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Cobimetinib and HM95573 in Patients With Locally Advanced or Metastatic Solid Tumors

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ClinicalTrials.gov Identifier: NCT03284502
Recruitment Status : Recruiting
First Posted : September 15, 2017
Last Update Posted : September 15, 2017
Sponsor:
Information provided by (Responsible Party):
Hanmi Pharmaceutical Company Limited

Tracking Information
First Submitted Date  ICMJE August 7, 2017
First Posted Date  ICMJE September 15, 2017
Last Update Posted Date September 15, 2017
Actual Study Start Date  ICMJE May 22, 2017
Estimated Primary Completion Date June 30, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 13, 2017)
  • Percentage of patients with Adverse Events, Serious Adverse Events and Adverse Events of Special Interest as assessed by CTCAE v4.0 [ Time Frame: up to approximately 3 years ]
  • Number of patients with DLT of cobimetinib and HM95573 [ Time Frame: 28 days ]
  • Number of patients with MTD of cobimetinib and HM95573 [ Time Frame: End of Stage 1, an approximately 2 years ]
  • Recommended Phase II dose (RPIID) of cobimetinib and HM95573 [ Time Frame: End of Stage 1, an approximately 2 years ]
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: September 13, 2017)
  • Area Under the Concentration-Time Curve (AUC) of cobimetinib and HM95573 [ Time Frame: Cycle1 Day1, Cycle1 Day15, Cycle1 Day21, Cycle2 Day1, Cycle3 Day2, Study completion, an approximately 2 years ]
  • Maximum Serum Concentration (Cmax) of cobimetinib and HM95573 [ Time Frame: Cycle1 Day1, Cycle1 Day15, Cycle1 Day21, Cycle2 Day1, Cycle3 Day2, Study completion, an approximately 2 years ]
  • Time to maximum concentration (Tmax) of cobimetinib and HM95573 [ Time Frame: Cycle1 Day1, Cycle1 Day15, Cycle1 Day21, Cycle2 Day1, Cycle3 Day2, Study completion, an approximately 2 years ]
  • FDG-PET and molecular biomarkers assessed in pre and post treatment tumor tissues [ Time Frame: Screening, Cycle1 Day15 ]
  • Preliminary assessment of the anti tumor activity of cobimetinib and HM95573 combination measured by RECIST v1.1. [ Time Frame: Screening, During Days 22-28 (Day 25 ± 3 days) in Cycle 2 and 4, and then every 8 weeks (±7 days), until disease progression, assessed approximately 3 years ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Cobimetinib and HM95573 in Patients With Locally Advanced or Metastatic Solid Tumors
Official Title  ICMJE A Phase Ib, Open-label, Multicenter, Dose Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Cobimetinib and HM95573 in Patients With Locally Advanced or Metastatic Solid Tumors
Brief Summary This study evaluates the safety, tolerability and pharmacokinetics of cobimetinib and HM95573 in patient with locally advanced or metastatic solid tumors.
Detailed Description

This is a Phase Ib, open label, multicenter dose escalation study designed to assess the safety, tolerability, and pharmacokinetics of oral dosing of cobimetinib and HM95573 administered in combination in patients with histologically/cytologically confirmed, locally advanced, or metastatic solid tumors with RAS- or RAF-mutation for which standard therapies either do not exist or have proven ineffective or intolerable. Treatment will continue until disease progression, unacceptable toxicity, or any other discontinuation criterion is met.

There are two stages of this study: Stage 1, a standard 3+3 dose escalation, and Stage 2, an indication specific dose expansion. Stage 1 is designed to establish the combination MTD for cobimetinib and HM95573. To acquire additional safety and PD data to more fully inform dose selection, up to six additional patients may be enrolled to backfill cohorts at dose levels that have been shown to not exceed the MTD.In Stage 2, the potential RP2D will be investigated in five indication specific expansion cohorts.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Locally Advanced Solid Tumor
  • Metastatic Solid Tumor
Intervention  ICMJE
  • Drug: HM95573, cobimetinib
    Drug: HM95573, cobimetinib Regimen: twice daily (BID), continuous dosing for HM95573, once daily (QD) 21 days, 7 days off for cobimetinib
  • Drug: HM95573, cobimetinib
    Drug: HM95573, cobimetinib based on the data for safety, tolerability, pharmacokinetics, and anti-tumor activity from the dosing schedules tested in Stage1, a potential RP2D and schedule will be selected for Stage 2.
Study Arms  ICMJE
  • Experimental: Stage 1
    Dose escalation
    Intervention: Drug: HM95573, cobimetinib
  • Experimental: Stage 2
    Expansion
    Intervention: Drug: HM95573, cobimetinib
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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 13, 2017)
272
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2020
Estimated Primary Completion Date June 30, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Signed Informed Consent Form
  2. Age ≥ 19 years
  3. ECOG performance status of 0 or 1
  4. Histologically or cytologically documented, locally advanced or metastatic solid tumors with RAS- or RAF-mutation for which standard therapy either does not exist or has proven ineffective or intolerable
  5. Evaluable disease or disease measurable per RECIST v1.1
  6. Life expectancy ≥ 12 weeks
  7. Adequate hematologic and end organ function, defined by the following laboratory results obtained within 2 weeks prior to the first dose of study-drug treatment:

    Absolute neutrophil count ≥1,500/uL Platelet count ≥ 100,000/uL Hemoglobin ≥ 9.0 g/dL Albumin ≥ 2.5 g/dL Total bilirubin ≤ 1.5 xULN

    AST or ALT ≤ 3 xULN, ALP ≤2.5 xULN, with the following exceptions:

