1560-GITCG

European Organisation for the Research and Treatment of Cancer (EORTC)

Avenue Emmanuel Mounier 83/11, Brussels, Belgium, 1200

Clinical Operations Department/RAU, European Organisation for the Research and Treatment of Cancer (EORTC), +32 27741023, regulatory@eortc.org

Clinical Operations Department/RAU, European Organisation for the Research and Treatment of Cancer (EORTC), +32 27741023, regulatory@eortc.org

No

No

No

Final

30 Jan 2023

Yes

22 Feb 2022

Yes

22 Feb 2022

No

The primary objective of this proof of concept study will be to investigate whether the combined use of local tumor ablation/radiation plus immunomodulating drugs may induce a significant immune response in patient with incurable liver metastases from colorectal cancer (CRC) (+/- limited extrahepatic disease) being stable or in partial response after a course of first- or second-line therapy. The primary objective of the study is to show an overall response rate of lesions not treated by ablation/radiotherapy including the extrahepatic lesions (according to iRECIST criteria) higher than 10%. With the continuation of first line systemic treatment, no further responses are expected. In order to be able to study the impact of the local technique on the final results (secondary objective), patients will be enrolled in two cohorts according whether they will be treated by RFA or with SBRT.

The responsible investigator will ensure that this study is conducted in agreement with either the Declaration of Helsinki (available on the World Medical Association web site (http://www.wma.net)) and/or the laws and regulations of the country, whichever provides the greatest protection of the patient.The protocol has been written, and the study was conducted according to the ICH Harmonized Tripartite Guideline on Good Clinical Practice (ICH-GCP, available online at https://www.ema.europa.eu/documents/scientific-guideline/ich-e6-r1-guideline-good-clinical-practice_en.pdf).The protocol was approved by the competent ethics committee(s) as required by the applicable national legislation.

26 Mar 2019

No

Yes

Netherlands: 9

Sweden: 1

France: 4

Switzerland: 9

23

14

0

0

0

0

0

0

17

6

0

From registration (Overall Trial) (overall period)

Non-randomised - controlled

Yes

Imfini

L01XC28

Durvalumab

Infusion

Intravenous use

There should be a maximum 8 weeks between receipt of the last dose of anti-cancer therapy and the first dose of study drugs. RFA must be performed within 8 to 14 days after start of immunotherapy. Combination durvalumab and tremelimumab will be administered for 4 cycles maximum of 4 weeks each (combined immunotherapy tremelimumab 75 mg and durvalumab 1500 mg for 4 cycles). Thereafter the treatment will continue as maintenance therapy with durvalumab alone (durvalumab 1500 mg every 4 weeks up to week 48). Subjects who have a dose interruption of less than 30 days due to toxicity in the first 12 months of treatment may resume treatment and complete the 12-month treatment period. Treatment (durvalumab) should be administered for a maximum of 12 months (maximum of 13 doses, last infusion on week 48). Subjects who have a dose interruption of less than 30 days due to toxicity in the first 12 months of treatment may resume treatment and complete the 12-month treatment period.

Imjudo

L01FX20

Tremelimumab

Infusion

Intravenous use

There should be a maximum 8 weeks between receipt of the last dose of anti-cancer therapy and the first dose of study drugs. RFA must be performed within 8 to 14 days after start of immunotherapy. Combination durvalumab and tremelimumab will be administered for 4 cycles maximum of 4 weeks each (combined immunotherapy tremelimumab 75 mg and durvalumab 1500 mg for 4 cycles). Thereafter the treatment will continue as maintenance therapy with durvalumab alone (durvalumab 1500 mg every 4 weeks up to week 48). Subjects who have a dose interruption of less than 30 days due to toxicity in the first 12 months of treatment may resume treatment and complete the 12-month treatment period. Treatment (durvalumab) should be administered for a maximum of 12 months (maximum of 13 doses, last infusion on week 48). Subjects who have a dose interruption of less than 30 days due to toxicity in the first 12 months of treatment may resume treatment and complete the 12-month treatment period.

Imfini

L01XC28

Durvalumab

Infusion

Intravenous use

There should be a maximum 8 weeks between receipt of the last dose of anti-cancer therapy and the first dose of study drugs. SBRT must start within 8 to 14 days after start of immunotherapy. SBRT to the PTV will be delivered in 3 fractions of 10 Gy over 1 week, preferably every other day, to a total of 30 Gy (BED10 60 Gy). Combination durvalumab and tremelimumab will be administered for 4 cycles maximum of 4 weeks each (combined immunotherapy tremelimumab 75 mg and durvalumab 1500 mg for 4 cycles). Thereafter the treatment will continue as maintenance therapy with durvalumab alone (durvalumab 1500 mg every 4 weeks up to week 48). Treatment (durvalumab) should be administered for a maximum of 12 months (maximum of 13 doses, last infusion on week 48). Subjects who have a dose interruption of less than 30 days due to toxicity in the first 12 months of treatment may resume treatment and complete the 12-month treatment period.

