Clinical Trials /

Treatment of Colorectal Liver Metastases With Immunotherapy and Bevacizumab

NCT03698461

Description:

Liver is the most common site of metastases from colorectal cancer. Neoadjuvant chemotherapy with targeted agents is usually recommended for borderline-resectable liver metastases that are technically difficult to resect for conversion to resectable disease and control of metastatic spread. However, the prognosis of these patients are still poor, and long term disease-free survival over 3 years is rare and <20%. More effective measures to prevent recurrence are needed before or after resection of colorectal liver metastases.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Treatment of Colorectal Liver Metastases With Immunotherapy and Bevacizumab
  • Official Title: Comparative Analysis of Immune Profile Following Neoadjuvant Chemotherapy in Colorectal Liver Metastases (CRLM): A Prospective Pilot Clinical Trial

Clinical Trial IDs

  • ORG STUDY ID: ASA-1
  • NCT ID: NCT03698461

Conditions

  • Colorectal Neoplasms
  • Neoplasm Metastasis
  • Colonic Neoplasms
  • Rectal Neoplasms

Interventions

DrugSynonymsArms
AtezolizumabTecentriqAtezolizumab, Bevacizumab, FOLFOX
BevacizumabAvastinAtezolizumab, Bevacizumab, FOLFOX
OxaliplatinAtezolizumab, Bevacizumab, FOLFOX
LevoleucovorinAtezolizumab, Bevacizumab, FOLFOX
5-FU5-fluorouracilAtezolizumab, Bevacizumab, FOLFOX

Purpose

Liver is the most common site of metastases from colorectal cancer. Neoadjuvant chemotherapy with targeted agents is usually recommended for borderline-resectable liver metastases that are technically difficult to resect for conversion to resectable disease and control of metastatic spread. However, the prognosis of these patients are still poor, and long term disease-free survival over 3 years is rare and <20%. More effective measures to prevent recurrence are needed before or after resection of colorectal liver metastases.

Detailed Description

      -  Atezolizumab is a humanized immunoglobulin G1 monoclonal antibody that targets
           Programmed Death-Ligand 1(PD-L1) and inhibits the interaction between PD-L1 and its
           receptors, Programmed cell Death protein 1(PD-1) and B7.1. Therapeutic blockade of PD-L1
           binding by atezolizumab has been shown to enhance the magnitude and quality of tumor
           specific T cell responses, resulting in improved anti tumor activity.

        -  Bevacizumab is a recombinant, humanized therapeutic antibody directed against vascular
           endothelial growth factor(VEGF). In addition to its well-characterized role in
           angiogenesis, VEGF is also believed to be involved in cancer immune evasion via the
           induction of myeloid- derived suppressor cells(MDSCs). These VEGF-induced MDSCs can
           suppress both T-cell and dendritic-cell function. Bevacizumab can restore and/or
           maintain the antigen presentation capacity of dendritic cells, leading to enhanced
           T-cell infiltration in tumors. When used in combination, VEGF targeting agents such as
           bevacizumab promote the normalization of tumor vasculature and may thereby increase
           access of therapeutic agents.

        -  Atezolizumab with bevacizumab, levoleucovorin, oxaliplatin, and 5-fluorouracil(FOLFOX).
           A translational study for renal cell carcinoma showed bevacizumab resulted in modulation
           of tumor immune microenvironment with Th1-related signatures, which was more potentiated
           by subsequent treatment with atezolizumab. This suggests potentiation of anti-tumor
           immunity with the combination of bevacizumab and atezolizumab.
    

