Clinical Trials /

Phase Ib, Single-arm Study of AZD6094 (Volitinib) in Combination With Docetaxel, in Any Solid Cancer and Sequential Phase II, Single-arm Study of AZD6094 (Volitinib) in Combination With Docetaxel in Advanced Gastric Adenocarcinoma Patients With MET Amplification as a Second Line Treatment

NCT02447406

Description:

Phase Ib/II, single-arm study of AZD6094 (Volitinib) in combination with docetaxel, in advanced gastric adenocarcinoma patients with MET amplification as a second-line treatment. Phase Ib:Investigational product, dosage and mode of administration Volitinib is an orally available, potent, selective, small molecule c-MET inhibitor. Volitinib should be administered at least 200mg orally once a day in 21 days for achieving appropriate antitumor activity. Docetaxel 60 mg/m2 will be administered via intravenous access once every 3 weeks Phase II: Investigational product, dosage and mode of administration Volitinib is an orally available, potent, selective, small molecule c-MET inhibitor. Subjects will receive Volitinib once daily ( at the MTD determined from Phase Ib) for 21 days as one cycle. Docetaxel 60 mg/m2 will be administered via intravenous access once every 3 weeks.

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

Unknown status

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase Ib, Single-arm Study of AZD6094 (Volitinib) in Combination With Docetaxel, in Any Solid Cancer and Sequential Phase II, Single-arm Study of AZD6094 (Volitinib) in Combination With Docetaxel in Advanced Gastric Adenocarcinoma Patients With MET Amplification as a Second Line Treatment
  • Official Title:

Clinical Trial IDs

  • ORG STUDY ID: 2014-07-169
  • NCT ID: NCT02447406

Conditions

  • Advanced Gastric Adenocarcinoma

Interventions

DrugSynonymsArms
AZD6094VolitinibAZD6094 (Volitinib) in combination with docetaxel
docetaxelAZD6094 (Volitinib) in combination with docetaxel

Purpose

Phase Ib/II, single-arm study of AZD6094 (Volitinib) in combination with docetaxel, in advanced gastric adenocarcinoma patients with MET amplification as a second-line treatment. Phase Ib:Investigational product, dosage and mode of administration Volitinib is an orally available, potent, selective, small molecule c-MET inhibitor. Volitinib should be administered at least 200mg orally once a day in 21 days for achieving appropriate antitumor activity. Docetaxel 60 mg/m2 will be administered via intravenous access once every 3 weeks Phase II: Investigational product, dosage and mode of administration Volitinib is an orally available, potent, selective, small molecule c-MET inhibitor. Subjects will receive Volitinib once daily ( at the MTD determined from Phase Ib) for 21 days as one cycle. Docetaxel 60 mg/m2 will be administered via intravenous access once every 3 weeks.

Detailed Description

      Volitinib is a potent and selective small molecule c-Met kinase inhibitor. Volitinib was
      found to inhibit c-Met kinase at the enzyme and cell levels with IC50s of 4 nM for both
      enzyme and Met phosphorylation in the cell. Consistent with its potent enzyme and cell
      activity, volitinib was found to inhibit cell growth in vitro against tumors with c-Met gene
      amplification in the absence of HGF stimulation with IC50s generally below 10 nM. It also
      potently inhibited HGF-stimulated cell proliferation against tumors with c-Met overexpression
      or carrying a HGF/c-Met autocrine loop.

      In a xenograft model Hs746T with c-Met gene amplification, suboptimal doses 0.6 mg/kg
      volitinib and 3 mg/kg docetaxel induced TGI(expand) of 55.8% and 80.8%, respectively, whereas
      combination resulted in a TGI by 101.1%, and statistical significance was seen between
      combination group and either of mono-therapy group. Plasma exposures of volitinib and
      docetaxel were determined after last dose at the end of study, and there was no significant
      difference between combination and single agent on exposures of either volitinib or
      docetaxel. More importantly, combination was well tolerant and no body weight loss was found
      in the animals. These results suggested that it would be worthwhile to study the combination
      use of volitinib and docetaxel in clinic.
    

Trial Arms

NameTypeDescriptionInterventions
AZD6094 (Volitinib) in combination with docetaxelExperimentalPhase Ib:Volitinib should be administered at least 200mg orally once a day in 21 days for achieving appropriate antitumor activity. Phase II: Subjects will receive Volitinib once daily ( at the MTD determined from Phase Ib) for 21 days as one cycle. Docetaxel 60 mg/m2 will be administered via intravenous access once every 3 weeks.
  • AZD6094
  • docetaxel

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. For Phase Ib: Have histologically or cytologically confirmed diagnosis of relapsed or
             refractory locally advanced or metastatic solid tumors for whom no alternative
             effective standard therapy is available or for whom standard therapy is considered
             unsuitable or intolerable.

             - Although it is preferred to enroll patients with solid tumors harboring MET
             amplification, this will not be an enrollment requirement.

             For Phase II: Advanced gastric adenocarcinoma (including GEJ expand and maybe include
             in list of abbreviations) 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 1st line therapy.

               -  Patients with gastric adenocarcinoma harboring MET amplification by MET FISH.

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

          5. Provision or availability of biopsy sample for analysis; e.g mandatory pre-treatment
             biopsy, or available diagnostic biopsy of sufficient quantity/quality

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

          7. ECOG performance status 0-1.

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

          9. 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) (does not
                  include patients with Glibert's disease)

               -  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

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

         11. Negative urine or serum pregnancy test within 28 days of study treatment, confirmed
             prior to treatment on day 1 for women of childbearing potential.

         12. Provision of consent for mandatory biopsy at progression. (fresh frozen will be
             mandatory if clinically feasible)

        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 MET inhibitors

          3. Any previous treatment with docetaxel.

          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 28 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 denosumab for bone metastases, before and
             during the study as long as these were started at least 4 weeks prior to treatment.

          9. With the exception of alopecia, any ongoing toxicities (>CTCAE grade 1) caused by
             previous cancer therapy.

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

         11. 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.

         12. Patients with cardiac problem as follows: uncontrolled hypertension (BP ≥150/95 mmHg
             despite medical therapy) Baseline Left ventricular ejection fraction below the LLN of
             <55% measured by echocardiography or institution's LLN for MUGA, 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

         13. Female patients who are breast-feeding or child-bearing and Male or female patients of
             reproductive potential who are not employing an effective method of contraception

         14. 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)

         15. Patients currently receiving (or unable to stop use at least 2 weeks) prior to
             receiving the first dose of AZD6094, medications known to be potent inhibitors of
             CYP1A2 or CYP3A4, potent inducers of CYP3A4 or CYP3A4 substrates with a narrow
             therapeutic range.
      
Maximum Eligible Age:20 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Hematologic toxicity and non-hematologic toxicity according to NCI-CTCAE version 4.0
Time Frame:expected average of 24 weeks
Safety Issue:
Description:To determine maximal tolerate dose (MTD) of volitinib when given in combination with fixed dose of docetaxel in any solid cancer

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

Last Updated

February 15, 2017