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Vaccination With Autologous Dendritic Cells Loaded With Autologous Tumor Lysate or Homogenate Combined With Immunomodulating Radiotherapy and/or Preleukapheresis IFN-alfa in Patients With Metastatic Melanoma: a Randomized "Proof-of-principle" Phase II Study

NCT01973322

Description:

Title: Vaccination with autologous dendritic cells loaded with autologous tumor lysate or homogenate combined with immunomodulating radiotherapy and/or preleukapheresis IFN-alfa in patients with metastatic melanoma: a randomized "proof-of-principle" phase II study. Study Design: Randomized selection design, proof of principle study Study Duration: 36 months Number of Subjects: 24 evaluable patients Diagnosis and Main Inclusion Criteria: Patients with non resectable stage III or stage IV malignant melanoma carrying at least 2 measurable lesions, any line after 1st line Vemurafenib in patients carrying BRAF mutation-positive melanoma and/or ≥ 2nd line Ipilimumab. Study Product, Dose, Route, Regimen and duration of administration: Intradermal Autologous Dendritic Cell vaccine loaded with autologous tumor lysate or homogenate on weeks 1, 4 6 and 8 during induction phase, and every 4 weeks during maintenance phase up to a maximum of 14 vaccine doses (each dose followed by IL-2 3 MU day 2-6) COMBINED OR NOT WITH - IFN-alfa 3 MU daily for 7 days before leukapheresis AND/OR - Three daily doses of 8 Gy up to 12 Gy delivered to one metastatic field between vaccine doses 1 and 2 (optional to one additional field between doses 7 and 8) utilizing IMRT-IMAT techniques.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Vaccination With Autologous Dendritic Cells Loaded With Autologous Tumor Lysate or Homogenate Combined With Immunomodulating Radiotherapy and/or Preleukapheresis IFN-alfa in Patients With Metastatic Melanoma: a Randomized "Proof-of-principle" Phase II Study
  • Official Title: Vaccination With Autologous Dendritic Cells Loaded With Autologous Tumor Lysate or Homogenate Combined With Immunomodulating Radiotherapy and/or Preleukapheresis IFN-alfa in Patients With Metastatic Melanoma: a Randomized "Proof-of-principle" Phase II Study

Clinical Trial IDs

  • ORG STUDY ID: IRST172.02
  • SECONDARY ID: 2012-001410-41
  • NCT ID: NCT01973322

Conditions

  • Malignant Melanoma of Skin Stage III
  • Malignant Melanoma of Skin Stage IV

Interventions

DrugSynonymsArms
arm 4: DC Vaccinevaccinearm 4: DC Vaccine

Purpose

Title: Vaccination with autologous dendritic cells loaded with autologous tumor lysate or homogenate combined with immunomodulating radiotherapy and/or preleukapheresis IFN-alfa in patients with metastatic melanoma: a randomized "proof-of-principle" phase II study. Study Design: Randomized selection design, proof of principle study Study Duration: 36 months Number of Subjects: 24 evaluable patients Diagnosis and Main Inclusion Criteria: Patients with non resectable stage III or stage IV malignant melanoma carrying at least 2 measurable lesions, any line after 1st line Vemurafenib in patients carrying BRAF mutation-positive melanoma and/or ≥ 2nd line Ipilimumab. Study Product, Dose, Route, Regimen and duration of administration: Intradermal Autologous Dendritic Cell vaccine loaded with autologous tumor lysate or homogenate on weeks 1, 4 6 and 8 during induction phase, and every 4 weeks during maintenance phase up to a maximum of 14 vaccine doses (each dose followed by IL-2 3 MU day 2-6) COMBINED OR NOT WITH - IFN-alfa 3 MU daily for 7 days before leukapheresis AND/OR - Three daily doses of 8 Gy up to 12 Gy delivered to one metastatic field between vaccine doses 1 and 2 (optional to one additional field between doses 7 and 8) utilizing IMRT-IMAT techniques.