Trial Arms

NameTypeDescriptionInterventions
Atezolizumab, Bevacizumab, FOLFOXExperimentalAtezolizumab 1200mg IV Once, Atezolizumab (840mg IV D1 of C1-12) + Bevacizumab (5mg/kg IV D1 of C1-12) + FOLFOX(Oxaliplatin 85mg/m2 IV D1 of C1-12, Levoleucovorin 200mg/m2 IV D1 of C1-12, 5-FU - bolus 400mg/m2 IV D1 of C1-12, - infusional 2400mg/m2 IV continuous(46 hours) D1-3 of C1-12)
  • Atezolizumab
  • Bevacizumab
  • Oxaliplatin
  • Levoleucovorin
  • 5-FU

Eligibility Criteria

        <Inclusion Criteria>

        Patient-related consideration

          1. Have provided written informed consent prior to any study specific procedures

          2. Willing and able to comply with the protocol

          3. ≧ 20 years of age at the time of signing Informed Consent Form

          4. Eastern Cooperative Oncology Group (ECOG) status of ≤1

        Disease-related consideration

          1. Histologically diagnosed colorectal adenocarcinoma

          2. Liver metastases from colorectal adenocarcinoma confirmed through biopsy

          3. Liver metastatic lesions should be considered to be potentially resectable after
             conversion chemotherapy by multi-disciplinary team and should meet one of the
             following criteria:

               -  Number of metastatic deposit ≧ 4

               -  Possibility of resection margin could be involved

               -  Involvement of major hepatic vessels

               -  Presence of extrahepatic metastases (if they are supposed to be treated with
                  curative aim and not to alter a plan for hepatic metastasectomy)

               -  High likelihood of insufficient residual hepatic volume after surgery

          4. Measurable by RECIST criteria 1.1.

          5. One or more hepatic lesions should be accessible for biopsy

          6. Archival tumor tissue from the metastatic liver lesion obtained at the time of the
             initial diagnosis must be available.

          7. Adequate major organ functions as following:

               -  Hematopoietic function: Absolute neutrophil count(ANC) ≧ 1,500/mm3, Platelet ≧
                  100,000/mm3

               -  Hepatic function: serum bilirubin ≦ 2 x Upper limit of normal(ULN), Aspartate
                  aminotransferase(AST)/Alanine aminotransferase(ALT) ≦ levels 5 x ULN

               -  Renal function: serum creatinine ≦ 1.5 x ULN

          8. International normalised ratio(INR) < 1.5 or Activated partial thromboplastin(aPTT) <
             1.5 x ULN within 7 days prior to the start of study treatment for patients not
             receiving anti-coagulation. For patients receiving anticoagulants, INR and aPTT must
             be within the medical standard of enrolling institution.

        Other considerations

          1. For women of childbearing potential: agreement to remain abstinent (refrain from
             heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per
             year during the treatment period and for 6 months after the last dose of study
             treatment after the last dose of study treatment

             i. A woman is considered to be of childbearing potential if she is postmenarcheal, has
             not reached a postmenopausal state (≧12 continuous months of amenorrhea with no
             identified cause other than menopause), and has not undergone surgical sterilization
             (removal of ovaries and/or uterus).

             ii. Examples of contraceptive methods with a failure rate of < 1% per year include
             bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit
             ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.

          2. For men, they must practice abstinence or condom use, and abstain from sperm donation
             during the treatment period and for 6 months after their last dose of study treatment
             during the treatment period and for 6months after the last dose of study treatment.

        <Exclusion Criteria>

        Patients who meet any of the following criteria will be excluded from study entry:

          1. Extrahepatic metastases that are not candidates for treatment of curative aim (e.g.
             resection, radiation or radiofrequency ablation)

          2. Presence of central nervous system (CNS) metastases

          3. Concurrent or previous history of another primary cancer within 3 years prior to study
             treatment except for curatively treated cervical cancer in situ, non-melanomatous skin
             cancer, superficial bladder cancer (pTis or pT1) and curatively treated thyroid cancer
             of any stage. Concurrent, histologically confirmed, unresected thyroid cancer without
             distant metastasis could be allowed with the agreement of the principal investigator.

          4. Chronic alcoholic hepatitis or cirrhosis

          5. Chronic hepatitis B, defined as HBV DNA (> 2,000 IU / mL) and ALT> upper limit of
             normal range, must be treated with antiviral drugs before enrollment to reach
             appropriate viral suppression (HBV DNA <2000 IU / mL), and the antiviral drugs must be
             maintained during the study treatment period and for 6 months after the last dose of
             study treatment.

