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Trial record 17 of 176 for:    immunotherapeutic agent | colon cancer

Synergism of Immunomodulation and Tumor Ablation (ILOC)

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ClinicalTrials.gov Identifier: NCT03101475
Recruitment Status : Recruiting
First Posted : April 5, 2017
Last Update Posted : June 17, 2019
Sponsor:
Information provided by (Responsible Party):
European Organisation for Research and Treatment of Cancer - EORTC

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

Condition or disease Intervention/treatment Phase
Colorectal Cancer Liver Metastases Drug: Durvalumab (MEDI4736) Drug: Tremelimumab Radiation: Sterotactic body radiation therapy (SBRT) Other: Radiofrequency ablation (RFA) Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II of Immunotherapy Plus Local Tumor Ablation (RFA or Stereotactic Radiotherapy) in Patients With Colorectal Cancer Liver Metastases
Actual Study Start Date : November 23, 2018
Estimated Primary Completion Date : August 31, 2021
Estimated Study Completion Date : January 31, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Durvalumab

Arm Intervention/treatment
Experimental: immunotherapy + local tumor ablation
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)
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.

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

Radiation: Sterotactic body radiation therapy (SBRT)
delivered in 3 fractions of 10 Gy over 1 week starting 8 to 14 days after first dose of immunotherapy

Other: Radiofrequency ablation (RFA)
performed percutaneously under CT, MRI or sonographic guidance 8 to 14 days after start of immunotherapy




Primary Outcome Measures :
  1. Best overall immune response rate (iBOR) of lesions not treated by ablation/radiotherapy including the extrahepatic lesions according to iRECIST (with response confirmation) [ Time Frame: 36 months from first patient in ]
    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


Secondary Outcome Measures :
  1. Best overall immune response rate of liver lesions not treated with local therapy according to iRECIST (with response confirmation) [ Time Frame: 36 months from first patient in ]
    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.

  2. 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) [ Time Frame: 36 months from first patient in ]
    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.

  3. Response duration [ Time Frame: 54 months from first patient in ]
    Response duration will be presented using the median, range (minimum, maximum) and inter-quartile range as well as the mean and standard deviation.

  4. Stable disease duration [ Time Frame: 54 months from first patient in ]
    Stable disease duration will be presented using the median, range (minimum, maximum) and inter-quartile range as well as the mean and standard deviation.

  5. Progression free survival according to iRECIST and to RECIST v1.1 [ Time Frame: 54 months from first patient in ]
    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.

  6. Overall survival [ Time Frame: 54 months from first patient in ]
    Overall survival curve will be estimated using the Kaplan-Meier technique. Medians will be displayed with their two-sided 95% confidence intervals.

  7. Safety: 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. [ Time Frame: 54 months from first patient in ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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.
  • Men and women ≥ 18 years of age at time of study entry
  • WHO performance status 0 to 1, at registration as well as before start of first line systemic treatment
  • Body weight >30kg
  • Available baseline imaging, before start of first line treatment, measurable disease according to RECIST 1.1
  • Stable disease or partial remission by RECIST criteria after 4-6 months of first line therapy for CRC (at least doublet of a fluoropyrimidine/irinotecan or fluoropyrimidine/oxaliplatin combination with or without a VEGF-inhibitor or an anti-EGFR agent).
  • Complete responders or partial responders with a 80% or more decrease in the sum of measures (longest diameter for tumour lesions and short axis measure for nodes) of target lesions following first line 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.
  • Liver metastases amenable to ablation or stereotactic radiotherapy (SBRT) at completion of 4-6 months of first line 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
  • After local tumour ablation/SBRT, at least two measurable liver metastases or at least 1 measurable liver metastasis and 1 measurable extrahepatic lesion should remain unaffected 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 accounted separately as one site. So, two abdominal lesions will be accounted as 1 extra-hepatic site, one lung and one abdominal lesion will be accounted two sites. Individual extrahepatic lesions should be ≤ 5 cm.
  • Availability of tumour sample for biomarkers testing (MSI, PDL-1, etc) (archival tissue from primary tumour )
  • Adequate normal organ and marrow function before initial first line systemic treatment as well as at baseline as defined below:
  • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (> 1500 per mm3)
  • Platelet count ≥ 100 x 109/L (>100,000 per mm3)
  • Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN). This will not apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician.
  • AST (SGOT)/ALT (SGPT) ≤ 5 x institutional upper limit of normal
  • Creatinine ≤ 1.5 ULN or measured or calculated creatinine clearance >40 mL/min by the Cockcroft-Gault formula
  • Haemoglobin ≥ 9.0 g/dL at baseline
  • Evidence of post-menopausal status or for female pre-menopausal patients negative urinary or serum pregnancy test. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
  • Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
  • Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
  • Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab + tremelimumab combination therapy. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.
  • Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab + tremelimumab combination therapy.
  • Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
  • Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations

