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出境医 / 临床实验 / Phase I Study of HL-085 in Patients With Advanced Solid Tumors

Phase I Study of HL-085 in Patients With Advanced Solid Tumors

Study Description
Brief Summary:

The study drug, HL-085 is a MEK inhibitor with the potential indication for cancers. It is an oral medication to be given daily.

The purposes of this study is to find answers to the following research questions:

  1. What is the highest tolerable dose of HL-085 that can be given to subjects when given orally (by mouth) on a twice daily basis?
  2. What are the side effects of HL-085?
  3. How much HL-085 is in the blood at specific times after dosing and how does the body get rid of the HL-085?

Condition or disease Intervention/treatment Phase
Solid Tumor, Adult Drug: HL-085 Phase 1

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 4 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I, Single Arm, Dose Escalation Study to Evaluate Safety, Pharmacokinetics and Preliminary Efficacy of HL-085 in Subjects With Advanced Solid Tumors
Actual Study Start Date : June 17, 2019
Actual Primary Completion Date : November 12, 2020
Actual Study Completion Date : November 12, 2020
Arms and Interventions
Arm Intervention/treatment
Experimental: Dose escalation
Subjects in the dose escalation cohorts will receive ascending doses of HL-085 until the MTD is determined. The first three subjects will receive twice-daily doses (BID) of HL-085 6 mg. Additional cohorts may receive doses of HL-085 9, 12 or 18 mg BID respectively and sequentially. If DLTs are observed in <33.3% of subjects at the 18 mg dose.
 Drug: HL-085
HL-085 is a MEK inhibitor with potential indication for cancers. it will be given twice daily continuously in the study until disease progression; or the risks outweigh the benefits, if the subject continues study treatment; or subjects with poor compliance; or subjects need to receive or have already started alternative anti-tumor drugs; or Subjects who need to receive or have already started alternative any other concomitant medication and/or treatment, which would significantly impact their safety; or interruption of IP administration for more than 14 days due to IP-related AEs.
Other Name: No other interventions
Outcome Measures
Primary Outcome Measures :
  1. Adverse events (AEs) [ Time Frame: Duration of the study, estimated to be approximately 24 months. ]
    An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

  2. Dose limitation toxicities (DLT) [ Time Frame: During Cycle 1 (the first 28 days) ]

    A DLT is defined as the occurrence of any of the following AE considered possibly, probably, or definitely related to the IP, HL-085, by the Investigator and/or the Sponsor that occurs during Cycle 1 as described in below:

    • Any death not clearly due to the underlying disease or extraneous causes; or
    • Non-hematologic toxicities Grade 3 or higher.
    • Grade 3 thrombocytopenia with clinically significant bleeding, or other hematologic toxicity at Grade 4 or above.
    • Neutropenic fever
    • liver parameter abnormalities
    • Any toxicity requiring permanent discontinuation of the IP

  3. Maximum tolerated dose (MTD) [ Time Frame: MTD will be determined when DLT occurs in great or equal to 33.3% of the same cohort subjects during During Cycle 1 (the first 28 days) ]
    MTD is defined as the highest dose level at which DLT occurs in less than 33.3% of subjects.


Secondary Outcome Measures :
  1. cMAX [ Time Frame: Duration of the study, estimated to be approximately 24 months ]
    cMAX is the maximum plasma concentration of HL-085 or metabolite(s).

  2. Overall response rate (ORR) [ Time Frame: Duration of the study, estimated to be approximately 24 months ]
    ORR is the proportion of patients with a best overall response of complete response (CR) or partial response (PR), as assessed per response evaluation criteria in solid tumors (RECIST) v1.1.


Other Outcome Measures:
  1. pERK expression [ Time Frame: Duration of the study, estimated to be approximately 24 months ]
    Correlation between phosphorylated extracellular-signal-regulated kinase (pERK) expression and efficacy endpoints.


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

Inclusion Criteria:

  1. Must have a pathologically documented solid tumor(s) that has relapsed from, or is refractory to standard treatment, or for which no standard treatment is available.
  2. Must have at least one measurable lesion as defined by RECISTv1.1 criteria for solid tumors.
  3. Must have received biological chemotherapy, immunotherapy or radiotherapy ≥4 weeks prior to starting the study treatment. Must have received small molecule chemotherapy ≥2 weeks or five half-lives (whichever is longer) prior to starting the study treatment.
  4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
  5. Life expectancy ≥3 months (as judged by the Investigator).
  6. Must have adequate hematologic, hepatic and renal function.

