HM95573 in Combination With Either Cobimetinib or Cetuximab in Patients With Locally Advanced or Metastatic Solid Tumors

NCT03284502 | Unknown Phase 1

• 1 other identifier: HM-RAFI-103
• Study Type: interventional
• Target: 148
• Locations: 1 country
• Sites: 9

Brief Summary

This study evaluates the safety, tolerability and pharmacokinetics of HM95573 In combination with either cobimetinib or cetuximab in patients with locally advanced or metastatic solid tumors.

Conditions

Locally Advanced Solid Tumor; Metastatic Solid Tumor

Keywords

Belvarafenib; HM95573; GDC-5573; RG6185; Cobimetinib; Cetuximab

Outcome Measures

Primary Outcomes (4)

• Percentage of patients with Adverse Events, Serious Adverse Events, and Adverse Events of Special Interest as assessed by CTCAE v4.03

  up to approximately 3 years

• Number of patients with DLTs

  28 days

• MTDs of HM95573 and cobimetinib, or HM95573 and cetuximab

  End of Stage 1, an approximately 2 years

• Recommended Phase II dose (RPIID) of HM95573 and cobimetinib, or HM95573 and cetuximab

  End of Stage 1, an approximately 2 years

Secondary Outcomes (5)

• Area Under the Concentration-Time Curve (AUC) of HM95573 and cobimetinib, or HM95573 and cetuximab

  Cycle1 Day1, Cycle1 Day15, Cycle1 Day21, Cycle2 Day1, Cycle3 Day1, Study completion, an approximately 2 years

• Maximum Serum Concentration (Cmax) of HM95573 and cobimetinib, or HM95573 and cetuximab

  Cycle1 Day1, Cycle1 Day15, Cycle1 Day21, Cycle2 Day1, Cycle3 Day1, Study completion, an approximately 2 years

• Time to maximum concentration (Tmax) of HM95573 and cobimetinib, or HM95573 and cetuximab

  Cycle1 Day1, Cycle1 Day15, Cycle1 Day21, Cycle2 Day1, Cycle3 Day1, Study completion, an approximately 2 years

• FDG-PET and molecular biomarkers assessed in pre- and post-treatment tumor tissues

  Screening, Cycle1 Day15

• Preliminary assessment of the antitumor activity of HM95573 and cobimetinib, or HM95573 and cetuximab measured by RECIST v1.1.

  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

Study Arms (4)

Stage 1

EXPERIMENTAL

Dose-escalation

Drug: HM95573, cobimetinib

Stage 1b

EXPERIMENTAL

Dose-escalation

Drug: HM95573, cetuximab

Stage 2 (Cohort I and II)

EXPERIMENTAL

Dose-expansion

Drug: HM95573, cobimetinib

Stage 2 (Cohort III)

EXPERIMENTAL

Dose-expansion

Drug: HM95573, cetuximab

Interventions

HM95573, cobimetinib DRUG

Regimen: twice daily (BID), continuous dosing for HM95573, once daily (QD) 21 days, 7 days off for cobimetinib

Stage 1

HM95573, cetuximab DRUG

Regimen: twice daily (BID), continuous dosing for HM95573

Stage 1b

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Signed Informed Consent Form
• Age ≥ 19 years at time of signing Informed Consent Form
• ECOG performance status of 0 or 1
• 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
• Measurable disease per RECIST v1.1
• Life expectancy ≥ 12 weeks
• 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/μL Platelet count ≥ 100,000/μL Hemoglobin ≥ 9.0 g/dL (this criterion has to be met without transfusion within 2 weeks prior to laboratory test) Albumin ≥ 2.5 g/dL Total bilirubin ≤ 1.5 × ULN AST or ALT ≤ 3 × ULN, ALP ≤ 2.5 × ULN, with the following exceptions:
• Patients with documented liver metastases: AST and/or ALT ≤ 5 × ULN
• Patients with documented liver or bone metastases:
• ALP ≤ 5 × ULN Serum creatinine ≤ 1.5 × ULN, or creatinine clearance ≥ 50 mL/min on the basis of the Cockroft-Gault glomerular filtration rate estimation PT/INR and PTT ≤ 1.5 × ULN
• 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 HM95573 in combination with either cobimetinib or cetuximab.
• 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 HM95573 in combination with either cobimetinib or cetuximab 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.
• 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, EGFR and PI3K mutational status.
• 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:
• No more than five prior systemic therapies for locally advanced or metastatic cancer

You may not qualify if:

• Patients who meet any of the following criteria will be excluded from study entry:
• History of prior significant toxicity from another RAF, MEK, ERK, or EGFR inhibitor requiring discontinuation of treatment
• 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:
• 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)
• History of glaucoma
• Allergy or hypersensitivity to components of the cobimetinib, cetuximab or HM95573 formulation
• Palliative radiotherapy within 2 weeks prior to first dose of study-drug treatment in Cycle 1
• Experimental therapy within 4 weeks prior to first dose of study-drug treatment in Cycle 1
• 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
• 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 halflives 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).
• Current Grade \> 1 toxicity (except alopecia and anorexia) from prior therapy or Grade \> 1 neuropathy from any cause
• Current severe, uncontrolled systemic disease (including, but not limited to, clinically significant cardiovascular, pulmonary, or renal disease, ongoing or active infection)
• History of clinically significant cardiac dysfunction, including the following: Current uncontrolled Grade ≥ 2 hypertension or unstable angina
• 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

Sponsors & Collaborators

• Hanmi Pharmaceutical Company Limited: lead

Study Sites (9)

National Cancer Center

Goyang-si, Gyeonggi-do, 10408, South Korea

Location

Seoul National University Bundang Hospital

Seongnam-si, Gyeonggi-do, 13620, South Korea

Location

Chonnam National University Hwasun Hospital

Hwasun, Jeollanam-do, 58128, South Korea

Location

Dong-A University Hospital

Pusan, 49201, South Korea

Location

Seoul National University Hospital

Seoul, 03080, South Korea

Location

Yonsei University Health System Severance Hospital

Seoul, 03722, South Korea

Location

Asan Medical Center

Seoul, 05505, South Korea

Location

Samsung Medical Center

Seoul, 06351, South Korea

Location

Seoul National University Borame Hospital

Seoul, 07061, South Korea

Location

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

cobimetinib; Cetuximab

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 7, 2017
• First Posted: September 15, 2017
• Study Start: May 22, 2017
• Primary Completion: September 30, 2024
• Study Completion: December 31, 2024
• Last Updated: August 1, 2023

Record last verified: 2023-07

Locations

KR (9)