Efficacy and Safety Trial of Apatinib Plus Best Supportive Care Compared to Placebo Plus Best Supportive Care in Patients With Gastric Cancer (ANGEL)

Study Description

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Brief Summary:

The purpose of this study is to evaluate the clinical benefit and safety of Apatinib plus Best Supportive Care in comparison to Placebo plus Best Supportive Care in patients with advanced or metastatic gastric cancer

Condition or disease	Intervention/treatment	Phase
Gastric Cancer; Gastric Adenocarcinoma	Drug: Apatinib; Other: Placebo	Phase 3

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	459 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Triple (Participant, Care Provider, Investigator)
Masking Description:	Double Blind
Primary Purpose:	Treatment
Official Title:	A Prospective, Randomized, Double-Blinded, Placebo-Controlled, Multinational, Multicenter, Parallel-group, Phase III Study to Evaluate the Efficacy and Safety of Apatinib Plus Best Supportive Care (BSC) Compared to Placebo Plus BSC in Patients With Advanced or Metastatic Gastric Cancer
Actual Study Start Date :	February 24, 2017
Estimated Primary Completion Date :	August 30, 2018
Estimated Study Completion Date :	December 30, 2018

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Apatinib	Drug: Apatinib; Daily oral dose of Apatinib plus Best Supportive Care defined as palliative non-cancer therapy at the Investigator's discretion
Experimental: Placebo	Other: Placebo; Daily oral dose of Placebo with Best Supportive Care defined as palliative non-cancer therapy at the Investigator's discretion

Outcome Measures

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Primary Outcome Measures :

1. Overall Survival [ Time Frame: Time from randomization until death, assessed up to approximately 18 months ]
   Subjects alive or lost to follow-up at the end of study are censored

Secondary Outcome Measures :

1. Progression Free Survival [ Time Frame: Time from randomization to either radiologic disease progression or death, assessed up to approximately 18 months ]
   Subjects alive and free of progression at the end of study are censored
2. Objective Response Rate [ Time Frame: Approximately every 8 weeks from baseline through End of Treatment (EOT) and study completion, assessed up to approximately 18 months ]
   Percentage of subjects with a Best Overall Response of Complete Response (CR) or Partial Response (PR). RECIST Guideline version 1.1 will be used to assess tumor response
3. Disease Control Rate [ Time Frame: Approximately every 8 weeks from baseline through EOT and study completion, assessed up to approximately 18 months ]
   Proportion of subjects with a Best Overall Response of complete response, partial response, or stable disease. RECIST Guideline Version 1.1 will be used to assess tumor response
4. Quality of Life Assessed by EORTC QLQ-C30 [ Time Frame: Every 28 days from baseline through EOT and study completion, assessed up to approximately 18 months ]
   Global health status/quality of life score according to European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)
5. Quality of Life Assessed by EORTC QLQ-STO22 [ Time Frame: Every 28 days from baseline through EOT and study completion, assessed up to approximately 18 months ]
   Global health status/quality of life score according to European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-EORTC QLQ-STO22
6. Quality of Life Assessed by EQ-5D-5L [ Time Frame: Every 28 days from baseline through EOT and study completion, assessed up to approximately 18 months ]
   Each dimension response according to EuroQol 5-Dimension 5-Level (EQ-5D-5L) Questionnaire
7. Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: Screening through 28 days after last dose of study drug and study completion, assessed up to approximately 18 months ]
   Assessed by: Adverse events, laboratory tests, vital signs, physical examination, 12-lead ECG, and ECOG performance status
8. Tumor Pharmacodynamic Markers [ Time Frame: Every 28 days from baseline through EOT and study completion, assessed up to approximately 18 months ]
   Vascular Endothelial Growth Factor (VEGF), sVEGFR-1, sVEGFR2 and sVEGFR3
9. Pharmacokinetics of Apatinib as assessed by Maximum Plasma Concentration [Cmax] [ Time Frame: Cycle 1 Day 1 and Day 15 assessed within approximately 9 months after last patient enrolled ]
   Maximum Plasma Concentration [Cmax]
10. Pharmacokinetics of Apatinib as assessed by Trough level of Plasma Concentrations [ Time Frame: Every 28 days from baseline up to EOT through study completion, assessed up to approximately 18 months ]
    Trough Level Plasma Concentration
11. Pharmacokinetics of Apatinib as assessed by Area Under the Curve [AUC] [ Time Frame: Every 28 days from baseline up to EOT through study completion and Cycle 1 Day 15, assessed up to approximately 18 months ]
    Area under the plasma concentration vs time curve (AUC)

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Male or female ≥ 18 years of age.
2. Documented primary diagnosis of histologic- or cytologic-confirmed adenocarcinoma of the stomach or gastroesophageal junction.
3. Locally advanced unresectable or metastatic disease that has progressed since last treatment.
4. One or more measurable or nonmeasurable evaluable lesions per RECIST 1.1.

