Clinical trial NCT05354843: SHP2 Inhibitor ET0038 Monotherapy in Patients With Advanced Solid Tumors
Official title: A Phase I, Open-Label, Multi-Center Dose Finding Study to Investigate the Safety, Pharmacokinetics, and Preliminary Efficacy of SHP2 Inhibitor ET0038 Monotherapy in Patients With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Advanced Solid Tumor
Lead sponsor: Etern BioPharma (Shanghai) Co., Ltd
Sponsor class: INDUSTRY
First posted: 2022-04-29
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: Anticipated ET0038 Dose Escalation Schedule Cohort ET0038 dose at each treatment administration point

1. SDL = 10 mg QD 2 .SDL × 2 = 20 mg QD 3. SDL × 4 = 40 mg QD 4 .SDL × 6 = 60 mg QD 5 .SDL × 8 = 80 mg QD Maximum Dose Level Abbreviations: QD=once a day; SDL=Starting Dose Level
Primary purpose: TREATMENT

Brief summary: This is a Phase I, open-label, multi-center, dose-finding study to assess the safety, pharmacokinetics, and preliminary efficacy of ET0038 in patients with advanced solid tumors. It is anticipated that approximately 37 subjects will be enrolled in the dose-escalation phase of the study. ET0038 will be administered orally once daily (QD) in 21-day treatment cycles.

Detailed description: This is an open-label, multicenter, Phase 1 study of oral ET0038 monotherapy in participants with advanced solid tumors. The study will include 2 components: 1) a Dose-Escalation Component for participants with advanced solid tumors and 2) a Dose-Expansion Component for participants with advanced solid tumors harboring certain specific mutations/rearrangements that result in hyperactivation of the RAS-MAPK pathway. Participants will be treated until disease progression per RECIST v1.1, unacceptable toxicity, or other criteria for withdrawal are met, whichever occurs first.

Eligibility criteria: Inclusion Criteria:

1. Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses.
2. Aged at least 18 years at the time of ICF signature.
3. Histological or cytological confirmation of a solid tumor and have progressed despite standard therapy(ies), or are intolerant to standard therapy (ies), or have a tumor for which no standard therapy(ies) exists. Locally recurrent disease must not be amenable to surgical resection or radiotherapy with curative intent (patients who are considered suitable for surgical or ablative techniques following down-staging with study treatment are not eligible).
4. Estimated life expectancy of minimum of 12 weeks.
5. Patient with solid tumors must have at least 1 lesion, not previously irradiated, that can be accurately measured at pre-dose as ≥ 10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with Computerised Tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for accurate repeated measurements.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 at ICF signature.
7. Males and Females of child-bearing potential must agree to use effective contraception from the time ICF signature until 12 weeks after the last dose. Females of childbearing potential include those who are premenopausal and those who are 2 years postmenopausal. Pregnancy tests for female of child-bearing potential must have a negative serum pregnancy test at Screening.

Exclusion Criteria:

1. Central nervous system metastatic disease, leptomeningeal disease, or metastatic cord compression.
2. As judged by the investigator, any evidence of significant ophthalmological abnormalities including but not limited to history or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO, retinal macular degeneration, uncontrolled glaucoma, cataract or marked decrease in visual acuity, symptomatic severe dry eye, conjunctivitis, or corneal ulcer.
3. Prior bone marrow or organ transplantation
4. Prior treatment with ET0038 or a SHP2 inhibitor.
5. Prior therapy with any investigational drugs or systemic anticancer treatment within 28 days (or a period of 5 'half-lives' of this investigational drugs or systemic anticancer treatment, whichever is the most appropriate and as judged by the investigator) at the time of ICF signature.
6. Radiotherapy with a wide field of radiation within 28 days, or radiotherapy with a limited field of radiation for palliation within 14 days at the time of ICF signature, or planning radical radiation therapy while participating in the study.
7. Prior major surgery (excluding placement of vascular access) within 28 days at the time of ICF signature, or planning for major surgery while participating in the study.
8. With the exception of alopecia, any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE5.0) Grade 1 at the time of ICF signature.
9. Any uncontrolled active infection requiring parenteral administration of antibiotics, antivirals, or antifungals at the time of ICF signature and/or within one week of Cycle 1 Day 1 (C1D1).
10. Patient with a history of active pulmonary tuberculosis infection within 1 year prior to screening (as judged by investigator, active pulmonary tuberculosis infection more than 1 year and no evidence of active pulmonary tuberculosis at present will be considering eligible)
11. Patient with history or presence of interstitial lung disease or interstitial pneumonitis.
12. An active, or previously, autoimmune disease that may recur (e.g., systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease,autoimmune thyroid disease, vasculitis, and psoriasis etc.) or high risk to such diseases.
13. Active infection including hepatitis B (Hepatitis B surface antigen \[HBsAg\] positive), and/or hepatitis C (HCV-RNA positive).
14. Active human immunodeficiency virus (HIV) infection (Patient with HIV positive and have well-controlled disease is exception).
15. Patient inability or unwillingness to comply with requirement for oral drug administration or presence of a gastro-intestinal condition, e.g., Refractory nausea and vomiting, inability to swallow the formulated product or previous significant bowel resection.
16. Have a history or present active bleeding disease within 6 months at the time of ICF signature.
17. History of COVID-19 infections, or COVID-19 nucleic acid test positive at the time of ICF signature and/or prior to the first dose of study treatment.
18. Pregnant or Breast-feeding women

Primary outcomes:
measure: RP2D of Phase 2 Dose of ET0038
timeFrame: Approximately 2 years
measure: MTD of ET0038
timeFrame: Approximately 2 years
measure: Number of participants with adverse events (AEs)
timeFrame: Approximately 2 years
Secondary outcomes:
measure: Area under the curve
timeFrame: Approximately 2 years
measure: Cmax
timeFrame: Approximately 2 years
measure: Tmax
timeFrame: Approximately 2 years
measure: T1/2
timeFrame: Approximately 2 years
measure: Objective response rate
timeFrame: Approximately 2 years
measure: Duration of response
timeFrame: Approximately 2 years
measure: Disease Control Rate
timeFrame: Approximately 2 years
measure: progression-free survival
timeFrame: Approximately 2 years
measure: overall survival
timeFrame: Approximately 2 years
Other outcomes:
measure: pERK
timeFrame: Approximately 2 years
measure: NGS test of RTK/MAPK pathway genes
timeFrame: Approximately 2 years
Locations:
city: Changsha
country: China
facility: Hunan Cancer Hospital
state: Hunan
city: Chengdu
country: China
facility: West China School of Medicine/West China Hospital of Sichuan University
state: Sichuan
Study officials:
affiliation: Etern BioPharma (Shanghai) Co., Ltd
name: Etern BioPharma (Shanghai) Co., Ltd
role: PRINCIPAL_INVESTIGATOR
References: