Synergism of Immunomodulation and Tumor Ablation

NCT03101475 | Completed Phase 2 DMC

• 2 other identifiers: 1560-GITCG2017-001375-22
• Study Type: interventional
• Target: 22
• Locations: 6 countries
• Sites: 10

Brief Summary

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

Conditions

Colorectal Cancer; Liver Metastases

Keywords

Colorectal Cancer; Liver Metastases; Durvalumab; Tremelimumab

Outcome Measures

Primary Outcomes (1)

• Best overall immune response rate (iBOR) of lesions not treated by ablation/radiotherapy including the extrahepatic lesions according to iRECIST (with response confirmation)

  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

  36 months from first patient in

Secondary Outcomes (7)

• Best overall immune response rate of liver lesions not treated with local therapy according to iRECIST (with response confirmation)

  36 months from first patient in

• Best overall response rate of lesions not treated by ablation/radiotherapy including or not the extrahepatic lesions according to RECIST v1.1 (with response confirmation)

  36 months from first patient in

• Response duration

  54 months from first patient in

• Stable disease duration

  54 months from first patient in

• Progression free survival according to iRECIST and to RECIST v1.1

  54 months from first patient in

Study Arms (1)

immunotherapy + local tumor ablation

EXPERIMENTAL

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.

Drug: Durvalumab (MEDI4736); Drug: Tremelimumab; Radiation: Sterotactic body radiation therapy (SBRT); Other: Radiofrequency ablation (RFA)

Interventions

Durvalumab (MEDI4736) DRUG

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.

immunotherapy + local tumor ablation

Tremelimumab DRUG

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

immunotherapy + local tumor ablation

Sterotactic body radiation therapy (SBRT) RADIATION

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

immunotherapy + local tumor ablation

Radiofrequency ablation (RFA) OTHER

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

immunotherapy + local tumor ablation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed CRC
• Patients with CRC liver metastases, with or without extrahepatic disease, in which curative treatment is not possible by resection and or local ablation/radiotherapy.
• ≥ 18 years of age at time of study entry
• WHO performance status 0 to 1
• Body weight \> 30kg
• Measurable disease according to RECIST 1.1
• Stable disease or partial remission by RECIST 1.1 criteria after at least 3 months systemic therapy for CRC. Patients following first- or second-line treatment are eligible. Note: if patient receives maintenance treatment after the first line treatment, she/he remains eligible for this study
• Complete responders or partial responders with a 80% or more decrease in the sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions following systemic therapy, taking as reference the sum of diameters from baseline scan prior to initiation of first line therapy are excluded as well as patients with almost complete cystic degeneration of liver metastases. Note: The interval between last dose of systemic treatment and first dose of study drugs must be maximum 8 weeks (in case bevacizumab was administered as part of the systemic treatment, a minimum 21 days wash out period is required from last administration to planned local ablative treatment initiation).
• Liver metastases amenable to ablation or stereotactic radiotherapy (SBRT) at completion of systemic therapy:
• For SBRT: allowing a total ablated volume of at least 25 cm3 and a maximum of 40 cm3 with a maximum of two lesions treated with SBRT
• For RFA: allowing a total ablated volume of at least 25 cm3 and a maximum advised volume of 120 cm3
• At least two measurable liver metastases, or at least 1 measurable liver metastasis and 1 measurable extrahepatic lesion should remain untreated by ablation or SBRT to allow response monitoring according to RECIST 1.1 and iRECIST.
• Limited extra hepatic disease is allowed, including up to 2 extra hepatic metastatic sites, either lung, abdominal, pelvis, bone, or localized lymph node metastases. Each will be counted separately as one site. So, two abdominal lesions will be counted as 1 extra-hepatic site; one lung and one abdominal lesion will be counted as two sites. Individual extrahepatic lesions should be ≤ 5 cm.
• Availability of tumor sample for biomarkers testing (MSI, PDL-1, etc) (archival tissue from primary tumor or biopsy)
• Adequate normal organ and marrow function before initial systemic treatment as well as at baseline as defined below:

You may not qualify if:

• Patients with known brain metastases or history of leptomeningeal carcinomatosis
• Hilar liver lesions close to central bile ducts to be treated by RFA
• Prior treatment:
• History of radiation therapy of the liver, upper abdomen or lower thorax
• History of radioembolization of the liver
• Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of durvalumab and tremelimumab.
• Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab, a CTLA-4 including tremelimumab or other checkpoint inhibitors or other immune therapy during the last 12 months
• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab and tremelimumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid, or steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)
• Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab
• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory pulmonary disorders, interstitial lung disease, inflammatory bowel disease \[eg, colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc\]).
• History of allogeneic organ transplant
• History of hypersensitivity to durvalumab, tremelimumab or any excipient
• Uncontrolled intercurrent illness including, but not limited to:

Sponsors & Collaborators

• European Organisation for Research and Treatment of Cancer - EORTC: lead

Study Sites (10)

Medical University Vienna - General Hospital AKH

Vienna, Austria

Location

Institut Bergonie

Bordeaux, France

Location

Universitaetsklinikum Carl Gustav Carus

Dresden, Germany

Location

Universitaetsklinikum Leipzig-Ambulanzen/Sprechstunden

Leipzig, Germany

Location

The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis

Amsterdam, Netherlands

Location

Radboud University Medical Center Nijmegen

Nijmegen, Netherlands

Location

Karolinska University Hospital - Karolinska Institutet - Danderyds Hospital

Stockholm, Sweden

Location

Inselspital

Bern, Switzerland

Location

Hôpitaux universitaires de Genève - HUG - site de Cluse-Roseraie

Geneva, Switzerland

Location

UniversitaetsSpital Zurich

Zurich, Switzerland

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

durvalumab; tremelimumab; Radiofrequency Ablation

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Radiofrequency Therapy; Therapeutics; Ablation Techniques; Surgical Procedures, Operative

Study Officials

• Theo Ruers

  The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis, The Netherlands

  STUDY CHAIR

• Jenny Seligmann

  Leeds Teaching Hospitals NHS Trust - St. James's University Hospital

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 30, 2017
• First Posted: April 5, 2017
• Study Start: November 23, 2018
• Primary Completion: March 3, 2021
• Study Completion: February 23, 2022
• Last Updated: May 31, 2022

Record last verified: 2022-05

Locations

DE (2); SE (1); FR (1); NL (2); AU (1); CH (3)