    • Patients with documented liver metastases: AST and/or ALT ≤ 5 x ULN
    • Patients with documented liver or bone metastases: ALP ≤ 5 xULN Serum creatinine ≤ 1.5 x ULN, or creatinine clearance ≥ 50 mL/min on the basis of the Cockcroft−Gault glomerular filtration rate estimation PT/INR and PTT ≤1.5 x ULN
  8. Consent to provide archival tissue (either a paraffin-embedded tissue block or unstained slides) for testing with the FoundationOne panel to assess and confirm genetic alterations
  9. FDG-PET avid disease on baseline scan. FDG avid disease is defined as the presence of at least one PET target lesion, at least 15 mm in longest diameter, that also fulfills criteria for a RECIST target lesion, and has a target-to-organ-background SUVmax (or similar radioactivity concentration measure) ratio of ≥ 2.0.

    Patients who are considered for enrollment into the cohort expansion (Stage 2) must meet all of the following additional eligibility criteria:

  10. Measurable disease, according to RECIST v1.1 criteria
  11. At least one target lesion on CT must also be an FDG-PET avid region of interest.
  12. Consent to undergo pre- and post-treatment tumor biopsies for PD biomarker analysis is mandatory, provided sites of disease are easily and safely accessible. In the absence of easily and safely accessible sites of disease, consent to undergo tumor biopsies is not required.

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from study entry:

  1. History of prior significant toxicity from another RAF, MEK, or ERK inhibitor requiring discontinuation of treatment
  2. History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for central serous retinopathy, retinal vein occlusion (RVO), or neovascular macular degeneration. Patients will be excluded from study participation if they currently are known to have any of the following risk factors for RVO:

    • Glaucoma with intraocular pressure ≥ 21 mmHg
    • Grade ≥ 2 serum cholesterol
    • Grade ≥ 2 hypertriglyceridemia
    • Grade ≥ 2 or symptomatic hyperglycemia (fasting)
    • Grade ≥ 2 uncontrolled hypertension (patients with a history of hypertension controlled with anti-hypertensive medication to Grade ≥ 1 are eligible)
  3. History of glaucoma
  4. Allergy or hypersensitivity to components of the cobimetinib or HM95573 formulation
  5. Palliative radiotherapy within 2 weeks prior to first dose of study-drug treatment in Cycle 1
  6. Experimental therapy within 4 weeks prior to first dose of study-drug treatment in Cycle 1
  7. Major surgical procedure or significant traumatic injury within 4 weeks prior to the first dose of study-drug treatment in Cycle 1, or anticipation of the need for major surgery during the course of study treatment
  8. Anti-cancer therapy within 28 days prior to the first dose of study-drug treatment in Cycle 1 (upon discussion with the Medical Monitor, fewer than 28 days for washout may be allowed provided that the patient has adequately recovered from any clinically relevant toxicity). Exceptions include a washout period of at least five half-lives for anti-PD1 or anti-PDL1 antibodies and ipilimumab during Stage I dose escalation and at least three half-lives for anti-PD1 or anti-PDL1 antibodies and ipilimumab during Stage II expansion phase, a washout of 6 weeks for nitrosoureas or mitomycin C, or 14 days for hormonal therapy or kinase inhibitors.
  9. Current Grade > 1 toxicity (except alopecia and anorexia) from prior therapy or Grade > 1 neuropathy from any cause
  10. Current severe, uncontrolled systemic disease (including, but not limited to, clinically significant cardiovascular, pulmonary, or renal disease, ongoing or active infection)
  11. History of clinically significant cardiac dysfunction, including the following:

    Current uncontrolled Grade ≥ 2 hypertension or unstable angina

  12. History of symptomatic congestive heart failure of any New York Heart Association class or serious cardiac arrhythmia requiring treatment, with the exceptions of atrial fibrillation and paroxysmal supraventricular tachycardia
  13. History of myocardial infarction within 6 months prior to the first dose of study-drug treatment in Cycle 1
  14. History of bradyarrhythmias, bradycardia or heart block or baseline HR < 55bpm
  15. History of congenital long QT syndrome or QTcF > 440 msec
  16. LVEF (as measured by echocardiography [ECHO] or multiple-gated acquisition scan [MUGA]) < 50% or below the lower limit of normal (LLN; whichever is lower)
  17. Inability or unwillingness to swallow pills
  18. History of malabsorption or other condition that would interfere with enteral absorption
  19. Clinically significant history of liver disease (including cirrhosis), current alcohol abuse, or current known active infection with HIV, hepatitis B virus, or hepatitis C virus
  20. Any hemorrhage or bleeding event CTCAE Grade 3 or higher within 28 days of Cycle 1, Day 1
  21. Patients receiving therapeutic anticoagulation or thrombolytic anticoagulants. Use of low molecular weight heparin and low dose aspirin are allowed.
  22. Active autoimmune disease
  23. Uncontrolled ascites requiring weekly large volume paracentesis for 3 consecutive weeks prior to enrollment
  24. Pregnancy, lactation, or breastfeeding
  25. Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms
  26. Inability to comply with study and follow-up procedures
  27. No other history of or ongoing malignancy that would potentially interfere with the interpretation of the PD or efficacy assays
  28. Need to take a concomitant medication, dietary supplement, or food that is prohibited during the study
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 19 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE Korea, Republic of
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03284502
Other Study ID Numbers  ICMJE HM-RAFI-103
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Hanmi Pharmaceutical Company Limited
Study Sponsor  ICMJE Hanmi Pharmaceutical Company Limited
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Hanmi Pharmaceutical Company Limited
Verification Date August 2017

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