Clinical Trials /

Trial of AZD5363 Plus Paclitaxel /AZD2014 Plus Paclitaxel in Biomarker Negative (PIK3CA/MEK/RAS/TP53/MET) Gastric Adenocarcinoma Patients as Second-line Chemotherapy

NCT02449655

Description:

Phase II trial of AZD5363 plus paclitaxel / AZD2014 plus paclitaxel in biomarker negative (PIK3CA/MEK/RAS/TP53/MET) advanced gastric adenocarcinoma patients as second-line chemotherapy. Each arm is composed of 25 patients. AZD5363 400mg bid 4 days on/ 3 days off of a 7 day cycle for each week that paclitaxel is given + paclitaxel 80mg/m2 given days 1, 8 and 15 of a 28 day cycle. AZD5363 and paclitaxel will be received for 3 consecutive weeks, followed by one week off-therapy in 4-week cycles.If paclitaxel therapy is stopped then AZD5363 can be given on a 4on/3off continuous schedule. AZD2014 50mg BD 3 days on 4 days off of a 7 day cycle + paclitaxel 80mg/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 (within 28 days prior to first dose) and every 8 weeks relative to the date of first dose, up to week 40, then every 16 weeks until objective disease progression (within a window of +/- 7 days of the scheduled date). Study treatment will be continued until objective disease progression. The purpose of this study is to investigate the safety and efficacy of AZD5363 plus paclitaxel in biomarker negative (PIK3CA/MEK/RAS/TP53/MET) advanced gastric adenocarcinoma patients as second-line chemotherapy.

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

Terminated

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Trial of AZD5363 Plus Paclitaxel /AZD2014 Plus Paclitaxel in Biomarker Negative (PIK3CA/MEK/RAS/TP53/MET) Gastric Adenocarcinoma Patients as Second-line Chemotherapy
  • Official Title:

Clinical Trial IDs

  • ORG STUDY ID: 2014-04-122
  • NCT ID: NCT02449655

Conditions

  • Advanced Gastric Adenocarcinoma

Interventions

DrugSynonymsArms
AZD5363AZD5363 plus paclitaxel
paclitaxelAZD5363 plus paclitaxel
AZD2014AZD2014 plus paclitaxel
paclitaxelAZD2014 plus paclitaxel

Purpose

Phase II trial of AZD5363 plus paclitaxel / AZD2014 plus paclitaxel in biomarker negative (PIK3CA/MEK/RAS/TP53/MET) advanced gastric adenocarcinoma patients as second-line chemotherapy. Each arm is composed of 25 patients. AZD5363 400mg bid 4 days on/ 3 days off of a 7 day cycle for each week that paclitaxel is given + paclitaxel 80mg/m2 given days 1, 8 and 15 of a 28 day cycle. AZD5363 and paclitaxel will be received for 3 consecutive weeks, followed by one week off-therapy in 4-week cycles.If paclitaxel therapy is stopped then AZD5363 can be given on a 4on/3off continuous schedule. AZD2014 50mg BD 3 days on 4 days off of a 7 day cycle + paclitaxel 80mg/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 (within 28 days prior to first dose) and every 8 weeks relative to the date of first dose, up to week 40, then every 16 weeks until objective disease progression (within a window of +/- 7 days of the scheduled date). Study treatment will be continued until objective disease progression. The purpose of this study is to investigate the safety and efficacy of AZD5363 plus paclitaxel in biomarker negative (PIK3CA/MEK/RAS/TP53/MET) advanced gastric adenocarcinoma patients as second-line chemotherapy.

Detailed Description

      AZD2014 is a selective dual mTOR kinase inhibitor targeting both mTORC1 (rapamycin sensitive)
      and mTORC2 (rapamycin insensitive) complexes of mammalian Target of Rapamycin (mTOR).

      AZD2014 is a selective dual mTOR kinase inhibitor targeting both mTORC1 (rapamycin sensitive)
      and mTORC2 (rapamycin insensitive) complexes of mammalian Target Of Rapamycin (mTOR) AZD2014
      is specific for mTOR and does not inhibit other members of the PI3K superfamily.

      The PI3K-AKT-mTOR pathway functions as a sensor of mitogen, energy and nutrient levels and is
      a central controller of cell growth.

      The mTOR is a protein kinase (PK) and a vital component of the PI3K/Akt/mTOR signaling
      pathway. This pathway is deregulated in 50% of all human cancers and, as such, is an
      important target for inhibitors that would alleviate the unregulated proliferation of cancer
      cells . AZD2014 is selective inhibitor of mTOR kinases and inhibits signalling of both mTOR
      complexes, mTORC1 and mTORC2.

      In this study, the researchers further investigated the effect of PI3K/mTOR inhibitor as a
      paclitaxel sensitizer and/or nonspecific targeted therapy in combination with standard
      chemotherapy, paclitaxel in patients with pretreated advanced or metastatic gastric cancer
      having all negative biomarkers (PIK3CA/MEK/RAS/TP53/MET).

      AZD5363 is a highly potent adenosine triphosphate (ATP)-competitive AKT inhibitor with
      IC50<10nmol/l for all three AKT isoforms.

      AZD5363 is a highly potent adenosine triphosphate (ATP)-competitive AKT inhibitor with
      IC50<10nmol/l for all three AKT isoforms. AKT pathway is activated in various human
      cancers.Although AKT inhibitor has known showing anti-tumor activity in cell lines mutated at
      the E542, E545, or H1047 positions in preclinical study, clinical studies with AKT inhibitor
      are conducted for non-selected cancer patients.
    

Trial Arms

NameTypeDescriptionInterventions
AZD5363 plus paclitaxelExperimentalAZD5363 4800mg bid 4 days on/ 3 days off of a 7 day cycle for each week that paclitaxel is given + paclitaxel 80mg/m2 given days 1, 8 and 15 of a 28 day cycle. AZD5363 and paclitaxel will be received for 3 consecutive weeks, followed by one week off-therapy in 4-week cycles.
  • AZD5363
  • paclitaxel
AZD2014 plus paclitaxelActive ComparatorAZD2014 50mg BD 3 days on 4 days off of a 7 day cycle + paclitaxel 80mg/m2 given days 1, 8 and 15 of a 28 day cycle
  • AZD2014
  • 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 that has progressed during or after first-line
             therapy.

               -  The 1st line regimen must have contained doublet 5-fluoropyrimidine and 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 first line therapy.

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

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

          6. Patients with biomarker negative

          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)

               -  AST (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 PIK3CA, AKT or mTOR inhibitor or agents with mixed PI3K /
             mTOR activity.

          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

          6. Patients unable to swallow orally administered medication.

          7. Any investigational drug or product administered within 30 days or 5 half-lives,
             whichever is longer, of the first dose of AZD5363.

          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. Previous major surgery within 4weeks prior to enrollment.

         10. For AZD2014: Exposure to potent or moderate inhibitors or inducers of CYP3A4/5 if
             taken within the stated washout periods before the first dose of study treatment

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

         12. Intestinal obstruction or Common Toxicity Criteria for Adverse Effects grade 3 or
             grade 4 upper GI bleeding within 4 weeks before the enrollment.

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

         14. 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

         15. Active or untreated brain metastases or spinal cord compression Patients with treated
             brain metastases or spinal cord compression are eligible if they have minimal
             neurologic symptoms, evidence of stable disease (for at least 1 month) or response on
             follow-up scan, and require no corticosteroid therapy for ≥ 1 week.

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

         17. 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)

         18. Patients with proteinuria (3+ on dipstick analysis )
      
Maximum Eligible Age:N/A
Minimum Eligible Age:20 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:expected average of 24 weeks
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Duration of response
Time Frame:expected average of 24 weeks
Safety Issue:
Description:
Measure:Disease control rate
Time Frame:8 weeks
Safety Issue:
Description:
Measure:Overall survival (OS)
Time Frame:expected average of 24 weeks
Safety Issue:
Description:
Measure:progression-free survival (PFS)
Time Frame:expected average of 24 weeks
Safety Issue:
Description:
Measure:Biomarker analysis
Time Frame:3 years
Safety Issue:
Description:responders vs non-responders with whole exome sequencing/RNA sequencing including re-biopsy specimens Lauren classification (intestinal vs diffuse)
Measure:Number of subjects with Adverse Events as a measure of safety and tolerability
Time Frame:expected average of 24 weeks
Safety Issue:
Description:

Details

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

Last Updated

February 10, 2017