Exclusion Criteria:

  1. Have undergone or plan to have major surgery or experienced severe trauma ≤28 days prior to starting the study treatment.
  2. Known hypersensitivity to IP ingredients or their analogues.
  3. Prior therapy with a MEK-inhibitor
  4. Receipt of any other investigational agent therapy within 4 weeks prior to starting study treatment.
  5. Any concurrent therapy for cancer treatment.
  6. Have active central nervous system lesion.
  7. Receiving and unable to discontinue medication which are strong inducers, strong inhibitors or enzyme substrates of cytochrome P450 CYP2C9 and CYP2C19 from 14 days prior to treatment.
  8. Grade 3 bleeding symptoms (NCI-CTCAE v5.0) within 4 weeks prior to starting study treatment.
  9. Unable to swallow IP or has refractory nausea and vomiting, malabsorption, external biliary diversion, or any significant small bowel resection that may interfere with adequate absorption of IP.
  10. ECG QTcB≥480msec in screening, or history of congenital long QT syndrome.
  11. Left ventricular ejection fraction (LVEF) <50%.
  12. History major cerebrovascular diseases within 6 months prior to enrollment.
  13. Infectious diseases requiring systemic treatment.
  14. History or current evidence of retinal diseases.
  15. Have active/chronic infection with hepatitis C, or positive hepatitis B surface antigen (HBsAg), or active/chronic infection with human immunodeficiency virus (HIV).
  16. Known active tuberculosis.
  17. History of allogeneic bone marrow transplantation or organ transplantation.
  18. Interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis.
  19. Pregnant or breast-feeding females.
  20. Previous or history of second malignancy within 5 years prior to study treatment
  21. Other conditions which may increase the risk associated with study participation, or interfere with the evaluation of study results.
Contacts and Locations

Locations
Layout table for location information
United States, Texas
Livestrong Cancer Institute, Dell Medical School, The University of Texas at Austin
Austin, Texas, United States, 78712
Next Oncology
San Antonio, Texas, United States, 78229
Sponsors and Collaborators
Shanghai Kechow Pharma, Inc.
Investigators
Layout table for investigator information
Study Director: Yi Liu, MD, PhD KeChow Pharma
Tracking Information
First Submitted Date  ICMJE June 2, 2019
First Posted Date  ICMJE June 5, 2019
Last Update Posted Date November 18, 2020
Actual Study Start Date  ICMJE June 17, 2019
Actual Primary Completion Date November 12, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 4, 2019)
  • Adverse events (AEs) [ Time Frame: Duration of the study, estimated to be approximately 24 months. ]
    An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
  • Dose limitation toxicities (DLT) [ Time Frame: During Cycle 1 (the first 28 days) ]
    A DLT is defined as the occurrence of any of the following AE considered possibly, probably, or definitely related to the IP, HL-085, by the Investigator and/or the Sponsor that occurs during Cycle 1 as described in below:
    • Any death not clearly due to the underlying disease or extraneous causes; or
    • Non-hematologic toxicities Grade 3 or higher.
    • Grade 3 thrombocytopenia with clinically significant bleeding, or other hematologic toxicity at Grade 4 or above.
    • Neutropenic fever
    • liver parameter abnormalities
    • Any toxicity requiring permanent discontinuation of the IP
  • Maximum tolerated dose (MTD) [ Time Frame: MTD will be determined when DLT occurs in great or equal to 33.3% of the same cohort subjects during During Cycle 1 (the first 28 days) ]
    MTD is defined as the highest dose level at which DLT occurs in less than 33.3% of subjects.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 4, 2019)
  • cMAX [ Time Frame: Duration of the study, estimated to be approximately 24 months ]
    cMAX is the maximum plasma concentration of HL-085 or metabolite(s).
  • Overall response rate (ORR) [ Time Frame: Duration of the study, estimated to be approximately 24 months ]
    ORR is the proportion of patients with a best overall response of complete response (CR) or partial response (PR), as assessed per response evaluation criteria in solid tumors (RECIST) v1.1.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: June 4, 2019) 		pERK expression [ Time Frame: Duration of the study, estimated to be approximately 24 months ]
Correlation between phosphorylated extracellular-signal-regulated kinase (pERK) expression and efficacy endpoints.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Phase I Study of HL-085 in Patients With Advanced Solid Tumors
Official Title  ICMJE A Phase I, Single Arm, Dose Escalation Study to Evaluate Safety, Pharmacokinetics and Preliminary Efficacy of HL-085 in Subjects With Advanced Solid Tumors
Brief Summary

The study drug, HL-085 is a MEK inhibitor with the potential indication for cancers. It is an oral medication to be given daily.

