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 (ABSIDE)

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.

Study Overview

• Status: Unknown
• Conditions: Malignant Melanoma of Skin Stage III; Malignant Melanoma of Skin Stage IV
• Intervention / Treatment: Other: arm 1: DC Vaccine + RT; Other: arm 2: DC Vaccine + IFN-alfa; Other: arm 3: both arm 1 and 2 + RT; Biological: arm 4: DC Vaccine

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.

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Oriana Nanni, PhD; Phone Number: +390543739266; Email: oriana.nanni@irst.emr.it

Study Locations

• Italy
  • FC
    • Meldola, FC, Italy, 47014
      • Recruiting
      • UO Immunoterapia e laboratorio TCS, IRST IRCCS
      • Contact: Massimo Guidoboni, MD; Phone Number: +390543739100; Email: massimo.guidoboni@irst.emr.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: arm 1: DC Vaccine + RT; 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	Other: arm 1: DC Vaccine + RT; 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; Other Names: vaccine + radiotherapy
Experimental: arm 2: DC Vaccine + IFN-alfa; daily 3 MU subcutaneous IFN-alfa for 7 days before leukapheresis (day -15 to -9, and for 7 days before any other additional leukapheresis)	Other: arm 2: DC Vaccine + IFN-alfa; daily 3 MU subcutaneous IFN-alfa for 7 days before leukapheresis (day -15 to -9, and for 7 days before any other additional leukapheresis); Other Names: vaccine + drug
Experimental: arm 3: both arm 1 and 2 + RT; 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)	Other: arm 3: both arm 1 and 2 + RT; 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); Other Names: vaccine + radiotherapy + drug
Experimental: arm 4: DC Vaccine; neither 1 or 2 external immunostimulant conditions (only Intradermal Autologous Dendritic Cell Vaccine)	Biological: arm 4: DC Vaccine; neither 1 or 2 external immunostimulant conditions (only Intradermal Autologous Dendritic Cell Vaccine); Other Names: vaccine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety, tolerability and feasibility assessments	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.	36 months
immune related Disease Control Rate (irDCR)	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.	36 months
immunologic efficacy	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.	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
biological effects of preleukapheresis IFN-alfa on DC (Dendritic Cells) yield	DC yield will be evaluated as the number of vaccinating DC obtained per ml of leukapheretically processed blood from each leukapheresis.	36 months
Overall Survival (OS)	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	36 months
immuno-related Time To Progression (irTTP)	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	36 months
immuno-related Overall Response Rate (irORR)	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.	36 months
immuno-related Duration of Response (irDOR)	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.	36 months
immuno-related Time To Response (irTTR)	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.	36 months
immuno-related Progression free Survival (irPFS)	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.	36 months
biological effects of preleukapheresis IFN-alfa on DC (Dendritic Cells) potency	DC potency will be evaluated by a validated assay measuring the costimulatory ability of the vaccine (ELISPOT-COSTIM assay).	36 months
biological effects of preleukapheresis IFN-alfa on TEM-8 upregulation at the mRNA level upon DC (Dendritic Cells) maturation	TEM-8 upregulation at the mRNA level upon DC maturation will be investigated by flow cytometry and real-time PCR.	36 months

Collaborators and Investigators

• Sponsor: Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
• Investigators: Principal Investigator: Massimo Guidoboni, MD, IRST IRCCS, Meldola

Study record dates

Study Major Dates

• Study Start (Actual): October 8, 2013
• Primary Completion (Anticipated): March 1, 2021
• Study Completion (Anticipated): August 1, 2021

Study Registration Dates

• First Submitted: October 21, 2013
• First Submitted That Met QC Criteria: October 25, 2013
• First Posted (Estimate): October 31, 2013

Study Record Updates

• Last Update Posted (Actual): February 26, 2021
• Last Update Submitted That Met QC Criteria: February 25, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: vaccination; autologous dendritic cells; Malignant melanoma stage III or IV; pretreated melanoma; autologous tumor lysate or homogenate; immunomodulating radiotherapy
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Melanoma; Skin Neoplasms; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Vaccines; Complement Factor H
• Other Study ID Numbers: IRST172.02; 2012-001410-41 (EudraCT Number)