A Phase I/IIa, Open-label, Dose-escalation and Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetic and Preliminary Anti-tumor Activity of H002 in Patients With Active EGFR Mutation Locally Advanced or Metastatic NSCLC
Overview
- Phase
- Phase 1
- Intervention
- H002
- Conditions
- Non-small Cell Lung Cancer
- Sponsor
- RedCloud Bio
- Enrollment
- 76
- Locations
- 4
- Primary Endpoint
- DOSE EXPANSION PHASE：Incidence and severity of TEAEs, with severity determined according to NCI CTCAE v5.0.
- Status
- Recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
This is a phase I/IIa, open-label, dose-escalation and expansion study to evaluate the safety, tolerability, PK and preliminary anti-tumor activity of H002 when given orally in patients with active EGFR mutation locally advanced or metastatic non-small cell lung cancer (NSCLC).
The study will contain two parts: Part A is dose escalation phase (i.e., Phase I) and Part B is dose expansion phase (i.e., Phase IIa).
Detailed Description
Part A (Dose Escalation Phase) Approximately 36 subjects will be enrolled, based on the "3+3" design for dose escalation and safety evaluation requirements. The total number of subjects will depend upon the number of dose escalations necessary. Part B (Dose Expansion Phase) Up to 20 subjects will be enrolled in each expansion arm, the total number of subjects will depend upon the number of dose expansions (expansions may be at more than one dose depending upon emerging data).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Males or females aged ≥ 18 years at time of signing informed consent form (ICF).
- •Histological or cytological confirmed diagnosis of unresectable locally advanced or metastatic NSCLC.
- •Subjects must have NSCLC harboring one or more active EGFR mutations known to be associated with EGFR-TKI sensitivity (including, but not limited to Del19 and L858R).
- •Part A: All subjects may provide tumor sample to central laboratory to analyze the EGFR mutation status according to their own willingness;
- •Part B: All subjects must provide tumor sample to central laboratory to analyze the EGFR mutation status. And subjects must have NSCLC harboring EGFR C797S mutation.
- •Note: Tumor sample can be either an archival sample or a sample obtained by pretreatment biopsy prior to H002 treatment.
- •Subjects must have radiological documented disease progression while on a previous continuous treatment with osimertinib or another third-generation EGFR-TKI as well as disease progression on the last treatment administered prior to enrolling in the study.
- •Presence of at least one measurable lesion according to RECIST v1.1 per investigator assessment.
- •ECOG performance status of 0-
- •Life expectancy ≥ 12 weeks.
Exclusion Criteria
- •Treatment with any of the following:
- •Prior treatment with an EGFR-TKI within 8 days or approximately 5 × t1/2 prior to the first dose of H002, whichever is longer; Prior treatment with immunotherapy or biotherapy within 4 weeks prior to the first dose of H002; Radiotherapy (palliative radiotherapy is completed at least 2 weeks prior to the first dose of H002 can be enrolled) within 4 weeks prior to the first dose of H002; Herbal therapy that has anti-tumor effects within 2 weeks prior to the first dose of H002; Mitomycin and nitrosourea within 6 weeks prior to the first dose of H002; Oral fluorouracil such as tegafur and capecitabine within 2 weeks prior to the first dose of H002; Chemotherapy (except for mitomycin, nitrosourea, and fluorouracil oral drugs), or other anti-tumor drugs for the treatment of NSCLC within 4 weeks or approximately 5 × t1/2 prior to the first dose of H002, whichever is longer.
- •Subjects with EGFR exon 20 insertion mutations only.
- •Prior marketed and/or investigational treatment for EGFR C797S mutation (including, but not limited to BTP-661411, TQB3804 and BLU-945).
- •Is currently participating and receiving investigational therapy or using an investigational device, or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks or 5 × t1/2 of the investigational product, whichever is longer, prior to the first dose of H
- •Is expected to require any other form of anti-tumor therapy while on study.
- •Unresolved toxicity greater than CTCAE v5.0 Grade 1 from prior anti-tumor therapy.
- •≥ CTCAE v5.0 Grade 2 skin toxicity at screening.
- •Treatment with strong inhibitors, strong inducers and sensitive substrates of CYP3A4, substrates and inhibitors for P-glycoprotein (P-gp), as well as substrates for breast cancer resistance protein (BCRP) within 2 weeks prior to the first dose of H002, or anticipation of need for such drugs during study treatment.
- •Uncontrollable pleural effusion, ascites, or pericardial effusion.
Arms & Interventions
20 mg QD, oral
H002 20mg QD, orally administered in fasting state, receive a single dose of H002 orally, followed by a 4-day washout period. Then, the same dose of H002 will be administered QD until disease progression or not tolerated.
Intervention: H002
40 mg QD, oral
H002 40mg QD, orally administered in fasting state, receive a single dose of H002 orally, followed by a 4-day washout period. Then, the same dose of H002 will be administered QD until disease progression or not tolerated.
Intervention: H002
80 mg QD, oral
H002 80mg QD, orally administered in fasting state, receive a single dose of H002 orally, followed by a 4-day washout period. Then, the same dose of H002 will be administered QD until disease progression or not tolerated.
Intervention: H002
150 mg QD, oral
H002 150mg QD, orally administered in fasting state, receive a single dose of H002 orally, followed by a 4-day washout period. Then, the same dose of H002 will be administered QD until disease progression or not tolerated.
Intervention: H002
250 mg QD, oral
H002 250mg QD, orally administered in fasting state, receive a single dose of H002 orally, followed by a 4-day washout period. Then, the same dose of H002 will be administered QD until disease progression or not tolerated.
Intervention: H002
350 mg QD, oral
H002 350mg QD, orally administered in fasting state, receive a single dose of H002 orally, followed by a 4-day washout period. Then, the same dose of H002 will be administered QD until disease progression or not tolerated.
Intervention: H002
Outcomes
Primary Outcomes
DOSE EXPANSION PHASE：Incidence and severity of TEAEs, with severity determined according to NCI CTCAE v5.0.
Time Frame: Up to approximately 30 months
To evaluate the safety at the selected dose(s) of H002 when given orally.
DOSE ESCALATION PHASE：Incidence of dose-limiting toxicities (DLTs) at Cycle 0 and Cycle1. Incidence and severity of treatment-emergent adverse events (TEAEs), with severity determined according to National Cancer Institute (NCI) CTCAE v5.0.
Time Frame: At the end of Cycle 1 (include 4 days in Cycle 0 and 21 days in Cycle1)
To evaluate the safety and tolerability of H002 and to determine the maximal tolerable dose (MTD), or if possible, a dose/exposure predicted to result in optimal biological dose (OBD) or recommended phase II dose (RP2D).
DOSE EXPANSION PHASE：Objective Response Rate (ORR)
Time Frame: Up to approximately 30 months
To obtain a preliminary evaluation of the anti-tumor activity at the selected dose(s) of H002 when given orally as determined according to RECIST v1.1.
Secondary Outcomes
- Time for half the drug concentration to be eliminated（t1/2）(Up to approximately 30 months)
- Time to reach maximum concentration (Tmax)(Up to approximately 30 months)
- Peak Plasma Concentration (Cmax)(Up to approximately 30 months)
- Area under the plasma concentration versus time curve (AUC)(Up to approximately 30 months)
- Time to progression (TTP)(Up to approximately 30 months)
- Disease control rate (DCR)(Up to approximately 30 months)
- Duration of response (DOR)(Up to approximately 30 months)
- Progression-free survival (PFS)(Up to approximately 30 months)
- Overall survival (OS)(Up to approximately 30 months)
- DOSE ESCALATION PHASE：Objective Response Rate (ORR)(Up to approximately 30 months)