Combination of Targeted and Immunotherapy for Advanced Biliary Tract and Esophagogastric Gastric Cancer

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Brief Title

Combination of Targeted and Immunotherapy for Advanced Biliary Tract and Esophagogastric Gastric Cancer

Official Title

DKN-01/Atezolizumab as Second Line Treatment of biliarY Tract Cancer and in combiNAtion or Not With Paclitaxel as Second Line treatMent of esophagogastrIC Cancer: a Multi-center Phase II Trial

Brief Summary

      In this study, non-operable esophagogastric adenocarcinoma cancer patients or non-operable
      biliary cancer patients whose cancer progressed/spread/got worse after first line treatment
      will be treated with or without immunotherapy and chemotherapy. This study will take place in
      several countries across Europe. One hundred twenty-three (123) patients will be invited to
      participate in this study

      Biliary tract cancer (BTC), is a form of cancer that start in your bile ducts, a series of
      tubes that runs from the liver to the small intestines. It is not know yet the exact cause of
      BTC. For patients who have advanced or metastatic BTC (where surgery is not possible),
      chemotherapy is the first option for treatment. Chemotherapy with cisplatin and gemcitabine
      (CisGem) is the current standard of care.

      Esophagogastric cancer (EGC) is cancer that occurs in the esophagus, a long hollow tube that
      runs from your throat to your stomach. The accumulating abnormal cells form a tumor in the
      esophagus that can grow to invade nearby structures and spread to other parts of the body.
      It's thought that chronic irritation of your esophagus may contribute to the changes that
      cause esophageal cancer.

      The purpose of this study is to look at the risks and benefits of combining DKN-01 and
      atezolizumab (humanized monoclonal antibody) with or without paclitaxel (chemotherapy).
      Immune therapy boosts the body's natural defenses to fight cancer. It uses specific products
      made either by participants' body or in a laboratory to improve, target or restore immune
      system function and control or stop cancer. Atezolizumab is such an "immunotherapy" drug.
      DKN-01 is another new type of drug (humanized monoclonal antibody) in development as
      anticancer agent. Paclitaxel is a commonly-used chemotherapy drug of the class of taxanes
      used to treat a number of cancer types, it stimulates the cell to die or to stop the cell
      from dividing into two new cells.The idea behind combining these drugs is linked to targeting
      the immune system to attack the tumor. Combining immune and chemotherapy has already
      demonstrated clinical activity in relapsed (return of the disease)/refractory (not responding
      to treatment) esophagogastric cancer patients.
    


Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Objective response rate

Secondary Outcome

 Best overall response distribution

Condition

Esophageal Cancer

Intervention

DKN-01

Study Arms / Comparison Groups

 BTC Cohort
Description:  Patient in BTC cohort will receive immune therapy and DKN-01 IV until PD

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

0

Start Date

December 2019

Completion Date

April 2022

Primary Completion Date

April 2021

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically proven diagnosis of metastatic or locally unresectable adenocarcinoma
             of the biliary tract or esophagogastric adenocarcinoma.

          -  Measurable disease by CT/MRI (RECIST 1.1) within 28 days of randomization/enrollment

          -  Male and female subjects of age ≥18 years

          -  Performance status ECOG 0-1

          -  Life expectancy ≥ 4 months

          -  Normal 12-lead ECG (patients with abnormal ECG will be eligible if changes are not
             considered clinically significant by the local investigator)

          -  Adequate hematological function

               -  Hemoglobin ≥ 9 g/dl (prior transfusions are allowed if they have been done ≥ 7
                  days before testing the Hb)

               -  White blood cell (WBC) ≥ 3.0 x 109/L

               -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

               -  Platelet count ≥ 75 x 109/L

          -  Adequate liver function: screening labs should be performed within 7 days prior to
             randomization/enrollment:

               -  Total bilirubin ≤ 1.5 x upper limit of normal (ULN), except subjects with Gilbert
                  Syndrome who must have a total bilirubin level of < 3.0 x ULN.

               -  ALT, AST & alkaline phosphatase ≤ 3 x ULN; ≤ 5 x ULN in case of liver/bone
                  metastases

               -  Serum albumin ≥ 2.5 g/dL

          -  Adequate renal function:

             o Estimated glomerular filtration rate (eGFR) according to MDRD should be > 50 ml/min

          -  Adequate coagulation:

             o International Normalized Ratio (INR) or Prothrombin Time (PT): ≤ 1.5 x ULN unless
             patient is receiving anticoagulant therapy as long as PT or Partial Thromboplastin
             Time (PTT) is within therapeutic range of intended use of anticoagulants

          -  The following local treatment modalities are allowed within the rules described
             (provided there has been a full recovery):

               -  Surgery: patients may have undergone a non-curative operation (i.e. R2 resection
                  [with macroscopic residual disease] or palliative bypass surgery only), performed
                  at least 28 days before randomization/enrollment. Patients who have previously
                  undergone curative surgery, must have evidence of non-resectable and measurable
                  disease relapse requiring systemic chemotherapy prior to study entry.

