A DRF Study to Evaluate Safety, Tolerability, PK, and Activity of Oradoxel Monotherapy in Subjects w Adv. Malignancies

• ClinicalTrials.gov Identifier: NCT02963168
• Recruitment Status: Unknown
• First Posted: November 15, 2016
• Last Update Posted: October 17, 2019
• Sponsor: Athenex, Inc.
• Information provided by (Responsible Party): Athenex, Inc.

Study Description

Brief Summary:

This is a nonrandomized, open-label, dose escalation, safety, activity, and PK study to determine the MTD and optimal dosing regimen of Oradoxel. No control group has been included.

Condition or disease	Intervention/treatment	Phase
Solid Tumor	Drug: Oradoxel	Phase 1

Detailed Description:

This is a multicenter, open-label, safety, tolerability, pharmacokinetic, and activity study. Eligible subjects will be adults with advanced solid malignancies.

Groups of 3 to 6 subjects will receive a single dose of Oradoxel and will be followed for toxicity. If non linearity in PK is observed, additional subjects will receive Oradoxel as 2 single daily doses once every three weeks. Subjects who tolerate the drug and have stable disease or better response will be eligible to receive ongoing treatment.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 24 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Dose Regimen-Finding Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Activity of Oradoxel Monotherapy in Subjects With Advanced Malignancies
• Actual Study Start Date: April 20, 2017
• Estimated Primary Completion Date: March 30, 2020
• Estimated Study Completion Date: April 30, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Oradoxel; To determine the MTD of Oradoxel (oral docetaxel and oral HM30181A) when administered once every 3 weeks, then to determine the MTD of Oradoxel (oral docetaxel and oral HM30181A) when administered for two days every three weeks.	Drug: Oradoxel; oral docetaxel will be supplied in capsules and oral HM30181A-UK tablets; Other Name: oral docetaxel + oral HM30181A

Outcome Measures

Primary Outcome Measures :

1. The maximum tolerated dose (MTD) of Oradoxel based on dose-limiting toxicity (DLT) in subjects with advanced malignancies [ Time Frame: 3 weeks ]
   The MTD will be the highest dose at which no more than 1 of 6 subjects experience a DLT during treatment and Oradoxel pharmacokinetics are acceptable.

Secondary Outcome Measures :

1. Safety assessment using AEs of Oradoxel [ Time Frame: Weekly, up to 24 months ]
2. Safety assessment using SAEs of Oradoxel [ Time Frame: Weekly, up to 24 months ]
3. Laboratory evaluation for hematology [ Time Frame: Weekly, up to 24 months ]
4. Blood chemistry [ Time Frame: Weekly, up to 24 months ]
5. Urine analysis [ Time Frame: Weekly, up to 24 months ]
6. Periodic measurements of ECGs [ Time Frame: Screening, Day 1, every 6 weeks thereafter up to 24 months ]
7. Periodic measurements of vital signs [ Time Frame: Weekly, up to 24 months ]
8. The incidence of unacceptable toxicity with Oradoxel [ Time Frame: 24 months ]
   Unacceptable toxicity graded according to CTCAE v4.03
9. The recommended Phase 2 dose (RP2D) of Oradoxel [ Time Frame: 24 months ]
   Upon determination of the overall MTD for Oradoxel, the safety and PK profile of the study treatment from all Treatment Periods will be reviewed to determine the recommended Phase 2 dose.
10. The amount of docetaxel and HM30181A in blood stream by Area under the plasma concentration versus time curve (AUC) [ Time Frame: Part 1: 16 timepoints over 504 hours; Part 2: 26 timepoints over 480 hours ]
11. The peak plasma concentration (Cmax) and Minimum plasma concentration (Cmin) [ Time Frame: Part 1: 16 timepoints over 504 hours; Part 2: 26 timepoints over 480 hours ]
12. A biological half-life or elimination half-life (t1/2) [ Time Frame: Part 1: 16 timepoints over 504 hours; Part 2: 26 timepoints over 480 hours ]
13. The accumulation ratio (R) [ Time Frame: Part 1: 16 timepoints over 504 hours; Part 2: 26 timepoints over 480 hours ]
14. The apparent total clearance of the drug from plasma (CL/F) [ Time Frame: Part 1: 16 timepoints over 504 hours; Part 2: 26 timepoints over 480 hours ]
15. The apparent volume of distribution (Vd/F) [ Time Frame: Part 1: 16 timepoints over 504 hours; Part 2: 26 timepoints over 480 hours ]
16. To evaluate tumor response [ Time Frame: Every 12 weeks, up to 24 months ]
    Tumor response will be evaluated according to RECIST v1.1

