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Study of Oraxol and Pembrolizumab in Subjects With Advanced Solid Tumors

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ClinicalTrials.gov Identifier: NCT03588039
Recruitment Status : Recruiting
First Posted : July 17, 2018
Last Update Posted : January 10, 2019
Sponsor:
Information provided by (Responsible Party):
Athenex, Inc.

Brief Summary:
This is an open-label, Phase 1 dose-escalation study followed by a 3-arm expansion cohort of Oraxol administered in combination with pembrolizumab.

Condition or disease Intervention/treatment Phase
Solid Tumor Drug: Oraxol Biological: Pembrolizumab Phase 1

Detailed Description:
This is a two part study. The dose escalation part will enroll subjects with advanced solid tumors for which pembrolizumab is an FDA-approved therapy, to determine the MTD and identify the recommended phase 2 dose of paclitaxel administered as Oraxol in combination with pembrolizumab. Upon determination of the phase 2 dose, the dose expansion part will enroll subjects with advanced/metastatic urothelial, gastric/gastro-esophageal, or NSCLC into 3 independent cohorts/arms to further evaluate the activity and safety of the study treatment.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 114 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1 Study With Expansion Cohorts to Assess the Safety, Tolerability, and Activity of Oraxol (Paclitaxel + HM30181A) in Combination With Pembrolizumab in Subjects With Advanced Solid Malignancies
Actual Study Start Date : October 25, 2018
Estimated Primary Completion Date : October 30, 2020
Estimated Study Completion Date : December 30, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Dose escalation-Arm 1
During the dose escalation period Oraxol will be administered once daily for 2 days per week for 2 weeks followed by 1 week off treatment (2 weeks on and 1 week off). Pembrolizumab will be administered on Day 1 of each 3-week cycle.
Drug: Oraxol
Oral paclitaxel will be supplied in capsules and oral HM30181AK-US will be supplied in tablets
Other Name: oral HM30181A + oral paclitaxel

Biological: Pembrolizumab
Intravenously administered
Other Name: Keytruda

Experimental: Dose escalation-Arm 2
During the dose escalation period Oraxol will be administered once daily for 3 days per week for 2 weeks followed by 1 week off treatment (2 weeks on and 1 week off). Pembrolizumab will be administered on Day 1 of each 3-week cycle.
Drug: Oraxol
Oral paclitaxel will be supplied in capsules and oral HM30181AK-US will be supplied in tablets
Other Name: oral HM30181A + oral paclitaxel

Biological: Pembrolizumab
Intravenously administered
Other Name: Keytruda

Experimental: Dose escalation-Arm 3
During the dose escalation period Oraxol will be administered once daily for 4 days per week for 2 weeks followed by 1 week off treatment (2 weeks on and 1 week off). Pembrolizumab will be administered on Day 1 of each 3-week cycle.
Drug: Oraxol
Oral paclitaxel will be supplied in capsules and oral HM30181AK-US will be supplied in tablets
Other Name: oral HM30181A + oral paclitaxel

Biological: Pembrolizumab
Intravenously administered
Other Name: Keytruda

Experimental: Dose escalation-Arm 4
During the dose escalation period Oraxol will be administered once daily for 5 days per week for 2 weeks followed by 1 week off treatment (2 weeks on and 1 week off). Pembrolizumab will be administered on Day 1 of each 3-week cycle.
Drug: Oraxol
Oral paclitaxel will be supplied in capsules and oral HM30181AK-US will be supplied in tablets
Other Name: oral HM30181A + oral paclitaxel

Biological: Pembrolizumab
Intravenously administered
Other Name: Keytruda

Experimental: Dose escalation-Arm 5
During the dose escalation period Oraxol will be administered once daily for 5 days per week for 2 weeks followed by 1 week off treatment (2 weeks on and 1 week off). Pembrolizumab will be administered on Day 1 of each 3-week cycle.
Drug: Oraxol
Oral paclitaxel will be supplied in capsules and oral HM30181AK-US will be supplied in tablets
Other Name: oral HM30181A + oral paclitaxel

