Clinical Trials /

AZD8186 and Paclitaxel in Advanced Gastric Cancer

NCT04001569

Description:

AZD8186 is an orally-dosed, selective Phosphatidylinositol 3-kinase (PI3K) β/δ inhibitor that binds to PI3Kβ and PI3Kδ, and inhibits kinase activity and downstream pathways in vitro and in vivo. AZD8186 has shown significant anti-tumor activity in PTEN-deficient preclinical models, including prostate, triple negative breast cancer, squamous lung and germinal center diffuse large B-cell lymphoma models. PTEN deficiency is reported in approximately 20% of patients with gastric cancer and in 35-48% of those with human epidermal growth factor receptor 2(HER2)-positive gastric cancer. To date, there have been no clinical trials with AZD8186 alone or in combination with paclitaxel in advanced gastric cancer. Therefore, it is very important to conduct clinical trials of combination therapy of AZD8186 and paclitaxel in patients with metastatic/recurrent gastric cancer who have failed previous therapy, and to identify the clinical factors and biomarkers that predict effects of the combination therapy. The purpose of the study is to define the maximal tolerated dose (MTD) and recommended phase 2 dose (RP2D) of paclitaxel and AZD8186 combination therapy in patients with advanced tumors and to evaluate the efficacy of paclitaxel and AZD8186 combination therapy as a second-line therapy in patients with advanced gastric cancer with PTEN aberrations. This study is divided into Phase 1b and Phase 2.

Related Conditions:
  • Gastric Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: AZD8186 and Paclitaxel in Advanced Gastric Cancer
  • Official Title: Phase1b/2 Study of AZD8186 in Combination With Paclitaxel in Patients With Advanced Gastric Cancer

Clinical Trial IDs

  • ORG STUDY ID: KCSG-ST18-20
  • NCT ID: NCT04001569

Conditions

  • Solid Tumor
  • Stomach Cancer

Interventions

DrugSynonymsArms
AZD8186 in combination with paclitaxelAZD8186 in combination with paclitaxel

Purpose

AZD8186 is an orally-dosed, selective Phosphatidylinositol 3-kinase (PI3K) β/δ inhibitor that binds to PI3Kβ and PI3Kδ, and inhibits kinase activity and downstream pathways in vitro and in vivo. AZD8186 has shown significant anti-tumor activity in PTEN-deficient preclinical models, including prostate, triple negative breast cancer, squamous lung and germinal center diffuse large B-cell lymphoma models. PTEN deficiency is reported in approximately 20% of patients with gastric cancer and in 35-48% of those with human epidermal growth factor receptor 2(HER2)-positive gastric cancer. To date, there have been no clinical trials with AZD8186 alone or in combination with paclitaxel in advanced gastric cancer. Therefore, it is very important to conduct clinical trials of combination therapy of AZD8186 and paclitaxel in patients with metastatic/recurrent gastric cancer who have failed previous therapy, and to identify the clinical factors and biomarkers that predict effects of the combination therapy. The purpose of the study is to define the maximal tolerated dose (MTD) and recommended phase 2 dose (RP2D) of paclitaxel and AZD8186 combination therapy in patients with advanced tumors and to evaluate the efficacy of paclitaxel and AZD8186 combination therapy as a second-line therapy in patients with advanced gastric cancer with PTEN aberrations. This study is divided into Phase 1b and Phase 2.

Trial Arms

NameTypeDescriptionInterventions
AZD8186 in combination with paclitaxelExperimental
  • AZD8186 in combination with paclitaxel

Eligibility Criteria

        Inclusion Criteria:

          1. Have the willingness to sign a written informed consent document prior to any study
             specific procedures

          2. Age ≥ 19 years of male and female

          3. At each phase of the trial, subjects who meet the following requirements in the
             appropriate phase will be enrolled.

             A. Phase 1b: Subjects with a histologically confirmed metastatic solid tumor that have
             progressed after treatment with approved therapies or for which there is no standard
             effective therapy available.

             B. Phase 2b: Subjects with histologically confirmed locally advanced or metastatic
             gastric cancer that have progressed after treatment with first-line
             fluoropyrimidine-based chemotherapy, with PTEN loss by immunohistochemistry (IHC),
             PTEN gene abnormality (PTEN gene deletion or loss of function mutation) or
             Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Beta(PIK3CB) gene
             abnormality (amplification or gain of function mutation) identified by next generation
             sequencing (NGS). If the subject received adjuvant chemotherapy after curative gastric
             resection and lymph node dissection, adjuvant chemotherapy is considered to be the
             first-line palliative chemotherapy if the disease recurred during adjuvant
             chemotherapy or within 6 months after the completion of adjuvant chemotherapy.

          4. Patients must have measurable disease based on RECIST 1.1 (Phase 2 part only).
             Measurable disease will not be required for enrollment in the phase1b part. Patients
             with evaluable lesion only (without measurable lesion) can be enrolled in the phase 1b
             part.

          5. Eastern Cooperative Oncology Group(ECOG) performance status 0-1

          6. Patients must have adequate organ and marrow function as defined below:

             A. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, B. Hemoglobin ≥ 9.0 g/dL, C.
             Platelet ≥ 100 x 109/L, D. Aspartate transaminase(AST) and/or alanine
             transaminase(ALT) ≤ 3 × upper limit of normal (ULN) [Regardless of the presence of
             liver metastases, only subjects who have AST/ALT ≤ 3 × ULN can be enrolled in phase 1b
             part; In phase 2 part, subjects with AST and/or ALT ≤ 5 X ULN can be enrolled if they
             have liver metastases] E. Total bilirubin: ≤ 1 × ULN; Subjects with a bile duct
             obstruction will be eligible if they meet the criteria after appropriate bile
             drainage; Patients with Gilbert syndrome should also be registered after confirming
             that the total bilirubin level is within the normal range through a follow-up
             screening test F. Serum creatinine clearance >50 milliliter/min

          7. Adequate cardiac function with corrected QT interval(QTc) < 470 msec

          8. Patients must be able to swallow and retain oral medications

          9. Serum β-human chorionic gonadotropin (HCG) test negative within 14 days before the
             first administration (women of childbearing potential only).

         10. Requirements for contraception must be followed.

        Exclusion Criteria:

          1. Active central nervous system (CNS) lesions (ie, those with radiologically unstable or
             symptomatic brain lesions). For those who receive radiation or surgical treatment, the
             subject can be enrolled if the subject is maintained without evidence of CNS disease
             progression for more than 4 weeks. However, patients with a leptomeningeal metastases
             are excluded.

          2. Treatment with any of the following:

               -  Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment

               -  Any cytotoxic chemotherapy from a previous treatment regimen within 14 days. If
                  the subject received an investigational drug from another clinical trial, the
                  subject can be enrolled after 2 weeks of last administration and more than 5 x
                  half-life of the investigational drug. If monoclonal antibody therapy was given,
                  the subject can be enrolled after four weeks after the last dose.

               -  Strong or moderate inducers or inhibitors of CYP3A4 within 2 weeks before the
                  first dose of study treatment

               -  Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a
                  limited field of radiation for palliation within 2 weeks of the first dose of
                  study treatment.

               -  Any previous exposure to a Phosphatidylinositol 3-kinase (PI3K) inhibitor
                  (including selective or pan PI3K inhibitors), Akt, mammilian target of rapamycin
                  (mTOR) inhibitors.

          3. History of allogeneic bone marrow transplantation or organ transplantation

          4. History of another primary cancer (excluding gastric cancer):

             Exceptions are:

               -  Adequately treated non-melanoma skin cancer (basal cell or squamous cell
                  carcinoma), curatively treated in situ cancer of the cervix, completely resected
                  thyroid cancer without distant metastasis in which all treatment has been
                  completed (Appropriate wound healing is required prior to clinical trial
                  enrollment)

               -  Other curatively treated solid tumors except for gastric cancer with no evidence
                  of disease recurrence at least 36 months before participating in this trial

          5. Clinically significant cardiovascular disease including but not limited to:

               -  Acute coronary syndrome within the 6 months prior to the initiation of study drug
                  (including myocardial infarction or unstable angina, Coronary Artery Bypass Graft
                  surgery, percutaneous coronary intervention and stenting)

               -  Current heart failure or past history of heart failure

               -  Current or past history of clinically significant cardiac arrhythmia (eg,
                  complete left bundle branch block, third degree heart block)

               -  Any risk factors that prolong QTc or increase the probability of arrhythmia,
                  including medication (eg: heart failure, hypokalemia, congenital long QT
                  syndrome, history of Torsades de Pointes)

          6. Persistent uncontrolled hypertension as defined by: systolic >180 mmHg or diastolic
             >100 mmHg despite medical treatment

          7. Seropositivity of HIV, or known active hepatitis B and/or active hepatitis C
             infection. Hepatitis B carriers may be enrolled if prophylactic use of an antiviral
             agent with minimal interaction with CYP3A4 is administered to inhibit hepatitis B
             virus (HBV) activation (eg. Entecavir, adefovir)

          8. Impairment of gastrointestinal function or gastrointestinal disorders (eg. untreated
             ulcerative disorders; uncontrolled nausea, vomiting, or diarrhea; absorption disorder
             syndrome; small bowel resection; ileostomy). Patients with ileostomy will not allowed
             to be enrolled, but patients with colostomy can be enrolled to this study.

          9. As judged by the Investigator, all other symptoms and associated disease for which the
             investigator determined that participation in this study is contraindicated (e.g.
             Infection/inflammation; severe liver dysfunction; bilateral diffuse interstitial lung
             disease; uncontrolled renal disease; unstable heart and lung disease; hemorrhagic
             disease; intestinal obstruction; unable to swallow oral pills; social and
             psychological problems, etc)

         10. Pregnant or lactating women.

         11. Medical, psychiatric, cognitive, or other conditions that may interfere with the
             ability of the subject to understand the study information, provide the informed
             consent, follow the protocol process, or complete the clinical trial

         12. Hypersensitivity to paclitaxel
      
Maximum Eligible Age:N/A
Minimum Eligible Age:19 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximal tolerated dose
Time Frame:4 weeks
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Dose-limiting toxicity
Time Frame:4 weeks
Safety Issue:
Description:Dose-limiting toxicity (DLT) assessment will be performed during the first cycle in phase 1b part, and is based on NCI-CTCAE (version 4.0).
Measure:Overall survival
Time Frame:1-year
Safety Issue:
Description:
Measure:Progression-free survival
Time Frame:1-year
Safety Issue:
Description:
Measure:Objective response rate
Time Frame:1-year
Safety Issue:
Description:
Measure:Adverse event
Time Frame:1-year
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Seoul National University Bundang Hospital

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