Detailed Description

      Title: Vaccination with autologous dendritic cells loaded with autologous tumor lysate or
      homogenate combined with immunomodulating radiotherapy and/or preleukapheresis IFN-alfa in
      patients with metastatic melanoma: a randomized "proof-of-principle" phase II study.

      Short Title/Acronym: ABSIDE (ABScopal effect-Interferon alpha-DEndritic cells)

      Protocol Code IRST172.02

      Phase: phase II clinical trial

      Study Design: Randomized selection design, proof of principle study

      Study Duration: 36 months

      Study Center(s): Monocentric (IRCCS IRST Meldola)

      Objectives:

      Primary objectives

        1. Safety assessments: to determine the safety of the autologous tumor lysate loaded DC
           vaccine in combination with IFN-alfa and/or radiotherapy in patients with advanced
           melanoma.

        2. Clinical objective: to select the regimen that has the best immune related Disease
           Control Rate (irDCR) in the different external immunostimulant conditions utilized in
           combinations with autologous tumor lysate loaded DC vaccine.

        3. Immunological objective: to compare between the different treatment arms the immunologic
           efficacy, defined as the proportion of subjects developing positive DTH to ATL and/or
           KLH, combined with quantification of tumor antigen-specific circulating immune effectors
           performed by IFNalfa-ELISPOT analysis at the base line and after at least 4
           immunizations, if DTH analysis will not detect differences in terms of immunologic
           efficacy between the different arms.

      Number of Subjects: 24 evaluable patients

      Diagnosis and Main Inclusion Criteria: Patients with non resectable stage III or stage IV
      malignant melanoma carrying at least 2 measurable lesions, any line after 1st line
      Vemurafenib in patients carrying BRAF mutation-positive melanoma and/or ≥ 2nd line
      Ipilimumab.

      Study Product, Dose, Route, Regimen and duration of administration:

      Intradermal Autologous Dendritic Cell vaccine loaded with autologous tumor lysate or
      homogenate on weeks 1, 4 6 and 8 during induction phase, and every 4 weeks during maintenance
      phase up to a maximum of 14 vaccine doses (each dose followed by IL-2 3 MU day 2-6) COMBINED
      OR NOT WITH

        -  IFN-alfa 3 MU daily for 7 days before leukapheresis AND/OR

        -  Three daily doses of 8 Gy up to 12 Gy delivered to one metastatic field between vaccine
           doses 1 and 2 (optional to one additional field between doses 7 and 8) utilizing
           IMRT-IMAT techniques.

      Statistical Methodology: The RANDOMIZED SELECTION DESIGN was chosen basing on the assumption
      that immunotherapy is expected to be effective only in patients showing efficient induction
      of antitumor immune responses ("targeted endpoint"), allowing to reduce the number of
      patients required to evaluate the potential efficacy of an experimental treatment.

      The Steinberg and Venzon approach will be employed to select one among different treatment
      arms as being worthy of further evaluation. This method requires that an adequate gap in the
      number of responses among different arms be observed in order to limit the probability that
      the selected arm is actually inferior by more than an indifferent amount. Assuming an error
      probability of selecting inferior arm pW =10%, with 6 patients per arm, regardless of
      proportion of irOR expected in each arm, the gap of 2, the largest minimal difference in the
      number of irOR which must be observed in order to select the arm with the higher number of
      irOR, provides that difference between highest probability of response and the maximum on the
      remaining arms is 15%. Therefore, outcomes of at least 4/6 versus the maximum on the
      remaining 3 arms of 2/6, at least 5/6 versus the maximum on the remaining 3 arms of 3/6 and
      so forth will lead to selection the most promising arm on the basis of irOR. with an error
      probability of 10% Otherwise no treatment arm could be considered better than others.
    

