AZD8186 and Paclitaxel in Advanced Gastric Cancer

NCT04001569 | Unknown Phase 1

• 1 other identifier: KCSG-ST18-20
• Study Type: interventional
• Target: 49
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Solid Tumor; Stomach Cancer

Outcome Measures

Primary Outcomes (3)

• Maximal tolerated dose

  4 weeks

• Recommended phase 2 dose

  4 weeks

• Progression-free survival rate

  4 months

Secondary Outcomes (5)

• Dose-limiting toxicity

  4 weeks

• Overall survival

  1-year

• Progression-free survival

  1-year

• Objective response rate

  1-year

• Adverse event

  1-year

Study Arms (1)

AZD8186 in combination with paclitaxel

EXPERIMENTAL

Drug: AZD8186 in combination with paclitaxel

Interventions

AZD8186 in combination with paclitaxel DRUG

Phase 1b is planned for a 4-stage dose level and the traditional 3+3 design is applied. The RP2D will be determined based on the MTD and toxicity profiles. In phase 2 part, RP2D from the phase 1b part will be applied. * AZD8186 ( )mg po bid, 5 days on, 2 days off * Paclitaxel ( )mg/m² on D1,8,15 every 4 weeks

AZD8186 in combination with paclitaxel

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Have the willingness to sign a written informed consent document prior to any study specific procedures
• Age ≥ 19 years of male and female
• 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.
• 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.
• Eastern Cooperative Oncology Group(ECOG) performance status 0-1
• 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
• Adequate cardiac function with corrected QT interval(QTc) \< 470 msec
• Patients must be able to swallow and retain oral medications
• Serum β-human chorionic gonadotropin (HCG) test negative within 14 days before the first administration (women of childbearing potential only).
• Requirements for contraception must be followed.

You may not qualify if:

• 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.
• 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.
• History of allogeneic bone marrow transplantation or organ transplantation
• 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
• 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

Sponsors & Collaborators

• Seoul National University Bundang Hospital: lead

Study Sites (3)

Hallym University Sacred Heart Hospital

Anyang-si, Gyeonggi-do, 14068, South Korea

NOT YET RECRUITING

Seoul National University Bundang Hospital

Seongnam-si, Gyeonggi-do, 13620, South Korea

RECRUITING

Asan Medical Center

Seoul, 05505, South Korea

NOT YET RECRUITING

Related Publications (1)

• Suh KJ, Ryu MH, Zang DY, Bae WK, Lee HS, Oh HJ, Kang M, Kim JW, Kim BJ, Mortimer PGS, Kim HJ, Lee KW. AZD8186 in Combination With Paclitaxel in Patients With Advanced Gastric Cancer: Results From a Phase Ib/II Study (KCSG ST18-20). Oncologist. 2023 Sep 7;28(9):e823-e834. doi: 10.1093/oncolo/oyad059.

  PMID: 37036671 DERIVED

MeSH Terms

Conditions

Stomach Neoplasms

Interventions

AZD8186; Paclitaxel

Condition Hierarchy (Ancestors)

Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Study Officials

• Keun-Wook Lee, MD. & Ph.D

  Seoul National University Bundang Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Yong Min Shin

CONTACT

82-31-787-8324; r0012@snubh.org

Keun-Wook Lee, MD. & Ph.D

CONTACT

82-31-787-7039; hmodoctor@snubh.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: June 23, 2019
• First Posted: June 28, 2019
• Study Start: May 14, 2019
• Primary Completion: December 31, 2021
• Study Completion: December 31, 2022
• Last Updated: June 28, 2019

Record last verified: 2019-06

Locations

KR (3)