5. Failure or intolerance to at least two prior lines of standard chemotherapies with each containing one or more of the following agents:

   • fluoropyrimidine (IV 5-FU capecitabine, or S-1),
   • platinum (cisplatin or oxaliplatin),
   • taxanes (paclitaxel or docetaxel) or epirubicin,
   • irinotecan,
   • trastuzumab in case of HER2-positive
   • ramucirumab
6. Disease progression within 6 months after the last treatment.
7. Adequate bone-marrow, renal and liver function.
8. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1.
9. Expected survival of ≥ 12 weeks, in the opinion of the investigator.
10. Ability to swallow the investigational product tablets.
11. Female patients with negative pregnancy test at Screening and use of acceptable method of birth control for study duration, unless surgically sterile or postmenopausal for at least 1 year prior to Screening.
12. Ability and willingness to comply with the study protocol for the duration of the study and with follow-up procedures.

Exclusion Criteria:

1. Malignancies other than adenocarcinoma of the stomach or gastroesophageal junction (including hematologic malignancies) within 3 years.
2. CNS metastases as shown by radiology records or clinical evidence of symptomatic CNS involvement in the last 3 months prior to randomization.
3. Cytotoxic chemotherapy, surgery, immunotherapy, radiotherapy or other targeted therapies within 4 weeks (6 weeks in cases of ramucirumab, mitomycin C, nitrosourea, lomustine; 2 weeks in case of biopsy) prior to randomization (Adjuvant radiotherapy given to local area for non-curative symptom relief is allowed until 2 weeks before randomization.).
4. Therapy with clinically significant systemic anticoagulant or antithrombotic agents within 7 days prior to randomization that may prevent blood clotting and, in the investigator's opinion, could place the subject at risk.
5. Patients who had therapeutic paracentesis of ascites (> 1L) within the 3 months prior to starting study treatment or who, in the opinion of the investigator, will likely need therapeutic paracentesis of ascites (> 1L) within 3 months of starting study treatment.
6. Previous treatment with Apatinib.
7. Known hypersensitivity to Apatinib or components of the formulation.
8. Concomitant treatment with strong inhibitors or inducers of CYP3A4, CYP2C9 and CYP2C19.
9. Active bacterial infections.
10. Substance abuse or medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
11. Participation in any other clinical trial within 4 weeks prior to randomization.
12. Pregnant or breast-feeding women.
13. History of drug or alcohol abuse within past 5 years.
14. Medical or psychiatric illnesses that, in the investigator's opinion, may impact the safety of the subject or the objectives of the study.
15. History of uncontrolled hypertension (Blood pressure ≥ _140/90 mmHg and change in antihypertensive medication within 7 days prior to randomization) that is not well managed by medication and the risk of which may be precipitated by a VEGF inhibitor therapy.
16. Known history of symptomatic congestive heart failure (New York Heart Association III-IV), symptomatic or poorly controlled cardiac arrhythmia, complete left bundle branch block, bifascicular block, or any clinically significant ST segment and/or T-wave abnormalities, QTcF > 450 msec prior to randomization.
17. Prior major surgery or fracture within 3 weeks prior to randomization or presence of any non-healing wound.
18. History of bleeding diathesis or clinically significant bleeding within 14 days prior to randomization.
19. History of clinically significant thrombosis within the past 3 months prior to randomization that, in the investigator's opinion, may place the patient at risk of side effects from anti-angiogenesis products.
20. History of gastrointestinal bleeding, gastric stress ulcerations, or peptic ulcer disease within the past 3 months prior to randomization that, in the investigator's opinion, may place the patient at risk of side effects from anti-angiogenesis products.
21. Myocardial infarction or unstable angina pectoris within 6 months prior to randomization.
22. History of severe adverse events, in the investigator's opinion, related to ramucirumab.
23. History of other significant cardiovascular diseases or vascular diseases within the last 6 months prior to randomization that, in the investigator's opinion, may pose a risk to the patient on VEGF inhibitor therapy.
24. History of clinically significant glomerulonephritis, biopsy-proven tubulointerstitial nephritis, crystal nephropathy, or other renal insufficiencies.
25. Gastrointestinal malabsorption, or any other condition that in the opinion of the investigator might affect the absorption of the study drug.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Rahul Gowda (South Korea)	+82-2-546-1008	AM301Study@lskglobal.com
Contact: llu.fan@statplus.com (TaiwanCRO), koji.tomita@mpi-cro.jp (Japan CRO), Vyacheslav.Lyskov@chiltern.com	(EU US CRO)

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Sponsors and Collaborators

LSK BioPartners Inc.

Investigators

Study Director:	Scott Houston	LSK BioPartners Inc.

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	LSK BioPartners Inc.
ClinicalTrials.gov Identifier:	NCT03042611 History of Changes
Other Study ID Numbers:	LSK-AM301
First Posted:	February 3, 2017
Last Update Posted:	April 4, 2018
Last Verified:	April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by LSK BioPartners Inc.:

Gastric Cancer; Gastric Adenocarcinoma; Gastro-esophageal Cancer; Gastro-esophageal junction Cancer; Stomach Cancer	Tumor; Oncology; Antiangiogenesis; Metastatic

Additional relevant MeSH terms:

Adenocarcinoma; Stomach Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms	Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases