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
Information source: Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
ClinicalTrials.gov processed this data on August 20, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Malignant Melanoma of Skin Stage III; Malignant Melanoma of Skin Stage IV
Intervention: arm 1: DC Vaccine + RT (Other); arm 2: DC Vaccine + IFN-alfa (Other); arm 3: both arm 1 and 2 + RT (Other); arm 4: DC Vaccine (Biological)
Phase: Phase 2
Status: Recruiting
Sponsored by: Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori Official(s) and/or principal investigator(s): Massimo Guidoboni, MD, Principal Investigator, Affiliation: IRST IRCCS, Meldola
Overall contact: Oriana Nanni, PhD, Phone: +390543739266, Email: oriana.nanni@irst.emr.it
Summary
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.
Clinical Details
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
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Safety, tolerability and feasibility assessmentsimmune related Disease Control Rate (irDCR) immunologic efficacy
Secondary outcome: biological effects of preleukapheresis IFN-alfa on DC (Dendritic Cells) yieldOverall Survival (OS) immuno-related Time To Progression (irTTP) immuno-related Overall Response Rate (irORR) immuno-related Duration of Response (irDOR) immuno-related Time To Response (irTTR) immuno-related Progression free Survival (irPFS) biological effects of preleukapheresis IFN-alfa on DC (Dendritic Cells) potency biological effects of preleukapheresis IFN-alfa on TEM-8 upregulation at the mRNA level upon DC (Dendritic Cells) maturation
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.
Eligibility
Minimum age: 18 Years.
Maximum age: 70 Years.
Gender(s): Both.
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).
Locations and Contacts
Oriana Nanni, PhD, Phone: +390543739266, Email: oriana.nanni@irst.emr.it
UO Immunoterapia e laboratorio TCS, IRST IRCCS, Meldola, FC 47014, Italy; Recruiting Massimo Guidoboni, MD, Phone: +390543739100, Email: massimo.guidoboni@irst.emr.it Massimo Guidoboni, MD, Principal Investigator
Additional Information
Starting date: July 2013
Last updated: June 19, 2015
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