals of 21 days.

Biological: A2/4-1BBL melanoma vaccine; On days 14, 35, 56, 77 and 98 the appropriate dose of irradiated M20/A2B cells will be injected into three adjacent sites on the upper arm or thigh, avoiding limbs where lymph node dissection had been previously performed.; Other Names: M20/A2B vaccine; Procedure: DNP sensititzation; Include brand names, serial numbers and code names, if applicable. Other names are used to improve search results on the ClinicalTrials.gov web site. On days 1 and 2 patients will be sensitized to DNP by topically applying 0.1 ml of 2% DNP dissolved in acetone-corn oil (Sigma) to the inner aspect of the arm.; Drug: Cyclophosphamide; On day 10, intravenous low dose cyclophosphamide, 300 mg/m2, will be administered.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
grade 2-4 adverse events according to CTCEA criteria		Day 1
monitoring anti-tumor immune response	Anti-tumor immune response will be measured by delayed type hypersensitivity in vivo and by in vitro lymphocyte response.	Day 0
grade 2-4 adverse events according to CTCEA criteria		Day 28
grade 2-4 adverse events according to CTCEA criteria		Day 56
grade 2-4 adverse events according to CTCEA criteria		month 3
grade 2-4 adverse events according to CTCEA criteria		month 4
grade 2-4 adverse events according to CTCEA criteria		month 5
grade 2-4 adverse events according to CTCEA criteria		month 6
monitoring anti-tumor immune response	Anti-tumor immune response will be measured by delayed type hypersensitivity in vivo and by in vitro lymphocyte response	Day 28
monitoring anti-tumor immune response	Anti-tumor immune response will be measured by delayed type hypersensitivity in vivo and by in vitro lymphocyte response	Day 56
monitoring anti-tumor immune response	Anti-tumor immune response will be measured by delayed type hypersensitivity in vivo and by in vitro lymphocyte response	month 3
monitoring anti-tumor immune response	Anti-tumor immune response will be measured by delayed type hypersensitivity in vivo and by in vitro lymphocyte response	month 4
monitoring anti-tumor immune response	Anti-tumor immune response will be measured by delayed type hypersensitivity in vivo and by in vitro lymphocyte response	month 5
monitoring anti-tumor immune response	Anti-tumor immune response will be measured by delayed type hypersensitivity in vivo and by in vitro lymphocyte response	month 6

Secondary Outcome Measures

Outcome Measure	Time Frame
overall survival and disease free survival	D1, Mo6, Mo10, Mo14, Mo18, Mo20, Mo24 and every 4 months till year 5

Collaborators and Investigators

• Sponsor: Hadassah Medical Organization

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Anticipated): April 1, 2019
• Study Completion (Anticipated): April 1, 2019

Study Registration Dates

• First Submitted: May 9, 2013
• First Submitted That Met QC Criteria: July 10, 2013
• First Posted (Estimate): July 12, 2013

Study Record Updates

• Last Update Posted (Actual): September 18, 2018
• Last Update Submitted That Met QC Criteria: September 17, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: vaccine; malignant melanoma; cell line; high risk; residual disease
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Vaccines
• Other Study ID Numbers: 0419-12-HMO-CTIL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No