Neoplasms

Symptoms and General Pathology

All Conditions

Digestive System Diseases

Neoplasm Metastasis

Colorectal Neoplasms

Liver Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Neoplastic Processes

Liver Diseases

All Drugs and Chemicals

Antineoplastic Agents

Hematinics

Immunomodulating Agents

Durvalumab

Liver Extracts

Tremelimumab

Antineoplastic Agents, Immunological

Patients with unresectable colorectal liver metastases which show at least stable disease or partial remission after 4-6 months will receive treatment with durvalumab and tremelimumab plus local tumor ablation (Radiofrequency ablation RFA or Sterotactic body radiation therapy SBRT) of selected liver lesions, followed by maintenance treatment with durvalumab.

Durvalumab (MEDI4736) 1500mg Q4W in combination with tremelimumab for up to 4 doses/cycles, followed by durvalumab (MEDI4736) 1500mg Q4W for up to a maximum of 8 months with the last administration on week 48 unless there is unacceptable toxicity.

Durvalumab (MEDI4736)

Tremelimumab (75 mg IV Q4W) in combination with durvalumab (MEDI4736) (1500mg Q4W) for up to 4 doses/cycles

delivered in 3 fractions of 10 Gy over 1 week starting 8 to 14 days after first dose of immunotherapy

Sterotactic body radiation therapy (SBRT)

performed percutaneously under CT, MRI or sonographic guidance 8 to 14 days after start of immunotherapy

Radiofrequency ablation (RFA)

Theo Ruers

Jenny Seligmann

This is a single-arm, open-label, multi-center early phase II study. This proof of concept study will 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 remission after completion of 4-6 months first line systemic 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.

Secondary objectives are:

* To establish the feasibility and safety of the combined treatment modalities;
* To study the impact of the local technique (RFA/Radiotherapy) on the results;
* To investigate biomarkers to predict response to the combined treatment

Synergism of Immunomodulation and Tumor Ablation

Phase II of Immunotherapy Plus Local Tumor Ablation (RFA or Stereotactic Radiotherapy) in Patients With Colorectal Cancer Liver Metastases

The statistical design is based on the assumption that the continuation of first line systemic treatment would result in nearly no further response translating into a response rate of 0 to 5% at maximum in the enrolled patient's population. A response rate of 10% in the experimental arm (local treatment + immunotherapy) will be judged too low to justify this combined approach. On the contrary, a response rate of 25% will be judged very promising. An optimal Simon's two-stage design will be used for the rejection of a 10% or less iBOR rate

iBOR rate of liver lesions not treated with local therapy according to iRECIST (with response confirmation) will be displayed (point estimate) with their exact two-sided 95% confidence intervals.

BOR rate of lesions not treated by ablation/radiotherapy including or not the extrahepatic lesions according to RECIST v1.1 (with response confirmation) will be displayed (point estimate) with their exact two-sided 95% confidence intervals.

Response duration will be presented using the median, range (minimum, maximum) and inter-quartile range as well as the mean and standard deviation.

Stable disease duration will be presented using the median, range (minimum, maximum) and inter-quartile range as well as the mean and standard deviation.

Progression free survival according to iRECIST and RECIST v1.1 curve will be estimated using the Kaplan-Meier technique. Medians will be displayed with their two-sided 95% confidence intervals.

Overall survival curve will be estimated using the Kaplan-Meier technique. Medians will be displayed with their two-sided 95% confidence intervals.

Safety analyses will be performed on the Safety population. The worst toxicity grade per patient over the treatment period according to the CTCAE criteria version 4.0 will be displayed.

Spots Global Cancer Trial Database for sterotactic body radiation therapy (sbrt)