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Vaccines

boost radiotherapy (XRT) plus intradermal autologous dendritic cell vaccine loaded with autologous tumor homogenate (Autologous DC vaccine) plus High-Dose IL-2

Three daily doses boost radiotherapy (XRT) at 6-12 Gy to at least 1, and up to a maximum of 5, metastatic fields, will be administrated on days -4 -3 -2 or -3 -2 -1 before the first and the third cycle of vaccine+IL-2

boost radiotherapy (XRT)

The first dose (7 to 14 x 10_6 total dendritic cells) will be performed with freshly prepared vaccine, 9 days after leukapheresis; on day +1 starting from cycle 2 (3 weeks after the first cycle, on completion of QA assessments on the cryopreserved products), 5 additional doses will be administered every 3 weeks until maximum six vaccines.

Autologous DC vaccine

high dose IL-2: 18 MIU/m2/day in 500cc administered by continuous IV infusion for 72 hours starting day +2.

High-Dose IL-2

Laura Ridolfi, MD

Single center, open-label Proof of Principle phase II trial to assess objective response (ORR).

Three daily doses boost radiotherapy (XRT) at 6-12 Gy to at least 1, and up to a maximum of 5, metastatic fields, will be administrated on days -4 -3 -2 or -3 -2 -1 before the first and the third cycle of vaccine+IL-2. The first day of administration of vaccine is day +1 and of IL-2 is day +2.

Treatment vaccine plus IL-2 (dose 18 MIU/m2/day in 500cc by continuous IV infusion for 72 hours) will be administered every 3 weeks up to 6 cycles.

Total duration of the trial: 36 months

* Enrolment period: 24 months
* Treatment: maximum of 6 cycles (5 months) per patient
* Follow-up every three months until patient died (follow-up until PD and only survival contacts and subsequent therapy for metastatic disease after PD).

Vaccination with dendritic cells pulsed with autologous tumor homogenate in combination with HD-IL2 and immunomodulating radiotherapy in metastatic RCC: a phase II trial Proof of Principle phase II study Study Design Single center, open-label trial to assess response rate Study Duration Total duration: 36 months Enrollment: 24 months Treatment: 5 months per patient Follow-up every three months Primary objectives: Overall Response Rate (ORR) by irRC

Secondary end points:

1. Toxicity
2. Overall Survival
3. Duration of response
4. PFS
5. ORR by RECIST 1.1
6. Prognostic and predictive marker response
7. Immunological response Study Product, Dose, Route, Regimen and duration of administration Three daily doses boost radiotherapy (XRT) at 6-12 Gy to at least 1, and up to a maximum of 5, metastatic fields, will be administrated on days -4 -3 -2 or -3 -2 -1 before the first and the third cycle of vaccine+IL-2. The first day of administration of vaccine is day +1 and of IL-2 is day +2.

The intradermal autologous dendritic cell vaccine loaded with autologous tumor homogenate plus IL-2 (dose 18 MIU/m2/day in 500cc by continuous IV infusion for 72 hours) will be administered every 3 weeks up to 6 cycles.

Statistical Methodology

This is a Proof of Principle trial with a minimax two stage design:

• Step 1: 12 patients enrolled; A 5% response rate will preclude further study, whereas a 20% response rate will indicate that further study would be warranted.

Using alfa and beta errors of 0.10, if an objective response is observed in at least 1 of the 12 patients enrolled during the first stage the study will go on with a:

• Step 2: recruitment of an additional 25 patients The treatments will be considered active if an objective response is observed in 4 out of 37 patients treated.

The enrolment period will be 24 months. To ensure patients' safety, a continued safety evaluation by an independent DSMB will be performed and formal rules will be planned to continue or stop the recruitment; in particular, the enrollment will be interrupted when six patients completed at least one cycle of the combo treatment and they will be evaluated for safety: if grade ≥3 AEs (except for fever and rash that will be consider only for grade 4) in 2 (two) or more patients will be observed within 30 days after completion of the first dose of combo treatment, the study will be interrupted.

Vaccination With Dendritic Cells Pulsed With Autologous Tumor Homogenate in Combination With HD-IL2 and Immunomodulating Radiotherapy in Metastatic RCC

Vaccination With Dendritic Cells Pulsed With Autologous Tumor Homogenate in Combination With HD-IL2 and Immunomodulating Radiotherapy in Metastatic RCC: a Phase II Trial (RENALVax-2)

The analysis will be performed on an intention to treat population, i.e. all patients having received at least 2 cycles of therapy.

measured from the date of registration until the date of death from any cause or the last date the patient was known to be alive and will be estimated with Kaplan-Meier method and the log rank test

time calculated from documentation of tumor response to disease progression

measured from registration until disease progression or death

Immunologic efficacy will be measured by best DTH score (reactivity to homogenate or KLH) obtained after at least 4 vaccine doses, alone or combined with IFN-g ELISPOT analysis of tumor antigen-specific circulating effectors obtained after a minimum of 4 vaccine doses, both compared with prevaccine samples

Number of patients with treatment related Adverse events (AE) will be evaluated by CTCAE v 4.03 criteria The percentage of patients reporting an AE up to 30 days after HD-IL-2 treatment will be tabulated with 95% confidence intervals, by type of AE. The overall rate of grade 3-4 related AE will be computed

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Vaccination With Dendritic Cells Pulsed With Autologous Tumor Homogenate in Combination With HD-IL2 and Immunomodulating Radiotherapy in Metastatic RCC	NCT03226236	Carcinoma, Rena... Vaccination Secondary	boost radiother... Autologous DC v... High-Dose IL-2	19 Years -	Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori
Vaccination With Dendritic Cells Pulsed With Autologous Tumor Homogenate in Combination With HD-IL2 and Immunomodulating Radiotherapy in Metastatic RCC	NCT03226236	Carcinoma, Rena... Vaccination Secondary	boost radiother... Autologous DC v... High-Dose IL-2	19 Years -	Istituto Scientifico Romagnolo per lo Studio e la cura dei Tumori

Spots Global Cancer Trial Database for autologous tumor homogenate