Imjudo

L01FX20

Tremelimumab

Infusion

Intravenous use

There should be a maximum 8 weeks between receipt of the last dose of anti-cancer therapy and the first dose of study drugs. SBRT must start within 8 to 14 days after start of immunotherapy. SBRT to the PTV will be delivered in 3 fractions of 10 Gy over 1 week, preferably every other day, to a total of 30 Gy (BED10 60 Gy). Combination durvalumab and tremelimumab will be administered for 4 cycles maximum of 4 weeks each (combined immunotherapy tremelimumab 75 mg and durvalumab 1500 mg for 4 cycles). Thereafter the treatment will continue as maintenance therapy with durvalumab alone (durvalumab 1500 mg every 4 weeks up to week 48). Treatment (durvalumab) should be administered for a maximum of 12 months (maximum of 13 doses, last infusion on week 48). Subjects who have a dose interruption of less than 30 days due to toxicity in the first 12 months of treatment may resume treatment and complete the 12-month treatment period.

RFA with durvalumab and tremelimumab

SBRT with durvalumab and tremelimumab

RFA with durvalumab and tremelimumab

SBRT with durvalumab and tremelimumab

Per protocol population

Per protocol population: All patients who are eligible, have at least started their immunotherapy treatment with tremelimumab and durvalumab, underwent local treatment with RFA or SBRT and have their imaging assessment at baseline and their first post-baseline assessment available.

The primary endpoint iBOR (iCR+iPR), documented by iRECIST, is analyzed in the per protocol population as follow: the primary endpoint is binomial, i.e., each patient either has a response or not. The number of responding patients will be counted and decision rule will be applied according to a two-stage Simon design as described in statistical analysis.

Primary

The response evaluation is based on the whole period from the start of study treatment until confirmed progression according to iRECIST (iCPD) or the start of further anticancer treatment or 1 year maximum after start of study treatment.

The reference probability p0 was chosen at 10% in the statistical design because a response rate of 10% in the experimental arm will be judged too low to justify this combined approach. On the contrary, a response rate of 25% will be judged very promising. The null hypothesis that the true response rate is 10% (H0: p0=10%) will be tested against the one-sided alternative that true response rate is 25% (H1: p1=25%), using a one-sided type I error of 5%.

RFA with durvalumab and tremelimumab v SBRT with durvalumab and tremelimumab

20

Pre-specified

Progression free survival (iPFS) according to iRECIST is computed from the date of registration to the date of first progression according to the iRECIST criteria or death, whatever comes first. Patients alive and free of progression prior to the analysis cut-off date are censored at the date of the most recent assessment. The date used for calculation of iPFS is the first date that progression criteria are met (i.e. the date of iUPD) providing that iCPD is confirmed at the next assessment. If iUPD occurs, but is disregarded because of later iSD, iPR or iCR, that iUPD date is not used as the progression event date. In case the progression was not confirmed by imaging but there was lack of clinical benefit/clinical progression/start of new antitumoral treatment, it was considered as an event for iPFS and the date iUPD is used as the date of the event.

Secondary

Tumor assessments should be performed every 8 weeks (± 1 week) until week 48 relative to the date the treatment started and then every 12 weeks (± 1 week) until confirmed progression according to iRECIST.

Progression Free Survival (PFS) according to RECIST is computed from the date of registration to the date of first progression according to the RECIST criteria (version 1.1) or death, whatever comes first. Patients alive and free of progression prior to the analysis cut-off date are censored at the date of the most recent assessment.The date used for calculation of progression free survival (PFS) according to RECIST is defined as the first day when the RECIST (version 1.1) criteria for PD are met.

Secondary

Tumor assessments had been performed every 8 weeks (± 1 week) until week 48 relative to the date the treatment started and then every 12 weeks (± 1 week) until confirmed progression according to iRECIST.

Overall survival is computed from the date of registration to the date of death. Patients still alive at the analysis cut-off date are censored at the last date known to be alive.

Secondary

After end of treatment, patients had been followed for survival every 2 months till month 12 after registration and then every 6 months till minimum month 30 after registration or death. The median follow-up duration is 17.1 months (95% CI:12.5-22.0).

Best overall response rate according to RECIST v1.1 is computed as the rate of CR+PR in the per protocol population.

Secondary

All patients have their BEST OVERALL RESPONSE (BOR) according to RECIST 1.1 from the start of study treatment until progression or the start of further anticancer therapy or maximum 1 year after the start of study treatment whatever comes first.

AEs were collected at baseline, during treatment and until 90 days post last dose of immunotherapy. All AEs had to be followed until resolution or stabilization. SAEs/AESIs related to study treatment had to be reported until month 30 minimum or death.

CRF for AEs contains pre-specified items + additional boxes for all "other" AEs. AEs are evaluated using CTC grading, SAEs using MedDra. Non-SAEs have not been collected specifically, all AEs will be reported in non-SAE section.

19

SBRT(stereotactic radiotherapy)

RFA(radiofrequency ablation)