Biological: Pembrolizumab
Intravenously administered
Other Name: Keytruda

Experimental: Dose escalation-Arm 6
During the dose escalation period Oraxol will be administered once daily for 5 days per week for 2 weeks followed by 1 week off treatment (2 weeks on and 1 week off). Pembrolizumab will be administered on Day 1 of each 3-week cycle.
Drug: Oraxol
Oral paclitaxel will be supplied in capsules and oral HM30181AK-US will be supplied in tablets
Other Name: oral HM30181A + oral paclitaxel

Biological: Pembrolizumab
Intravenously administered
Other Name: Keytruda

Experimental: Dose expansion-Gastric/GE
The dose expansion period will enroll subjects with gastric/gastro-esophageal cancer to further evaluate the activity and safety of the study treatment. Oraxol will be administered at the dose determined from part 1 for 2 out of 3 weeks. Pembrolizumab will be administered on Day 1 of each 3-week cycle.
Drug: Oraxol
Oral paclitaxel will be supplied in capsules and oral HM30181AK-US will be supplied in tablets
Other Name: oral HM30181A + oral paclitaxel

Biological: Pembrolizumab
Intravenously administered
Other Name: Keytruda

Experimental: Dose expansion-NSCLC cancer
The dose expansion period will enroll subjects with NSCLC to further evaluate the activity and safety of the study treatment. Oraxol will be administered at the dose determined from part 1 for 2 out of 3 weeks. Pembrolizumab will be administered on Day 1 of each 3-week cycle.
Drug: Oraxol
Oral paclitaxel will be supplied in capsules and oral HM30181AK-US will be supplied in tablets
Other Name: oral HM30181A + oral paclitaxel

Biological: Pembrolizumab
Intravenously administered
Other Name: Keytruda

Experimental: Dose expansion-Urothelial cancer
The dose expansion period will enroll subjects with advanced/metastatic urothelial to further evaluate the activity and safety of the study treatment. Oraxol will be administered at the dose determined from part 1 for 2 out of 3 weeks. Pembrolizumab will be administered on Day 1 of each 3-week cycle.
Drug: Oraxol
Oral paclitaxel will be supplied in capsules and oral HM30181AK-US will be supplied in tablets
Other Name: oral HM30181A + oral paclitaxel

Biological: Pembrolizumab
Intravenously administered
Other Name: Keytruda




Primary Outcome Measures :
  1. Determination of MTD [ Time Frame: 3 weeks ]
    dose limiting toxicities occuring in the first cycle of therapy

  2. Tumor response rate [ Time Frame: 24 months ]
    Proportion of subjects in each arm and part 2 with confirmed tumor response


Secondary Outcome Measures :
  1. Progression free survival (PFS) [ Time Frame: 24 months ]
    To determine the progression free survival after initiation of treatment with Oraxol in subjects

  2. Overall survival (OS) [ Time Frame: 24 months ]
    To determine the overall survival after initiation of treatment with Oraxol in subjects

  3. duration of response (DOS) [ Time Frame: 24 months ]
    The duration of response will be measured in subjects associated with Oraxol administered in combination with pembrolizumab in subjects with advanced/metastatic urothelial, gastric/gastro-esophageal, or NSCLC who have stable disease or progressed on previous anti-PD1 or anti-PDL1 therapy

  4. Pharmacokinetics of Oraxol [ Time Frame: Day 1 and day 2 ]
    Plasma concentrations of Oraxol



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Able to understand and sign an informed consent form
  • Age ≥18 years
  • Dose Escalation: Histologically confirmed metastatic or unresectable solid tumors for which pembrolizumab is an FDA-approved therapy
  • Dose Expansion: Histologically confirmed diagnosis of advanced or metastatic urothelial carcinoma, gastric/gastro-esophageal adenocarcinoma or NSCLC. NSCLC patients with EGFR or ALK translocation must have previously progressed on FDA-approved therapy for these aberrations (accounting for PD-1 expression in each histologic subtype)
  • Dose Expansion: Must have stable disease or progressed on previously failed anti-PD1 or anti-PD-L1 therapy
  • Previously progressed on or become intolerant of at least 1 line of systemic chemotherapy for metastatic or advanced disease
  • Must have at least one measurable site of disease as defined as per RECIST v1.1 criteria
  • ECOG Performance Status ≤1
  • Must have adequate hematology, blood chemistry, liver function and renal function.
  • Willing and able to comply with scheduled visits, treatment plan and laboratory tests
  • No concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder
  • Subjects 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.
  • Men who are sterile (including vasectomy confirmed by post vasectomy semen analysis) OR agree to use a condom with spermicide and to not donate sperm during the study and for at least 30 days following last dose of Oraxol
  • Female subjects 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 assigned study treatment. Abstinence is also an acceptable form of contraception.
  • Subjects who are of childbearing potential must have a negative serum pregnancy test at Screening and within 96 hours before Week 1 dosing.
  • Willing to return for follow-up
  • Willing to provide blood samples for correlative research purposes
  • Life expectancy of at least 3 months

Exclusion Criteria:

  • Subjects with history of prior treatment with taxanes (eg, paclitaxel, docetaxel, cabazitaxel) in expansion cohorts only
  • History of prior significant toxicity from anti-PD-1 or anti-PDL1 therapy requiring discontinuation of treatment
  • Subjects who have not recovered from recent anti-cancer therapy received.
  • Current or prior use of immunosuppressive medication within 14 days before the first dose of pembrolizumab.
  • Vaccinated with live, attenuated vaccines within 28 days of the first dose of the study drug
  • Active or prior documented autoimmune or inflammatory disorders. The following are exceptions to this criterion:

    • Subjects with vitiligo or alopecia
    • Subjects with hypothyroidism (eg, following Hashimoto's thyroiditis) stable on hormone replacement therapy or psoriasis not requiring systemic treatment
  • Subject has impairment of GI function or GI disease that may significantly alter the absorption of study drugs (including gastric bypass surgery and total gastrectomy). Subjects with partial gastrectomy may be included in the trial.
  • Uncontrolled concurrent illness.
  • Known or suspected diagnosis of human immunodeficiency virus (HIV) or chronic active Hepatitis B or C, or cirrhosis.
  • Clinically significant pulmonary illness resulting in Grade ≥2 hypoxia.
  • Symptomatic or uncontrolled brain metastases requiring current treatment (less than 28 days from last cranial radiation or 28 days from last steroids use).
  • Impaired cardiac function or clinically significant cardiac disease.
  • Subjects with a healing or open wound
  • Lack of recovery of prior AEs to Grade ≤1 severity (NCI CTCAE v4.03) (except alopecia) due to medications administered prior to the first dose of the trial drugs.
  • Any other condition or finding (including social situation) that in the opinion of the Investigator may render the patient at excessive risk for treatment complications or may not be able provide evaluable outcome information.
  • Pregnant or breast-feeding women
  • Known allergy to any of the formulation components of Oraxol (oral paclitaxel or HM30181A) or

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): NCT03588039


Contacts
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Contact: David Cutler, MD (908) 757-7068 dcutler@athenex.com
Contact: Ildiko Bezi (908) 757-7068 ibezi@athenex.com

Locations
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United States, Arizona
Mayo Clinic Recruiting
Phoenix, Arizona, United States, 85054
Contact: Parminder Singh, MD    480-342-6073    Singh.Parminder@mayo.edu   
Principal Investigator: Parminder Singh, MD         
United States, Florida
Mayo Clinic Recruiting
Jacksonville, Florida, United States, 32224
Contact: Rami Manochakian, MD    904-953-0315    manochakian.rami@mayo.edu   
Principal Investigator: Rami Manochakian, MD         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Wen Wee MA, MD    507-538-0270    Ma.Wen@mayo.edu   
Principal Investigator: Wen Wee Ma, MD         
Sponsors and Collaborators
Athenex, Inc.
Investigators
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Study Director: Alia Jebara, MD Athenex, Inc.

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Responsible Party: Athenex, Inc.
ClinicalTrials.gov Identifier: NCT03588039     History of Changes
Other Study ID Numbers: KX-ORAX-011
First Posted: July 17, 2018    Key Record Dates
Last Update Posted: January 10, 2019
Last Verified: November 2018
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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Paclitaxel
Albumin-Bound Paclitaxel
Pembrolizumab
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological