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Ph1b Study of Oraxol in Comb. w. Ramucirumab in Patients w. Gastric, Gastro-esophageal, or Esophageal Cancers

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02970539
Recruitment Status : Active, not recruiting
First Posted : November 22, 2016
Last Update Posted : May 18, 2020
Sponsor:
Information provided by (Responsible Party):
Athenex, Inc.

Brief Summary:
This is a nonrandomized, open-label, single group assignment, safety, tolerability and pharmacokinetic (PK) study to determine the MTD and optimal dosing regimen of Oraxol in combination with ramucirumab.

Condition or disease Intervention/treatment Phase
Gastric Cancer Esophageal Cancer Gastro-esophageal Cancer Drug: Oraxol Drug: Ramucirumab Phase 1

Detailed Description:
This is a sequential-group, dose escalation trial to determine the maximum tolerated dose of oral Oraxol in combination with intravenous ramucirumab. After a screening period of up to 28 days subjects will be enrolled into the treatment phase of the study. Each cycle of therapy will last 4 weeks. Subjects may continue in the study until they experience disease progression or unacceptable toxicity. Three to six subjects will be enrolled at each dose level. Once the tolerability of a dose level has been determined, an additional 3-6 subjects may be enrolled at a higher dose level, to determine the maximum tolerated dose. Safety will be monitored through recording of adverse events, serious adverse events, monitoring of laboratory tests including hematology, blood chemistry, urinalyses, physical examinations and electrocardiograms. Subjects will undergo radiographic assessments for tumor response at specified time points. Blood samples will also be obtained in the first cycle of therapy at multiple time points for determination of the amount of paclitaxel and metabolites and HM30181 in the circulation. After the treatment period, there will be a follow-up period during which the subject or family may be contacted every three months for follow-up.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 36 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b Study of Oraxol in Combination With Ramucirumab in Patients With Gastric, Gastro-esophageal, or Esophageal Cancers
Actual Study Start Date : December 8, 2016
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : March 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Oraxol +Ramucirumab

Oraxol (oral HM30181 + oral paclitaxel)

  • HM30181 methanesulfonate monohydrate - supplied as 15-mg HM30181AK-US tablets
  • Paclitaxel - supplied as 30-mg capsules Ramucirumab - supplied as a solution at a concentration of 10 mg/mL
Drug: Oraxol
Oraxol (Paclitaxel and HM30181A) will be dosed orally. Paclitaxel will be supplied as capsules and HM30181A will be supplied as tablets.
Other Name: oral HM30181AK-US tablet and paclitaxel capsule

Drug: Ramucirumab
Ramucirumab will be administered by iv infusion and supplied as a solution at a concentration of 10 mg/mL
Other Name: LY3009806




Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) [ Time Frame: The first 4 weeks ]
    The primary endpoint of determining the MTD will be based on DLT


Secondary Outcome Measures :
  1. To determine the safety and tolerability of Oraxol in combination with ramucirumab [ Time Frame: through study completion ]
    Safety assessments will consist of determining and recording all AEs (including for both increasing and decreasing severity) and SAEs

  2. The recommended Phase 2 dose of Oraxol in combination with ramucirumab [ Time Frame: One month ]
    Evaluation of the 3-day MTD for Oraxol in combination with ramucirumab, including safety, tolerability, and pharmacokinetics, will be used to determine the recommended Phase 2 dose

  3. To characterize the area under the blood concentration curve (AUCt) of Oraxol in combination with ramucirumab [ Time Frame: Day 1 and 3: Predose, 8 timepoints up to 8 hours postdose; Day 2: Predose; Day 8 and 15: Predose, and between 1 and 3 hours postdose ]
    Derived by noncompartmental analysis using the plasma concentration-time data of Oraxol (paclitaxel and its major metabolites, 3'-p-hydroxy paclitaxel and 6α-hydroxy paclitaxel, and HM30181 methanesulfonate monohydrate and its M1 metabolite)

