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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

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ClinicalTrials.gov Identifier: NCT02447406
Recruitment Status : Unknown
Verified February 2017 by Seung tae Kim, Samsung Medical Center.
Recruitment status was:  Recruiting
First Posted : May 18, 2015
Last Update Posted : February 16, 2017
Sponsor:
Information provided by (Responsible Party):
Seung tae Kim, Samsung Medical Center

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Advanced Gastric Adenocarcinoma Drug: AZD6094 Drug: docetaxel Phase 1 Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 25 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Actual Study Start Date : April 30, 2015
Estimated Primary Completion Date : January 2018
Estimated Study Completion Date : January 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Docetaxel

Arm Intervention/treatment
Experimental: AZD6094 (Volitinib) in combination with docetaxel

Phase 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.

Drug: AZD6094
Other Name: Volitinib

Drug: docetaxel



Primary Outcome Measures :
  1. Hematologic toxicity and non-hematologic toxicity according to NCI-CTCAE version 4.0 [ Time Frame: expected average of 24 weeks ]
    To determine maximal tolerate dose (MTD) of volitinib when given in combination with fixed dose of docetaxel in any solid cancer

  2. Objective response rate (ORR) by RECIST 1.1 [ Time Frame: expected average of 24 weeks ]
    Phase II:To investigate the efficacy of volitinib when given in combination with docetaxel in patients with advanced gastric adenocarcinoma harboring MET amplification


Secondary Outcome Measures :
  1. Duration of response [ Time Frame: expected average of 24 weeks ]
  2. Disease control rate [ Time Frame: 8 weeks ]
  3. Overall survival (OS) [ Time Frame: expected average of 24 weeks ]
  4. progression-free survival (PFS) [ Time Frame: expected average of 24 weeks ]
  5. Number of subjects with Adverse Events as a Measure of safety and tolerability [ Time Frame: expected average of 24 weeks ]


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Ages Eligible for Study:   up to 20 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02447406


Contacts
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Contact: Seung Tae Kim, MD,Ph.D. 2-3410-3459 ext 82 seungtae1.kim@samsung.com

Locations
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Korea, Republic of
Samsung Medical Center Recruiting
Seoul, seoul, korea, Republic of, Korea, Republic of, 135-710
Contact: yoon Jeong Ahn    221487395 ext 82      
Principal Investigator: Seung Tae Kim, M.D., Ph.D.         
Sponsors and Collaborators
Samsung Medical Center

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Responsible Party: Seung tae Kim, MD,PhD, Samsung Medical Center
ClinicalTrials.gov Identifier: NCT02447406     History of Changes
Other Study ID Numbers: 2014-07-169
First Posted: May 18, 2015    Key Record Dates
Last Update Posted: February 16, 2017
Last Verified: February 2017
Additional relevant MeSH terms:
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Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Docetaxel
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action