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. Signed written informed consent
2. ≥18 years of age
3. Histologically or cytologically confirmed solid tumor that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective
4. Docetaxel monotherapy is a reasonable treatment in the judgement of the Investigator
5. Measurable disease as 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: Absolute neutrophil count (ANC) ≥1500 cells/mm3, Platelet count ≥100 x 109/L, Hemoglobin (Hgb) ≥10 g/dL
8. Adequate liver function as demonstrated by: Total bilirubin of < upper limit of normal (ULN), Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤1.5 × ULN, Alkaline phosphatase (ALP) ≤2.5x ULN or <5x ULN if bone metastases are present, Normal serum albumin
9. Adequate renal function as demonstrated by serum creatinine ≤1.5 x ULN or creatinine clearance>60 mL/min as calculated by the Cockroft and Gault formula
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
11. Life expectancy of at least 3 months
12. Willing to fast for 6 hours before and 2 hours after Oradoxel administration
13. Females must be postmenopausal (>12 months without menses) or surgically sterile (ie, by hysterectomy and/or bilateral oophorectomy) or, if sexually active, 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:

1. Currently taking a prohibited concomitant medication, other than a premedication, that are/is:

   • Strong inhibitors (eg, ketoconazole) or inducers (eg, rifampicin or St. John's Wort) of CYP3A4 (within 2 weeks prior to the start of dosing in the study)
   • Strong P-gp inhibitors or inducers. Subjects who are 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 through the end of PK sampling after the administration of the second study treatment
   • 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
2. Unresolved toxicity from prior chemotherapy (subjects must be recovered to ≤ Grade 1 toxicity from previous anticancer treatments or previous investigational products.
3. Planning to receive other medical, surgical, or radiological cancer treatments during the course of this study
4. Received investigational agents within 14 days or 5 half-lives prior to the first study dosing day, whichever is longer
5. Require therapeutic use of anticoagulants
6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, clinically significant myocardial infarction within the last 6 months, unstable angina pectoris, clinically significant cardiac arrhythmia, bleeding disorder, chronic pulmonary disease requiring oxygen, or psychiatric illness/social situations that would limit compliance with study requirements
7. Major surgery to the upper gastrointestinal (GI) tract, or have a history of GI disease or other medical condition that, in the opinion of the Investigator, may interfere with oral drug absorption
8. A known history of allergy to docetaxel, Cremophor or polysorbate 80 (Tween 80)
9. Evidence of fluid retention at Screening (including, for example, peripheral edema, pleural effusion, or ascites on physical or radiological examination) or history of severe capillary leak syndrome
10. Any other condition which the Investigator believes would make participation in the study not acceptable

Contacts and Locations

Contacts

Contact: E. Douglas Kramer, MD; 908-340-6996; dkramer@athenex.com

Contact: Ildiko Bezi; 908-340-6996; ibezi@athenex.com

Locations

United States, Arizona

Mayo Clinic; Recruiting

Phoenix, Arizona, United States, 85054

Contact: Clinical Trials Referral Office 855-776-0015

Principal Investigator: Parminder Singh, MD

United States, Minnesota

Mayo Clinic; Recruiting

Rochester, Minnesota, United States, 55905

Contact: Clinical Trials Referral Office 855-776-0015

United States, Texas

Cancer Therapy & Research Center at UTHSCSA; Recruiting

San Antonio, Texas, United States, 78229

Contact: Clinical Trials Office 210-450-1000

Principal Investigator: John Sarantopoulos, MD

Sponsors and Collaborators

Athenex, Inc.

Investigators

• Study Director: David Cutler, MD; Athenex, Inc.

More Information

• Responsible Party: Athenex, Inc.
• ClinicalTrials.gov Identifier: NCT02963168
• Other Study ID Numbers: KX-ORADOX-003
• First Posted: November 15, 2016
• Last Update Posted: October 17, 2019
• Last Verified: January 2019

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

Additional relevant MeSH terms:

Neoplasms; Docetaxel; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action