  4. To characterize the area under the plasma concentration-time curve from 0 to 8 hours (AUC0-8h) of Oraxol in combination with ramucirumab [ Time Frame: Day 1 and 3: Predose, 8 timepoints up to 8 hours postdose; Day 2: Predose; Day 8 and 15: Predose, and between 1 and 3 hours postdose ]
    Derived by noncompartmental analysis using the plasma concentration-time data of Oraxol (paclitaxel and its major metabolites, 3'-p-hydroxy paclitaxel and 6α-hydroxy paclitaxel, and HM30181 methanesulfonate monohydrate and its M1 metabolite)

  5. To characterize the maximum observed plasma concentration (Cmax) of Oraxol in combination with ramucirumab [ Time Frame: Day 1 and 3: Predose, 8 timepoints up to 8 hours postdose; Day 2: Predose; Day 8 and 15: Predose, and between 1 and 3 hours postdose ]
    Derived by noncompartmental analysis using the plasma concentration-time data of Oraxol (paclitaxel and its major metabolites, 3'-p-hydroxy paclitaxel and 6α-hydroxy paclitaxel, and HM30181 methanesulfonate monohydrate and its M1 metabolite)

  6. To characterize the minimum observed plasma concentration (Cmin) of Oraxol in combination with ramucirumab [ Time Frame: Day 1 and 3: Predose, 8 timepoints up to 8 hours postdose; Day 2: Predose; Day 8 and 15: Predose, and between 1 and 3 hours postdose ]
    Derived by noncompartmental analysis using the plasma concentration-time data of Oraxol (paclitaxel and its major metabolites, 3'-p-hydroxy paclitaxel and 6α-hydroxy paclitaxel, and HM30181 methanesulfonate monohydrate and its M1 metabolite)

  7. To characterize the plasma half-life (t1/2) of Oraxol in combination with ramucirumab [ Time Frame: Day 1 and 3: Predose, 8 timepoints up to 8 hours postdose; Day 2: Predose; Day 8 and 15: Predose, and between 1 and 3 hours postdose ]
    Derived by noncompartmental analysis using the plasma concentration-time data of Oraxol (paclitaxel and its major metabolites, 3'-p-hydroxy paclitaxel and 6α-hydroxy paclitaxel, and HM30181 methanesulfonate monohydrate and its M1 metabolite)

  8. To characterize the accumulation factor (R) of Oraxol in combination with ramucirumab [ Time Frame: Day 1 and 3: Predose, 8 timepoints up to 8 hours postdose; Day 2: Predose; Day 8 and 15: Predose, and between 1 and 3 hours postdose ]
    Derived by noncompartmental analysis using the plasma concentration-time data of Oraxol (paclitaxel and its major metabolites, 3'-p-hydroxy paclitaxel and 6α-hydroxy paclitaxel, and HM30181 methanesulfonate monohydrate and its M1 metabolite)

  9. To characterize the apparent volume of distribution (Vd/F) of Oraxol in combination with ramucirumab [ Time Frame: Day 1 and 3: Predose, 8 timepoints up to 8 hours postdose; Day 2: Predose; Day 8 and 15: Predose, and between 1 and 3 hours postdose ]
    Derived by noncompartmental analysis using the plasma concentration-time data of Oraxol (paclitaxel and its major metabolites, 3'-p-hydroxy paclitaxel and 6α-hydroxy paclitaxel, and HM30181 methanesulfonate monohydrate and its M1 metabolite)

  10. To characterize the apparent total clearance (CL/F) of Oraxol in combination with ramucirumab [ Time Frame: Day 1 and 3: Predose, 8 timepoints up to 8 hours postdose; Day 2: Predose; Day 8 and 15: Predose, and between 1 and 3 hours postdose ]
    Derived by noncompartmental analysis using the plasma concentration-time data of Oraxol (paclitaxel and its major metabolites, 3'-p-hydroxy paclitaxel and 6α-hydroxy paclitaxel, and HM30181 methanesulfonate monohydrate and its M1 metabolite)

