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

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03284502
Recruitment Status : Recruiting
First Posted : September 15, 2017
Last Update Posted : August 11, 2020
Sponsor:
Information provided by (Responsible Party):
Hanmi Pharmaceutical Company Limited

Brief Summary:
This study evaluates the safety, tolerability and pharmacokinetics of cobimetinib and HM95573 in patient with locally advanced or metastatic solid tumors.

Condition or disease Intervention/treatment Phase
Locally Advanced Solid Tumor Metastatic Solid Tumor Drug: HM95573, cobimetinib Phase 1

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 RD will be investigated in indication specific expansion cohorts.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 109 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : May 22, 2017
Estimated Primary Completion Date : September 30, 2023
Estimated Study Completion Date : December 31, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Cobimetinib

Arm Intervention/treatment
Experimental: Stage 1
Dose escalation
Drug: HM95573, cobimetinib
Drug: HM95573, cobimetinib Regimen: twice daily (BID), continuous dosing for HM95573, once daily (QD) 21 days, 7 days off for cobimetinib

Experimental: Stage 2
Expansion
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 RD and schedule will be selected for Stage 2.




Primary Outcome Measures :
  1. 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 ]
  2. Number of patients with DLT of cobimetinib and HM95573 [ Time Frame: 28 days ]
  3. Number of patients with MTD of cobimetinib and HM95573 [ Time Frame: End of Stage 1, an approximately 2 years ]
  4. Recommended Phase II dose (RPIID) of cobimetinib and HM95573 [ Time Frame: End of Stage 1, an approximately 2 years ]

Secondary Outcome Measures :
  1. Area Under the Concentration-Time Curve (AUC) of cobimetinib and HM95573 [ Time Frame: Cycle1 Day1, Cycle1 Day15, Cycle1 Day21, Cycle2 Day1, Cycle3 Day1, Study completion, an approximately 2 years ]
  2. Maximum Serum Concentration (Cmax) of cobimetinib and HM95573 [ Time Frame: Cycle1 Day1, Cycle1 Day15, Cycle1 Day21, Cycle2 Day1, Cycle3 Day1, Study completion, an approximately 2 years ]
  3. Time to maximum concentration (Tmax) of cobimetinib and HM95573 [ Time Frame: Cycle1 Day1, Cycle1 Day15, Cycle1 Day21, Cycle2 Day1, Cycle3 Day1, Study completion, an approximately 2 years ]
  4. FDG-PET and molecular biomarkers assessed in pre and post treatment tumor tissues [ Time Frame: Screening, Cycle1 Day15 ]
  5. 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 ]


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Ages Eligible for Study:   19 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

[Inclusion criteria]

  1. Signed Informed Consent Form
  2. Age ≥ 19 years at time of signing Informed Consent Form
  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. Measurable disease 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 X ULN

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

    1. Patients with documented liver metastases: AST and/or ALT ≤ 5 X ULN
    2. Patients with documented liver or bone metastases: ALP ≤ 5 X ULN Serum creatinine ≤ 1.5 X ULN, or creatinine clearance ≥ 50 mL/min on the basis of the Cockroft-Gault glomerular filtration rate estimation PT/INR and PTT ≤ 1.5 X ULN
  8. For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use one highly effective form (defined as a failure rate of less than 1% per year) of contraception (e.g., surgical sterilization, birth control pills, or contraceptive hormone implants) and to continue use for the duration of the study. Additionally, female patients of childbearing potential should use pregnancy prevention measures for a minimum of 3 months following discontinuation of cobimetinib and HM95573. Male patients with partners of childbearing potential should use pregnancy prevention measures for 3 months following discontinuation of cobimetinib and HM95573.
  9. For male patients: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below:

    For men with female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for 3 months after the last dose of cobimetinib and HM95573 to avoid exposing the embryo. Men must refrain from donating sperm during this same period.

    The length of time that pregnancy preventative measures are used following discontinuation of drug may be adjusted based on the human pharmacokinetics.

  10. 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 including, but not limited to, KRAS, NRAS, BRAF, and PI3K mutational status, as well as PI3K amplification, PTEN, RB1.
  11. FDG-PET avid disease on baseline scan.