               -  Radiotherapy: patients may have received prior radiotherapy (with or without
                  radiosensitising low-dose chemotherapy) for localised disease. However, there
                  must be clear evidence of disease progression post-treatment prior to inclusion
                  in this study. The radiotherapy should have been finished at least 15 days prior
                  to randomization/enrollment.

               -  Photodynamic therapy (PDT) for localized disease only with no evidence of
                  metastatic disease - patients may have received prior PDT, provided the patient
                  has fully recovered and at least 28 days have elapsed since the PDT and there is
                  clear evidence of disease progression at the local site or disease or at a new
                  metastatic site.

               -  Other previous localised treatments targeting intrahepatic lesions such as
                  selective internal radiation therapy (SIRT), transarterial chemoembolisation
                  (TACE) and radiofrequency ablation are allowed, provided the patient has finished
                  it at leas 15 days prior to randomization/enrollment, with recovering.

          -  Asymptomatic subjects with known Central Nervous system (CNS) metastases are eligible,
             provided that all of the following criteria are met:

               -  Measurable disease, per RECIST v1.1, must be present outside the CNS.

               -  The patient has no history of intracranial hemorrhage or spinal cord hemorrhage.

               -  The patient has not undergone stereotactic radiotherapy within 7 days prior to
                  initiation of study treatment, whole-brain radiotherapy within 14 days prior to
                  initiation of study treatment, or neurosurgical resection within 28 days prior to
                  initiation of study treatment.

               -  The patient has no ongoing requirement for corticosteroids as therapy for CNS
                  disease. In addition, subjects must be either off corticosteroids, or on a stable
                  or decreasing dose of ≤ 10 mg daily prednisone (or equivalent) for at least 2
                  weeks prior to enrollment /randomization.

               -  Any brain metastases must be stable for at least 6 months.

          -  Availability of 1 FFPE block (preferred) or if not available, minimum 15-20 freshly
             cut (≤ 7 days) unstained slides of tumor tissue (either from current or previous
             resection/biopsy) for biobanking/translational research if less tumor tissue available
             please contact the HQ study team.

          -  Women of child bearing potential (WOCBP) must have a negative serum (or urine)
             pregnancy test within 72 hours prior to the first dose of study treatment.

          -  Patients of childbearing / reproductive potential should use adequate birth control
             measures and agree to refrain from donating eggs, according the standard national
             guidelines during the study treatment period and for at least 6 months after the last
             study treatment. 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. Such methods include:

               -  Combined (estrogen and progestogen containing) hormonal contraception associated
                  with inhibition of ovulation (oral, intravaginal, transdermal)

               -  Progestogen-only hormonal contraception associated with inhibition of ovulation
                  (oral, injectable, implantable)

               -  Intrauterine device (IUD)

               -  Intrauterine hormone-releasing system (IUS)

               -  Bilateral tubal occlusion

               -  Vasectomised partner

               -  Sexual abstinence. Note: abstinence is acceptable if this is established and
                  preferred contraception for the patient and is accepted as a local standard.

          -  Female subjects who are breast feeding should discontinue nursing prior to the first
             dose of study treatment and until 6 months after the last study treatment.

          -  Before patient enrollment, written informed consent must be given according to
             ICH/GCP, and national/local regulations.

        Specific to BTC:

          -  Patients should have progressed after first line systemic therapy.

          -  If clinically indicated, adequate biliary drainage should have been performed, patient
             should have fully recovered.

        Specific to advanced EGC:

        •Patients who have progressed after first line therapy. HER2 positive patient should have
        received and progressed on trastuzumab therapy. In HER2 positive patient, neo/adjuvant
        therapy based on a platinum and a fluoropyrimidine could be considered a first line of
        therapy if the patient progressed within the first 3 months of completing it.

        Note: patients who have undergone palliative treatment for obstruction or bleeding maybe
        eligible as long as they fulfill the above mentioned hematologic and biochemistry criteria.

          -  Weight must be stabilized in the last 4 weeks , as assessed by the investigator

          -  Taxanes, such as paclitaxel or docetaxel are only allowed in the curative setting
             (perioperative treatment) if received at least 12 months before
             enrollment/randomization.

        Exclusion Criteria:

          -  Subjects with pleural effusion, pericardial effusion, or ascites with symptoms
             uncontrolled by medication or who requirere current drainage procedures (once monthly
             or more frequently).

          -  Leptomeningeal spread of disease.

          -  Patient is currently participating and receiving study therapy or has participated in
             a study of an investigational agent and received study therapy or used an
             investigation device within 4 weeks prior to enrollment

          -  Other concomitant or prior malignancy within the last 5 years, with the exception of
             currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma
             in-situ of the cervix.

          -  History of inflammatory bowel disease or any autoimmune disease, including but not
             limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
             erythematosus, rheumatoid arthritis, vascular thrombosis associated with
             antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome,
             Guillain-Barré syndrome, multiple sclerosis, type I diabetes mellitus, vasculitis, or
             glomerulonephritis

          -  Patients with a history of autoimmune-related hypothyroidism on a stable dose of
             thyroid replacement hormone are eligible for this study.

          -  Patients with controlled Type I diabetes mellitus on a stable insulin regimen are
             eligible.

          -  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 less than 10% of body surface area.

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

               -  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.

          -  History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
             obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active
             pneumonitis on screening chest CT scan

          -  History of radiation pneumonitis/fibrosis in the radiation field is permitted.

          -  Infections:

               -  Signs or symptoms of infection or therapeutic use of antibiotics (except
                  prophylactic antibiotics) within 2 weeks prior to randomization and severe
                  infections within 4 weeks prior to randomization, including but not limited to
                  hospitalization for complications of infection, bacteremia, or severe pneumonia.

               -  Known or current evidence of HIV (test to be performed within 14 days of
                  randomization)

               -  Active or chronic hepatitis B or hepatitis C

                    -  Patients with past/resolved HBV infection (defined as having a negative
                       HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc]
                       antibody test) are eligible. HBV DNA must be obtained in patients with
                       positive hepatitis B core antibody prior to randomization.

                    -  Patients positive for HCV antibody are eligible only if PCR is negative for
                       HCV RNA.

               -  Active tuberculosis

               -  Conditions leading to immune suppression or stimulation of the immune system,
                  such as:

                    -  Prior treatment with checkpoint inhibitors

                    -  Patients who have received prior treatment with anti-CTLA-4 may be enrolled,
                       provided at least 5 half-lives (approximately 75 days) have elapsed since
                       the last dose of anti-CTLA-4 and there was no history of severe
                       immune-mediated adverse effects from anti-CTLA-4 (NCI CTCAE Grade 3 or 4)

                    -  Treatment with systemic immunostimulatory agents (including but not limited
                       to IFN-a, IL-2) for any reason within 6 weeks or five half-lives of the
                       drug, whichever is shorter, prior to enrollment.

                    -  Prior allogeneic stem cell or solid organ transplant.

          -  Subjects with a condition requiring systemic treatment with either corticosteroids (≥
             10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14
             days of randomization/enrollment

          -  Prior treatment with an anti-DKK1 therapy

          -  Administration of a live, attenuated vaccine within 30 days prior to the first dose of
             study medication or anticipation that such a live attenuated vaccine will be required
             during the study. Any live, attenuated vaccine (e.g. FluMist®) is prohibited while the
             patient is receiving atezolizumab and for a period of 5 months after discontinuation
             of atezolizumab. Inactivated influenza vaccines are allowed only during flu season.

          -  History of osteonecrosis of the hip or evidence of structural bone abnormalities in
             the proximal femur on magnetic resonance imaging (MRI) scan that is symptomatic and
             clinically significant. Degenerative changes of the hip joint are not excluded.

          -  All non hematological toxicities attributed to prior anti-cancer therapy other than
             hearing loss, alopecia and fatigue must have resolved to Grade 1 (NCI CTCAE version 5)
             or baseline before administration of study drug.

          -  History of hypersensitivity to the investigational medicinal product or to any drug
             with similar chemical structure or to any excipient present in the pharmaceutical form
             of the investigational medicinal products.

          -  History of severe allergic, anaphylactic, or other hypersensitivity reactions to
             chimeric or humanized antibodies or fusion protein; known hypersensitivity to Chinese
             hamster ovary cell products or to any component of the atezolizumab formulation

          -  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.

          -  Uncontrolled tumor-related pain.

          -  Uncontrolled or symptomatic hypercalcemia (ionized calcium 1.5 mmol/L, calcium 12
             mg/dL or corrected serum calcium ULN)

          -  Significant cardiovascular disease (such as New York Heart Association Class II or
             greater cardiac disease, myocardial infarction, or cerebrovascular accident), unstable
             arrhythmia, or unstable angina within 3 months prior to initiation of study treatment.

        Specific to BTC:

          -  Ampullary or gallbladder carcinoma

          -  Patients with liver failure Child-Pugh B or C

        Specific to EGC:

        • History of hypersensitivity reactions to paclitaxel or other drugs formulated in
        Cremophor EL (polyoxyethylated castor oil)
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Markus Moehler, , 



Administrative Informations


NCT ID

NCT03818997

Organization ID

EORTC 1741-GITCG


Responsible Party

Sponsor

Study Sponsor

European Organisation for Research and Treatment of Cancer - EORTC

Collaborators

 Hoffmann-La Roche

Study Sponsor

Markus Moehler, Study Chair, Universitaetsmedizin - Mainz University Medical Center, Mainz, Germany


Verification Date

February 2020