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Neuroectodermal Tumors, Primitive

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Anti-Infective Agents

Vaccines

Interferon-alpha

Adjuvants, Immunologic

Complement System Proteins

Complement Factor H

Immunologic Factors

Immunosuppressive Agents

three 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

daily 3 MU subcutaneous IFN-alfa for 7 days before leukapheresis (day -15 to -9, and for 7 days before any other additional leukapheresis)

both 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)

neither 1 or 2 external immunostimulant conditions (only Intradermal Autologous Dendritic Cell Vaccine)

arm 1: DC Vaccine + RT

arm 2: DC Vaccine + IFN-alfa

arm 3: both arm 1 and 2 + RT

arm 4: DC Vaccine

Oriana Nanni, PhD

Massimo Guidoboni, MD

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.

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.

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

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.

The irDCR, defined as the proportion of subjects showing irBOR (immuno-related Best Overall Response) of confirmed irCR (immuno-related Complete Response), irPR (immuno-related Partial Response), or irSD (immuno-related Stable Disease), will be compared in the different treatment arms, with the aim to select the most effective treatment combination.

The immunologic efficacy will be evaluated through DTH (Delayed Type Hypersensitivity) and IFN-gamma ELISPOT analysis of circulating antitumor effectors, after at least 4 induction doses of vaccination.

DC yield will be evaluated as the number of vaccinating DC obtained per ml of leukapheretically processed blood from each leukapheresis.

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

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

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.

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.

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.

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.

DC potency will be evaluated by a validated assay measuring the costimulatory ability of the vaccine (ELISPOT-COSTIM assay).

TEM-8 upregulation at the mRNA level upon DC maturation will be investigated by flow cytometry and real-time PCR.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
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	Malignant Melan... Malignant Melan...	arm 1: DC Vacci... arm 2: DC Vacci... arm 3: both arm... arm 4: DC Vacci...	18 Years - 70 Years	Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
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	Malignant Melan... Malignant Melan...	arm 1: DC Vacci... arm 2: DC Vacci... arm 3: both arm... arm 4: DC Vacci...	18 Years - 70 Years	Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
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	Malignant Melan... Malignant Melan...	arm 1: DC Vacci... arm 2: DC Vacci... arm 3: both arm... arm 4: DC Vacci...	18 Years - 70 Years	Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori

Spots Global Cancer Trial Database for arm 4: dc vaccine