The purposes of this study is to find answers to the following research questions:

  1. What is the highest tolerable dose of HL-085 that can be given to subjects when given orally (by mouth) on a twice daily basis?
  2. What are the side effects of HL-085?
  3. How much HL-085 is in the blood at specific times after dosing and how does the body get rid of the HL-085?
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Solid Tumor, Adult
Intervention  ICMJE Drug: HL-085
HL-085 is a MEK inhibitor with potential indication for cancers. it will be given twice daily continuously in the study until disease progression; or the risks outweigh the benefits, if the subject continues study treatment; or subjects with poor compliance; or subjects need to receive or have already started alternative anti-tumor drugs; or Subjects who need to receive or have already started alternative any other concomitant medication and/or treatment, which would significantly impact their safety; or interruption of IP administration for more than 14 days due to IP-related AEs.
Other Name: No other interventions
Study Arms  ICMJE Experimental: Dose escalation
Subjects in the dose escalation cohorts will receive ascending doses of HL-085 until the MTD is determined. The first three subjects will receive twice-daily doses (BID) of HL-085 6 mg. Additional cohorts may receive doses of HL-085 9, 12 or 18 mg BID respectively and sequentially. If DLTs are observed in <33.3% of subjects at the 18 mg dose.
Intervention: Drug: HL-085
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: November 16, 2020) 		4
Original Estimated Enrollment  ICMJE
 (submitted: June 4, 2019) 		24
Actual Study Completion Date  ICMJE November 12, 2020
Actual Primary Completion Date November 12, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Must have a pathologically documented solid tumor(s) that has relapsed from, or is refractory to standard treatment, or for which no standard treatment is available.
  2. Must have at least one measurable lesion as defined by RECISTv1.1 criteria for solid tumors.
  3. Must have received biological chemotherapy, immunotherapy or radiotherapy ≥4 weeks prior to starting the study treatment. Must have received small molecule chemotherapy ≥2 weeks or five half-lives (whichever is longer) prior to starting the study treatment.
  4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
  5. Life expectancy ≥3 months (as judged by the Investigator).
  6. Must have adequate hematologic, hepatic and renal function.

Exclusion Criteria:

  1. Have undergone or plan to have major surgery or experienced severe trauma ≤28 days prior to starting the study treatment.
  2. Known hypersensitivity to IP ingredients or their analogues.
  3. Prior therapy with a MEK-inhibitor
  4. Receipt of any other investigational agent therapy within 4 weeks prior to starting study treatment.
  5. Any concurrent therapy for cancer treatment.
  6. Have active central nervous system lesion.
  7. Receiving and unable to discontinue medication which are strong inducers, strong inhibitors or enzyme substrates of cytochrome P450 CYP2C9 and CYP2C19 from 14 days prior to treatment.
  8. Grade 3 bleeding symptoms (NCI-CTCAE v5.0) within 4 weeks prior to starting study treatment.
  9. Unable to swallow IP or has refractory nausea and vomiting, malabsorption, external biliary diversion, or any significant small bowel resection that may interfere with adequate absorption of IP.
  10. ECG QTcB≥480msec in screening, or history of congenital long QT syndrome.
  11. Left ventricular ejection fraction (LVEF) <50%.
  12. History major cerebrovascular diseases within 6 months prior to enrollment.
  13. Infectious diseases requiring systemic treatment.
  14. History or current evidence of retinal diseases.
  15. Have active/chronic infection with hepatitis C, or positive hepatitis B surface antigen (HBsAg), or active/chronic infection with human immunodeficiency virus (HIV).
  16. Known active tuberculosis.
  17. History of allogeneic bone marrow transplantation or organ transplantation.
  18. Interstitial lung disease or interstitial pneumonitis, including clinically significant radiation pneumonitis.
  19. Pregnant or breast-feeding females.
  20. Previous or history of second malignancy within 5 years prior to study treatment
  21. Other conditions which may increase the risk associated with study participation, or interfere with the evaluation of study results.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03976050
Other Study ID Numbers  ICMJE HL-085-US-101
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Shanghai Kechow Pharma, Inc.
Study Sponsor  ICMJE Shanghai Kechow Pharma, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Yi Liu, MD, PhD KeChow Pharma
PRS Account Shanghai Kechow Pharma, Inc.
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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