  11. Preliminary activity of Oraxol plus ramucirumab as determined by response rate [ Time Frame: Subjects will be evaluated for tumor response per RECIST v1.1 criteria after every 8 weeks (ie, at Weeks 9, 17, 25, etc). ]
    Tumor response will be evaluated according to RECIST v1.1 criteria

  12. Preliminary activity of Oraxol plus ramucirumab as determined by progression-free survival [ Time Frame: Subjects will be evaluated for tumor response per RECIST v1.1 criteria after every 8 weeks (ie, at Weeks 9, 17, 25, etc). ]
    Tumor response will be evaluated according to RECIST v1.1 criteria

  13. Preliminary activity of Oraxol plus ramucirumab as determined by overall survival [ Time Frame: Investigator,telephone, or family member contact or public records access will be performed every 3 months for the purpose of assessing overall survival. ]
    There will be a Follow-up Period during which survival data will be collected



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

  • Subjects must meet all of the following criteria to be included in this study:

    1. Signed written informed consent 2. ≥18 years of age 3. Histologically or cytologically confirmed diagnosis of advanced stage gastric, gastro-esophageal (Part 1 or Part 2), or esophageal adenocarcinoma (Part 1 only) with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy 4. Have documented testing for HER2-neu overexpression, and for those with tumors overexpressing HER2-neu, have documented progression on Trastuzumab-containing therapy 5. Measurable disease on computed tomography (CT) scan of thorax, abdomen, and pelvis, per RECIST v1.1 criteria 6. Able to swallow oral medication as an intact dosage form 7. Adequate hematologic status as demonstrated by not requiring transfusion support or granulocyte-colony stimulating factor (G-CSF) to maintain:

    • ANC ≥1500 cells/mm3
    • Platelet count ≥100 x 109/L
    • Hemoglobin ≥10 g/dL; subjects with thalassemia having a hemoglobin <10 g/dL may be enrolled, per Investigator discretion 8. Adequate liver function as demonstrated by:
    • Total bilirubin of ≤1.5 mg/dL
    • Alanine aminotransferase (ALT) ≤3 x upper limit of normal (ULN) or ≤5 x ULN if liver metastasis is present
    • Alkaline phosphatase ≤3 x ULN or ≤5 x ULN if bone or liver metastasis is present
    • Gamma-glutamyl transferase (GGT) <10 x ULN 9. Adequate renal function as demonstrated by:
    • Serum creatinine ≤1.5 x ULN or creatinine clearance calculation ≥60 mL/min as calculated by the Cockcroft and Gault formula
    • Urinary protein ≤1+. If urinary protein is ≥2+, a 24-hour urine collection for protein must demonstrate <1000 mg of protein in 24 hours to allow participation in this protocol.

      10. Normal prothrombin time (PT) or international normalized ratio (INR) and normal activated partial thromboplastin time (aPTT) unless subject is on anticoagulation therapy 11. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 12. Life expectancy of at least 3 months 13. Women must be postmenopausal (>12 months without menses) or surgically sterile (ie, by hysterectomy and/or bilateral oophorectomy) or must be using effective contraception (ie, oral contraceptives, intrauterine device, double barrier method of condom and spermicide) and agree to continue use of contraception for 30 days after their last dose of study drug.

      14. Sexually active male subjects must use a barrier method of contraception during the study and agree to continue the use of male contraception for at least 30 days after the last dose of study drug.

Exclusion Criteria

Subjects who meet any of the following criteria will be excluded from this study:

  1. Unresolved toxicity from previous anticancer treatments, including investigational products (subjects must have recovered all unacceptable toxicity to ≤ Grade 1 Common Terminology Criteria for Adverse Events [CTCAE] toxicity). This does not extend to symptoms or findings that are attributable to the underlying disease.
  2. Received investigational products within 14 days or 5 half-lives of the first study dosing day, whichever is longer; subjects receiving biologic agents (eg, monoclonal antibodies) require a 30-day washout period.
  3. Are currently receiving other medications or radiation intended for the treatment of their malignancy
  4. Central nervous system metastases, including leptomeningeal involvement
  5. Women of childbearing potential who are pregnant or breastfeeding
  6. Currently taking a concomitant medication, other than a premedication, that is:

    • A strong P-glycoprotein (P-gp) inhibitor or inducer. Subjects who are taking such medications but who are otherwise eligible may be enrolled if they discontinue the medication ≥1 week before dosing
    • An oral medication with a narrow therapeutic index known to be a P-gp substrate within 24 hours prior to start of dosing in the study
    • Medications known to be strong inhibitors (gemfibrozil) or inducers (rifampin) of cytochrome P450 (CYP) 2C8 or medications known to be strong CYP3A4 inhibitors (eg, ketoconazole) or inducers (eg, rifampin or St. John's Wort). Subjects who are currently taking such medications but who are otherwise eligible may be enrolled if they discontinue the medication 1 week before dosing and remain off that medication during treatment with Oraxol.
  7. Use of warfarin. Participants receiving warfarin who are otherwise eligible and who may be appropriately managed with low molecular weight heparin, in the opinion of the Investigator, may be enrolled in the study provided they are switched to low molecular weight heparin at least 7 days prior to receiving study treatment.
  8. Require chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs), chronic antiplatelet therapy, dipyridamole, clopidogrel, or similar agents. Aspirin up to 325 mg per day is allowed.
  9. Unable to receive iv contrast for required CT scans
  10. Poorly-controlled hypertension (>160 mm Hg systolic or >100 mm Hg diastolic for >4 weeks) despite standard medical management. Subjects may be rescreened after adjustment of their antihypertensive medication.
  11. Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy
  12. Prior history of GI perforation/fistula (within 6 months of first dose of protocol therapy) or risk factors for perforation
  13. Grade 3 or 4 GI bleeding within 3 months prior to first dose of protocol therapy
  14. Arterial thromboembolic event including, but not limited to, myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina within 6 months prior to first dose of protocol therapy
  15. Deep vein thrombosis (DVT) or pulmonary embolus or any other significant thromboembolic event during the 3 months prior to first dose of protocol therapy
  16. Child-Pugh Class B or C cirrhosis of the liver or cirrhosis (any degree) and a history of hepatic encephalopathy or a history of ascites resulting from cirrhosis requiring diuretics or paracentesis
  17. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, poorly controlled diabetes or diabetes with established vascular complications, chronic pulmonary disease requiring oxygen, known bleeding disorders, or any concomitant illness or social situation that would limit compliance with study requirements
  18. Medical condition that, in the opinion of the investigator, may interfere with oral drug absorption
  19. Major surgery within 28 days prior to first dose of protocol therapy, or minor surgery/subcutaneous venous access device placement within 7 days prior to the first dose of protocol therapy, or elective or major surgery planned to be performed during the course of the clinical trial
  20. History of hypersensitivity to paclitaxel, not attributed to a hypersensitivity type reaction to Cremophor®, or history of hypersensitivity type reaction to polysorbate 80 or other components of the formulation of Oraxol
  21. History of developing any condition during prior treatment with ramucirumab for which ramucirumab must be permanently discontinued according to the ramucirumab Investigator's Brochure

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): NCT02970539


Locations
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United States, Texas
CTRC-UT
San Antonio, Texas, United States, 78229
Taiwan
China Medical University Hospital
Taichung, Taiwan
Tri-Service General Hospital
Taipei, Taiwan, 11490
Taipei Veterans General Hospital
Taipei, Taiwan
Lotung Poh-Ai Hospital
Yilan, Taiwan, 26546
Sponsors and Collaborators
Athenex, Inc.
Investigators
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Study Director: David Cutler, MD Athenex, Inc.
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Responsible Party: Athenex, Inc.
ClinicalTrials.gov Identifier: NCT02970539    
Other Study ID Numbers: KX-ORAX-005
First Posted: November 22, 2016    Key Record Dates
Last Update Posted: May 18, 2020
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Esophageal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Head and Neck Neoplasms
Esophageal Diseases
Paclitaxel
Ramucirumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action