          6. Prior chemotherapy for metastatic disease

          7. Uncontrolled medical illness congestive heart failure, myocardial infarction within 6
             months including medically uncontrolled infection, uncontrolled hypertension, unstable
             angina, symptomatic congestive heart failure, myocardial infarction within 6 months

          8. Prior adjuvant FOLFOX chemotherapy

          9. Prior adjuvant chemotherapy, if administered within 6 months before study entry

         10. Current or recent (within 10 days of start of study treatment) use of aspirin
             (>325mg/day), clopidogrel (>75mg/day), therapeutic or parenteral anticoagulants or
             thrombolytic agents for therapeutic purposes (therapeutic anticoagulation on a stable
             dose for at least 2 weeks prior to the start of study treatment is allowed)

         11. Known alcohol or drug abuse

         12. Active infection requiring intravenous antibiotics at the start of study treatment

         13. Inadequately controlled hypertension (defined as systolic blood pressure >150mmHg
             and/or diastolic blood pressure >100mmHg)

         14. Prior history of hypertensive crisis or hypertensive encephalopathy

         15. History or evidence upon physical or neurological examination of CNS disease (e.g.
             seizures) unrelated to cancer unless adequately treated with standard medical therapy

         16. Uncontrolled chronic peripheral neuropathy ≥ CTCAE grade 2

         17. Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent
             arterial thrombosis) within 6 months of start of study treatment

         18. Any previous venous thromboembolism > CTCAE Grade 3 within 12 months prior to start of
             study treatment

         19. History of haemoptysis ≥ Grade 2 (defined as ≥ 2.5 mL bright red blood per episode)
             within 1 month of start of study treatment

         20. History or evidence of inherited bleeding diathesis or significant coagulopathy at
             risk of bleeding (i.e. in the absence of therapeutic anticoagulation)

         21. Surgical procedure (including open biopsy, surgical resection, wound revision, or any
             other major surgery involving entry into a body cavity) or significant traumatic
             injury within 28 days prior to start of study treatment, or anticipation of need for
             major surgical procedure (other than hepatic metastasectomy) during the course of the
             study

         22. History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or
             active GI bleeding within 6 months prior to start of study treatment

         23. Serious, non-healing wound, active ulcer, or untreated bone fracture

         24. Known hypersensitivity to any component of any of the study medication

         25. History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanised antibodies or fusion proteins

         26. Known dihydropyrimidine dehydrogenase deficiency

         27. Pregnant or breastfeeding, or intending to become pregnant during the study or within
             6 months after the last dose of study treatment

         28. Women of childbearing potential must have a negative serum or urine pregnancy test
             result within 14 days prior to initiation of study treatment.

         29. Known hypersensitivity or allergy to Chinese hamster ovary cell products

         30. Active or history of autoimmune disease or immune deficiency, including, but not
             limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
             erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
             antibody syndrome, Wegener granulomatosis, Sjögren's syndrome, Guillain-Barré
             syndrome, or multiple sclerosis, with the following exceptions:

               -  Patients with a history of autoimmune-related hypothyroidism who are on thyroid
                  replacement hormone are eligible for the study.

               -  Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen
                  are eligible for the study.

               -  Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
                  dermatologic manifestations only (e.g., patients with psoriatic arthritis are
                  excluded) are eligible for the study provided all of following conditions are
                  met:

                    -  Rash must cover 10% of body surface area

                    -  Disease is well controlled at baseline and requires only low-potency topical
                       corticosteroids

                    -  No occurrence of acute exacerbations of the underlying condition requiring
                       psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic
                       agents, oral calcineurin inhibitors, or high potency or oral corticosteroids
                       within the previous 12 months

         31. Prior allogeneic bone marrow transplantation or prior solid organ transplantation

         32. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
             obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
             active pneumonitis on screening chest computed tomography (CT) scan (History of
             radiation pneumonitis in the radiation field (fibrosis) is permitted.)

         33. Positive test for human immunodeficiency virus (HIV)

         34. Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody
             test followed by a positive HCV RNA test at screening

               -  The HCV RNA test will be performed only for patients who have a positive HCV
                  antibody test.

               -  Patients positive for HCV antibody are eligible only if polymerase chain reaction
                  (PCR) is negative for HCV RNA.

         35. Active tuberculosis

         36. Administration of a live, attenuated vaccine within 4 weeks prior to start of study
             maintenance treatment or anticipation that such a live attenuated vaccine will be
             required during the study

         37. Prior treatment with Cluster of differentiation(CD)137 agonists, anti-cytotoxic
             T-lymphocyte-associated antigen(CTLA)4, anti-PD-1, or anti-PD-L1 therapeutic antibody
             or pathway-targeting agents

         38. Treatment with systemic immunostimulatory agents (including but not limited to
             interferons or interleukin-2) within 4 weeks or five half-lives of the drug, whichever
             is longer, prior to start of study maintenance treatment

         39. Treatment with systemic corticosteroids or other systemic immunosuppressive
             medications (including but not limited to prednisone, dexamethasone, cyclophosphamide,
             azathioprine, methotrexate, thalidomide, and anti-Tumour Necrosis Factor agents)
             within 2 weeks prior to start of study maintenance treatment, or requirement for
             systemic immunosuppressive medications during the trial.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:20 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Serial changes in Cluster of Differentiation(CD) 8+ T cell densities
Time Frame:Baseline, Day15 of first atezolizumab administration, and after at least 6 cycles (each cycle is 14days)
Safety Issue:
Description:Opal(TM) platform Immunohistochemistry(IHC)

Secondary Outcome Measures

Measure:Serial changes of Immune cell biomarkers CD3, CD4, Programmed death-Ligand 1(PD-L1),PD-1, granzyme B, CD45RO, Forkhead Box P3(FOXP3), CD68
Time Frame:Baseline, Day15 of atezolizumab, and after at least 6 cycles (each cycle is 14days)
Safety Issue:
Description:Opal(TM) platform IHC
Measure:Serial changes of Immune cell CD3+, CD8+ densities
Time Frame:Baseline, Day15 of atezolizumab, and after at least 6 cycles (each cycle is 14days)
Safety Issue:
Description:IMMUNOSCORE® (IMMUNOSCORE is a registered trademark owned by INSERM)
Measure:Serial changes of Density of Vascular marker CD31, CD34
Time Frame:Baseline, Day15 of atezolizumab, and after at least 6 cycles (each cycle is 14days)
Safety Issue:
Description:Opal(TM) platform IHC
Measure:Serial changes of Gene expression profile
Time Frame:Baseline, Day15 of atezolizumab, and after at least 6 cycles (each cycle is 14days)
Safety Issue:
Description:RNA-seq
Measure:Response Rate
Time Frame:Baseline, at 6th week from the first treatment, and then every 6±2 weeks up to 12 cycles (each cycle is 14days), every 3 months after the 12 cycles up to 24months
Safety Issue:
Description:RECIST 1.1 and immune RECIST(iRECIST)
Measure:Progression-Free Survival
Time Frame:Baseline, at 6th week from the first treatment, and then every 6±2 weeks up to 12 cycles (each cycle is 14days), every 3 months after the 12 cycles up to 24months
Safety Issue:
Description:RECIST 1.1 and iRECIST
Measure:R0 resection rate
Time Frame:At the time of hepatic resection
Safety Issue:
Description:All gross lesions are resected and all surgical margins are free from tumor cells (The proportion of patients who undergo R0 resection for liver metastases out of all patients who started at least one dose of study treatment.)
Measure:Incidence, nature and severity of adverse events with severity (Safety profile)
Time Frame:Consent to 90 days after the last dose of investigational medicinal product or until initiation of new systemic anti-cancer therapy, whichever occurs first.
Safety Issue:
Description:Common Terminology Criteria for Adverse Events (CTCAE) v4.0
Measure:Microbiome profile
Time Frame:Day1 before first atezolizumab administration, Day15 before the treatment and at time of hepatic metastasectomy or liver biopsy after 6 cycles of treatment (each cycle is 14days)
Safety Issue:
Description:In stool samples through whole metagenomic sequencing

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Asan Medical Center

Last Updated

May 15, 2019