Clinical Trials /

Study of AZD1775 in Combination With Paclitaxel, in Advanced Gastric Adenocarcinoma Patients Harboring TP53 Mutation as a Second-line Chemotherapy

NCT02448329

Description:

This study is a single arm, single center phase II study of AZD1775 in combination with paclitaxel in patients with advanced gastric adenocarcinoma harboring TP53 mutation as a second-line chemotherapy. Patients will receive AZD 1775 plus weekly paclitaxel combination regimen. The arm is composed of 25 patients. AZD1775 225 mg BID q 12 hours (x 5 doses) administered days 1~3 + paclitaxel 80 mg/m2 given days 1, 8 and 15 of a 28 day cycle. Tumour evaluation using Response Evaluation Criteria in Solid Tumors 1.1 will be conducted at screening every 16 weeks until objective disease progression .

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Gastric Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of AZD1775 in Combination With Paclitaxel, in Advanced Gastric Adenocarcinoma Patients Harboring TP53 Mutation as a Second-line Chemotherapy
  • Official Title:

Clinical Trial IDs

  • ORG STUDY ID: 2014-04-127
  • NCT ID: NCT02448329

Conditions

  • Advanced Gastric Adenocarcinoma

Interventions

DrugSynonymsArms
AZD1775AZD1775 in Combination With Paclitaxel
paclitaxelAZD1775 in Combination With Paclitaxel

Purpose

This study is a single arm, single center phase II study of AZD1775 in combination with paclitaxel in patients with advanced gastric adenocarcinoma harboring TP53 mutation as a second-line chemotherapy. Patients will receive AZD 1775 plus weekly paclitaxel combination regimen. The arm is composed of 25 patients. AZD1775 225 mg BID q 12 hours (x 5 doses) administered days 1~3 + paclitaxel 80 mg/m2 given days 1, 8 and 15 of a 28 day cycle. Tumour evaluation using Response Evaluation Criteria in Solid Tumors 1.1 will be conducted at screening every 16 weeks until objective disease progression .

Detailed Description

      AZD1775 is an inhibitor of Wee1, a protein tyrosine kinase. Wee1 phosphorylates and inhibits
      cyclin-dependent kinases 1 (CDK1) and 2 (CDK2), and is involved in regulation of the intra-S
      and G2 cell cycle checkpoints.

      In in vitro and in vivo preclinical models, AZD1775 selectively enhanced chemotherapy induced
      death of cells deficient in p53 signaling. Tumor context-specific sensitization to the DNA
      damaging agents gemcitabine and platinums was observed in TOV21G (ovarian carcinoma) cell
      lines matched for wild type and knock down of p53.
    

Trial Arms

NameTypeDescriptionInterventions
AZD1775 in Combination With PaclitaxelExperimentalAZD1775 225 mg BID q 12 hours (x 5 doses, 2.5 days) administered days 1~3 Weekly paclitaxel 80 mg/m2 IV on 1, 8 and 15 of a four week l cycle is an widely used dose of paclitaxel given on this schedule in gastric adenocarcinoma patients as second-line therapy.
  • AZD1775
  • paclitaxel

Eligibility Criteria

        Inclusion Criteria:

          1. Provision of fully informed consent prior to any study specific procedures.

          2. Patients must be ≥20 years of age.

          3. Advanced gastric adenocarcinoma (including GEJ) that has progressed during or after
             first line therapy.

               -  The 1st line regimen must have contained doublet 5-fluoropyrimidine or platinum
                  based regimen.

               -  Relapse within 6 months of completion of adjuvant/neoadjuvant chemotherapy
                  containing doublet 5-fluoropyrimidine and platinum-based regimen could be
                  considered as 1st line therapy.

          4. Previous adjuvant/neoadjuvant chemotherapy is allowed, if completed more than 6 months
             prior to starting the 1st line therapy.

          5. Provision of tumor sample (from either a resection or biopsy)

          6. Patients with p53mutation

          7. Patients are willing and able to comply with the protocol for the duration of the
             study including undergoing treatment and scheduled visits and examinations.