Exclusion Criteria:

  • Patients with with known brain metastases or history of leptomeningeal carcinomatosis
  • History of radiation therapy of the liver, upper abdomen or lower thorax
  • History of radioembolization of the liver
  • Hilar liver lesions close to central bile ducts to be treated by RFA
  • Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.
  • Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
  • 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.
  • 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
  • Active or prior documented autoimmune or inflammatory disorders (including 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]). The following are exceptions to this criterion:
  • Patients with vitiligo or alopecia
  • Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement
  • Any chronic skin condition that does not require systemic therapy
  • Patients without active disease in the last 5 years may be included but only after consultation with the study physician
  • Patients with celiac disease controlled by diet alone
  • History of allogeneic organ transplant
  • History of hypersensitivity to durvalumab, tremelimumab or any excipient
  • Uncontrolled intercurrent illness including, but not limited to:
  • Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
  • Symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia
  • Active peptic ulcer disease or gastritis
  • Liver cirrhosis CHILD B+, C
  • Active bleeding diatheses
  • History of primary immunodeficiency
  • Psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
  • Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Frediricia's Correction
  • Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab + tremelimumab combination therapy.
  • Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03101475


Contacts
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Contact: Sofie Verschueren, PhD +32 2 774 1051 sofie.verschueren@eortc.org
Contact: Khadija Rhioui, MsSc +32 2 774 1647 Khadija.Rhioui@eortc.org

Locations
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Austria
Innsbruck Universitaetsklinik Recruiting
Innsbruck, Austria
Contact: Stefan Staettner         
Medical University Vienna - General Hospital AKH Not yet recruiting
Vienna, Austria
Contact: Patrick Starlinger         
France
Institut Bergonie Recruiting
Bordeaux, France
Contact: Serge Evrard         
Institut de Cancérologie de Lorraine Not yet recruiting
Vandoeuvre-Les-Nancy, France
Contact: Pierre Lehair         
Germany
Universitaetsklinikum Carl Gustav Carus Not yet recruiting
Dresden, Germany
Contact: Gunnar Folprecht         
Universitaetsklinikum Leipzig-Ambulanzen/Sprechstunden Not yet recruiting
Leipzig, Germany
Contact: Hacker Ulrich Thorsten         
Otto-Von-Guericke-Universitaet Magdeburg - Universitaetsklinik Not yet recruiting
Magdeburg, Germany
Contact: Marino Venerito         
Netherlands
The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis Recruiting
Amsterdam, Netherlands
Contact: Theo Ruers         
Radboud University Medical Center Nijmegen Recruiting
Nijmegen, Netherlands
Contact: Sandra Radema         
Sweden
Karolinska University Hospital - Karolinska Institutet - Danderyds Hospital Not yet recruiting
Stockholm, Sweden
Contact: Jacob Freedman         
Switzerland
Inselspital Not yet recruiting
Bern, Switzerland
Contact: Anja Lachenmayer         
Hôpitaux universitaires de Genève - HUG - site de Cluse-Roseraie Not yet recruiting
Geneva, Switzerland
Contact: Thibaud Koessler         
UniversitaetsSpital Zurich Not yet recruiting
Zürich, Switzerland
Contact: Matthias Guckenberger         
Sponsors and Collaborators
European Organisation for Research and Treatment of Cancer - EORTC
Investigators
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Study Chair: Theo Ruers The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis, The Netherlands

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Responsible Party: European Organisation for Research and Treatment of Cancer - EORTC
ClinicalTrials.gov Identifier: NCT03101475     History of Changes
Other Study ID Numbers: 1560-GITCG
2017-001375-22 ( EudraCT Number )
First Posted: April 5, 2017    Key Record Dates
Last Update Posted: June 17, 2019
Last Verified: April 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by European Organisation for Research and Treatment of Cancer - EORTC:
Colorectal Cancer
Liver Metastases
Durvalumab
Tremelimumab
Additional relevant MeSH terms:
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Colorectal Neoplasms
Neoplasm Metastasis
Liver Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Colonic Diseases
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Antineoplastic Agents
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Neoplastic Processes
Pathologic Processes
Liver Diseases
Durvalumab
Tremelimumab
Antibodies, Monoclonal
Immunologic Factors