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

  12. No more than five prior systemic therapies for locally advanced or metastatic cancer
  13. For the expansion cohorts (except basket cohort in expansion cohort I, II): No prior therapy with a RAF, MEK or ERK inhibitor. No prior treatment with regorafenib in the CRC (KRAS G13D- and BRAF V600- mutant) expansion cohort II. No prior therapy with HM95573 or cobimetinib in the expansion cohort II.
  14. Current cancer must be one of the following:

    1. Expansion cohort I (HM95573 200 mg BID + cobimetinib 20 mg QD):

      • KRAS-mutant NSCLC
      • KRAS-mutant Pancreatic adenocarcinoma
      • RAS-mutant CRC
      • RAS- or RAF-mutant solid tumors (basket cohort; excludes KRAS-mutant NSCLC, KRAS-mutant pancreatic adenocarcinoma, and RAS-mutant CRC). A minimum of 10 melanoma patients will be enrolled.
    2. Expansion cohort II (HM95573 300 mg BID + cobimetinib 20 mg QOD (3 times a week: day 1, 3, 5, 8, 10, 12, 15, 17, 19 of 28 day cycle)):

      • KRAS G13D- mutant CRC
      • BRAF V600- mutant CRC
      • NRAS-mutant Melanoma
      • RAS- or RAF-mutant solid tumors (basket cohort: A minimum of 10 BRAF V600 melanoma will be enrolled)
      • BRAF Class II-mutant (including BRAF fusions) or Class III-mutant solid tumors
  15. At least one target lesion on CT must also be an FDG-PET avid region of interest which has a target-to-organ-background SUVmax (or similar radioactivity concentration measure) ratio of ≥ 2.0 and at least 15mm in longest diameter.
  16. Consent to undergo pre- and post-treatment tumor biopsies for PD biomarker analysis is optional, provided sites of disease are easily and safely accessible. In the absence of easily and safely accessible sites of disease, patients may enroll without consenting to tumor biopsies (Stage 2).

[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:

    1. Grade ≥ 2 or symptomatic hyperglycemia (fasting)
    2. 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. 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. (upon discussion with the Medical Monitor, fewer than stated wash-out period may be allowed provided that the patient has adequately recovered from any clinically relevant toxicity).
  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 New York Heart Association class III or IV 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

    a. Patients with a history of adequately treated brain metastases are eligible. Adequately treated brain metastases are defined as those having no ongoing requirement for medical therapy to control symptoms, and no evidence of progression or hemorrhage for ≥ 2 months after radiation treatment (such as whole brain radiotherapy or radiosurgery [Gamma Knife, linear accelerator, or equivalent]) and/or ≥ 3 months after surgical treatment, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or CT scan) during the screening period. Any medical therapy for brain metastases (e.g., steroids or seizure medications) must have been discontinued without the subsequent appearance of symptoms for ≥ 4 weeks before the first dose of study-drug treatment in Cycle 1.

  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 pharmacodynamics (PD) or efficacy assays
  28. Need to take a concomitant medication, dietary supplement, or food that is prohibited during the study

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): NCT03284502


Locations
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Korea, Republic of
National Cancer Center Recruiting
Goyang-si, Gyeonggi-do, Korea, Republic of, 10408
Contact: Moon Ki Choi, PI    02319201737    choi.moonki@ncc.re.kr   
Seoul National University Bundang Hospital Recruiting
Seongnam, Gyeonggi-do, Korea, Republic of, 13620
Contact: Yu Jung Kim, PI    0317877041    cong1005@gmail.com   
Chonnam National University Hwasun Hospital Recruiting
Hwasun, Jeollanam-do, Korea, Republic of, 58128
Contact: Sang-Hee Cho, PI    01094209735    shcho@jnu.ac.kr   
Dong-A University Hospital Recruiting
Pusan, Korea, Republic of, 49201
Contact: Sung Yong Oh, PI    0512402808    drosy@dau.ac.kr   
Seoul National University Hospital Recruiting
Seoul, Korea, Republic of, 03080
Contact: Tae Min Kim, PI    0220723559    gabriel9@snu.ac.kr   
Yonsei University Health System Severance Hospital Recruiting
Seoul, Korea, Republic of, 03722
Contact: Sang Joon Shin, PI    0222288138    ssj338@yuhs.ac   
Asan Medical Center Recruiting
Seoul, Korea, Republic of, 05505
Contact: Tae Won Kim, PI    0230103910    twkimmd@amc.seoul.kr   
Samsung Medical Center Recruiting
Seoul, Korea, Republic of, 06351
Contact: Jeeyun Lee, PI    0234101779    jyun.lee@samsung.com   
Seoul National University Borame Hospital Recruiting
Seoul, Korea, Republic of, 07061
Contact: Jin Soo Kim, PI    0228703202    gistmd@gmail.com   
Sponsors and Collaborators
Hanmi Pharmaceutical Company Limited
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Responsible Party: Hanmi Pharmaceutical Company Limited
ClinicalTrials.gov Identifier: NCT03284502    
Other Study ID Numbers: HM-RAFI-103
First Posted: September 15, 2017    Key Record Dates
Last Update Posted: August 11, 2020
Last Verified: August 2020

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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
Keywords provided by Hanmi Pharmaceutical Company Limited:
Belvarafenib
HM95573
GDC-5573
RG6185
Cobimetinib
Additional relevant MeSH terms:
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Neoplasms