Trial Arms

NameTypeDescriptionInterventions
arm 1: DC Vaccine + RTExperimentalthree daily doses of 8 Gy up to 12 Gy delivered to one non-index metastatic field between vaccine doses 1 and 2 (optional to one additional field between vaccine doses 7 and 8) utilizing IMRT-IMAT techniques
    arm 2: DC Vaccine + IFN-alfaExperimentaldaily 3 MU subcutaneous IFN-alfa for 7 days before leukapheresis (day -15 to -9, and for 7 days before any other additional leukapheresis)
      arm 3: both arm 1 and 2 + RTExperimentalboth 1 and 2 external immunostimulant conditions (Intradermal Autologous Dendritic Cell Vaccine + 3 single boosts of RT + IFN-alfa, 3 MU daily for 7 days before leukapheresis)
        arm 4: DC VaccineExperimentalneither 1 or 2 external immunostimulant conditions (only Intradermal Autologous Dendritic Cell Vaccine)
        • arm 4: DC Vaccine

        Eligibility Criteria

                Inclusion Criteria:
        
                  1. Signed Written Informed Consent: patients must be willing and able to give written
                     informed consent, that have to be given before starting of screening procedure.
        
                  2. Availability of autologous tumor tissue fulfilling acceptance criteria prescribed by
                     the "Product Specification File".
        
                  3. Patients must have histologically or cytologically confirmed malignant unresectable
                     stage III or stage IV melanoma;
        
                  4. Patients must have a minimum of two lesions, one of which must be measurable,(i.e.
                     that can be accurately measured in two perpendicular dimensions, with at least 1
                     diameter >20 mm and the other dimension >10 mm with conventional techniques or at
                     least 10 x 10 mm with spiral CT scan).
        
                  5. Patients carrying BRAF mutation-positive melanoma must have received previous
                     Vemurafenib, unless they are not eligible or refuse the treatment.
        
                  6. Patients treated with previous first line therapy must have received Ipilimumab,
                     unless they are not eligible or refuse the treatment.
        
                  7. Pretreated brain metastases which have been clinically stable for at least 6 months
                     and not requiring corticosteroids are allowed;
        
                  8. ECOG performance status 0-1;
        
                  9. Negative screening tests for HIV, HBV HCV and syphilis not older than 30 days before
                     performing any of the GMP-regulated activities required (leukapheresis, collection of
                     tumor biopsies to be used for tumor lysate/homogenate preparation);
        
                 10. Prior lines of chemotherapy, immunotherapy or biological therapy (e.g. inhibitors of
                     B-Raf or c-Kit, Ipilimumab, etc.) for advanced disease are allowed (patients must have
                     lasted prior treatments at least 4 weeks before the first vaccine dose);
        
                 11. Men and women aged 18-70 years.
        
                 12. Women of childbearing potential (WOCBP) must be using an adequate method of
                     contraception to avoid pregnancy throughout the study and for up 8 weeks after the
                     study, in order to minimize the risk of pregnancy;
        
                 13. Patients must have normal organ and marrow function as defined below:
        
                       -  leukocytes >1,500/microL
        
                       -  absolute neutrophil count >1,000/microL
        
                       -  platelets >80,000/microL
        
                       -  total bilirubin within 2 x ULN
        
                       -  AST(SGOT)/ALT(SGPT) <2.5 x ULN
        
                       -  creatinine ≤ 2 mg/dl
        
                Exclusion Criteria:
        
                  1. Patients who have positive tests to HCV, HBV, HIV, or syphilis (specific blood testing
                     must be performed within 30 days before any GMP-regulated activity (leukapheresis and
                     collection of tumor biopsies to be used for tumor lysate/homogenate preparation).
        
                  2. Patients with unresectable or metastatic melanoma BRAF V600 mutation-positive eligible
                     to Vemurafenib cannot be enrolled in first line, unless they refuse this treatment.
        
                  3. Patients eligible for Ipilimumab treatment, cannot be enrolled unless they refuse this
                     treatment.
        
                  4. Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering
                     the study or those who have not recovered from adverse events due to agents
                     administered more than 4 weeks earlier.
        
                  5. Participation in another clinical trial with any investigational agents within 30 days
                     prior to study screening.
        
                  6. Patients with known progressing and/or symptomatic brain metastases.
        
                  7. 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 limit compliance with
                     study requirements (on physician's judgment).
        
                  8. Other known malignant neoplastic diseases in the patient's medical history with a
                     disease-free interval of less than 3 years (except for previously treated basal cell
                     carcinoma and in situ carcinoma of the uterine cervix);
        
                  9. Any contraindication to undergo leukapheresis as evaluated by transfusionist (e.g.
                     severe anemia, piastrinopenia, oral anticoagulant therapy).
              
        Maximum Eligible Age:70 Years
        Minimum Eligible Age:18 Years
        Eligible Gender:All
        Healthy Volunteers:No

        Primary Outcome Measures

        Measure:Safety, tolerability and feasibility assessments
        Time Frame:36 months
        Safety Issue:
        Description:Evaluation of safety, tolerability and feasibility of the experimental treatments through the determination of the percentage of patients in each treatment group reporting an AE up to 30 days after vaccination.

        Secondary Outcome Measures

        Measure:biological effects of preleukapheresis IFN-alfa on DC (Dendritic Cells) yield
        Time Frame:36 months
        Safety Issue:
        Description:DC yield will be evaluated as the number of vaccinating DC obtained per ml of leukapheretically processed blood from each leukapheresis.
        Measure:Overall Survival (OS)
        Time Frame:36 months
        Safety Issue:
        Description:OS is defined by median survival and survival rates at 1 and 2 year of follow-up) and will be compared in the different treatment arms
        Measure:immuno-related Time To Progression (irTTP)
        Time Frame:36 months
        Safety Issue:
        Description:irTTP is the time from randomization to the first date of documented irPD (immuno-related Progressive Disease) or death and will be compared in the different treatment arms
        Measure:immuno-related Overall Response Rate (irORR)
        Time Frame:36 months
        Safety Issue:
        Description:irORR is the proportion of treated subjects with a irBOR (immuno-related Best Overall Response) of confirmed irCR (immuno-related Complete Response) or confirmed irPR (immuno-related Partial Response). It will be compared in the different treatment arms.
        Measure:immuno-related Duration of Response (irDOR)
        Time Frame:36 months
        Safety Issue:
        Description:irDOR is defined as the time between the date of the first irCR (immuno-related Complete Response) or irPR (immuno-related Partial Response) and the date of irPD (immuno-related Progressive Disease) or death. It will be compared in the different treatment arms.
        Measure:immuno-related Time To Response (irTTR)
        Time Frame:36 months
        Safety Issue:
        Description:irTTR is defined as the time from first dosing date until the first irPR (immuno-related Partial Response) or irCR (immuno-related Complete Response). It will be compared in the different treatment arms.
        Measure:immuno-related Progression free Survival (irPFS)
        Time Frame:36 months
        Safety Issue:
        Description:irPFS is defined as the time between the first dosing date and the date of irPD (immuno-related Progressive Disease), or date of death. It will be compared in the different treatment arms.
        Measure:biological effects of preleukapheresis IFN-alfa on DC (Dendritic Cells) potency
        Time Frame:36 months
        Safety Issue:
        Description:DC potency will be evaluated by a validated assay measuring the costimulatory ability of the vaccine (ELISPOT-COSTIM assay).
        Measure:biological effects of preleukapheresis IFN-alfa on TEM-8 upregulation at the mRNA level upon DC (Dendritic Cells) maturation
        Time Frame:36 months
        Safety Issue:
        Description:TEM-8 upregulation at the mRNA level upon DC maturation will be investigated by flow cytometry and real-time PCR.

        Details

        Phase:Phase 2
        Primary Purpose:Interventional
        Overall Status:Recruiting
        Lead Sponsor:Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori

        Trial Keywords

        • Malignant melanoma stage III or IV
        • pretreated melanoma
        • vaccination
        • autologous dendritic cells
        • autologous tumor lysate or homogenate
        • immunomodulating radiotherapy

        Last Updated

        April 20, 2020