          8. Eastern Cooperative Oncology Group performance status 0-1

          9. Patients must have a life expectancy ≥ 3 months from proposed first dose date.

         10. Patients must have acceptable bone marrow, liver and renal function measured within 28
             days prior to administration of study treatment as defined below:

               -  Haemoglobin ≥9.0 g/dL (transfusion allowed)

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

               -  White blood cells (WBC) > 3 x 109/L

               -  Platelet count ≥100 x 109/L (transfusion allowed)

               -  Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN)

               -  aspartate aminotransferase (SGOT)/ALT (SGPT) ≤ 2.5 x institutional upper limit of
                  normal unless liver metastases are present in which case it must be ≤ 5x ULN

               -  Serum creatinine ≤1.5 x institutional ULN

         11. At least one measurable lesion that can be accurately assessed by imaging or physical
             examination at baseline and following up visits.

         12. Negative urine or serum pregnancy test within 28 days of study treatment, confirmed
             prior to treatment on day 1.

        Exclusion Criteria:

          1. More than one prior chemotherapy regimen (except for adjuvant/neoadjuvant chemotherapy
             with more than 6 month wash out period) for the treatment of gastric cancer in the
             advanced setting.

          2. Any previous treatment with P53 inhibitors (small molecules)

          3. Any previous treatment with paclitaxel

          4. Patients with second primary cancer, except: adequately treated non-melanoma skin
             cancer,curatively treated in-situ cancer of the cervix, or other solid tumours
             curatively treated with no evidence of disease for ≤5 years.

          5. HER2 positive patients (defined by HER2 3+ by immunohistochemistry or HER2 SISH +)

          6. Patients unable to swallow orally administered medication.

          7. Treatment with any investigational product during the last 14 days before the
             enrollment (or a longer period depending on the defined characteristics of the agents
             used).

          8. Patients receiving any systemic chemotherapy, radiotherapy (except for palliative
             reasons), within 3 weeks from the last dose prior to study treatment (or a longer
             period depending on the defined characteristics of the agents used). The patient can
             receive a stable dose of bisphosphonates or denusomab for bone metastases, before and
             during the study as long as these were started at least 4 weeks prior to treatment.

          9. Concomitant use of known potent CYP3A4 inhibitors such as ketoconazole,
             itraconazole,ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and
             nelfinavir.

         10. With the exception of alopecia, any ongoing toxicities (>Common Toxicity Criteria for
             Adverse Effects grade 1) caused by previous cancer therapy.

         11. Intestinal obstruction or CTCAE grade 3 or grade 4 upper GI bleeding within 4 weeks
             before the enrollment.

         12. Resting ECG with measurable QTcB > 480 msec on 2 or more time points within a 24hour
             period or family history of long QT syndrome.

         13. Patients with cardiac problem as follows: uncontrolled hypertension (BP ≥150/95 mmHg
             despite medical therapy) Left ventricular ejection fraction <55% measured by
             echocardiography, Atrial fibrillation with a ventricular rate >100 bpm on ECG at rest
             , Symptomatic heart failure (NYHA grade II-IV), Prior or current cardiomyopathy,
             Severe valvular heart disease, Uncontrolled angina (Canadian Cardiovascular Society
             grade II-IV despite medical therapy), Acute coronary syndrome within 6 months prior to
             starting treatment

         14. Ophthalmological conditions as follows:Intra-ocular pressure >21 mmHg, or uncontrolled
             glaucoma (irrespective of intra-ocular pressure), Current or past history of central
             serous retinopathy or retinal vein occlusion

         15. Female patients who are breast-feeding or child-bearing

         16. Any evidence of severe or uncontrolled systemic disease, active infection, active
             bleeding diatheses or renal transplant, including any patient known to have hepatitis
             B, hepatitis C or human immunodeficiency virus (HIV)
      
Maximum Eligible Age:20 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:8weeks
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Duration of response
Time Frame:24weeks
Safety Issue:
Description:
Measure:Disease control rate
Time Frame:8weeks
Safety Issue:
Description:
Measure:Overall survival
Time Frame:24weeks
Safety Issue:
Description:
Measure:progression-free survival (PFS)
Time Frame:24weeks
Safety Issue:
Description:
Measure:safety and tolerability measured by Adverse Events,Vital signs,Collection of clinical chemistry/haematology parameters,ECGs
Time Frame:24weeks
Safety Issue:
Description:

Details

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

Last Updated

January 15, 2018