Solid Tumor, Adult
Conditions
Brief summary
This clinical trial is a Phase 1-2, open-label, sequential-group, dose-escalation and cohort-expansion study evaluating the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of Zotatifin (eFT226) in subjects with selected advanced solid tumor malignancies.
Detailed description
Part 1 (Dose Escalation): Completed; Recommended Phase 2 Dose (RP2D) and Maximum Tolerated Dose (MTD) identified Part 1a (Dose Escalation) This cohort will enroll patients with an advanced breast cancer that is refractory or intolerant to SOC therapy. Part 1b (Dose Escalation) This cohort will enroll patients with an advanced breast cancer that is refractory or intolerant to SOC therapy. Part 2 (Expansion Cohort) provides defined expansion cohorts to further explore the safety, pharmacology, and clinical activity of eFT226 monotherapy and in various combinations in subjects with previously treated advanced solid tumor malignancies.
Interventions
DRUGeFT226
eFT226 is a novel small-molecule, investigational drug being developed by eFFECTOR Therapeutics as an anticancer therapy. eFT226 is a potent and selective inhibitor of eIF4A1-mediated translation and selectively regulates the translation of a subset of mRNAs based on sequence specific recognition motifs in their 5'-UTR. eIF4A1 inhibition by eFT226 downregulates expression of receptor tyrosine kinases and KRAS, leading to decreased signaling through the PI3K/AKT and MAPK pathways. Preclinical efficacy testing of eFT226 demonstrates activity across models of solid tumor cancers with amplifications in HER2, FGFR1/2 and mutations in KRAS (including breast, NSCLC and CRC).
DRUGSotorasib
Recommended dosage: 960 mg orally once daily
DRUGFulvestrant
500 mg administered intramuscularly on Days 1, 15, 29, and once monthly thereafter
DRUGAbemaciclib
Dose in combination with fulvestrant: 150 mg twice daily
DRUGTrastuzumab
600 mg every 3 weeks
Sponsors
Effector Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Dose Escalation, 3+3, 3+3+3
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Criteria: Parts 1a and 1b (Dose Escalation + Fulvestrant): * Patient has histological or cytological confirmation of breast cancer. * Patient has metastatic disease or locoregionally recurrent disease which is refractory or intolerant to existing therapy(ies) known to provide clinical benefit. * Patient has had prior chemotherapy, endocrine therapy, or other therapy as follows: * Minimum of one prior line of therapy for advanced/metastatic disease. * Maximum of five prior lines of therapy for advanced/metastatic disease. * Recurrence or progression on at least one line of endocrine therapy in the advanced/metastatic disease setting. * Prior treatment has included a CDK4/6 inhibitor. * Tumor is ER+ (defined as ER IHC staining \> 0%). Cohort EMNK: * Patient has undergone treatment with platinum-based chemotherapy and an anti-PD-1/L1 agent, if appropriate. * Tumor has a known KRAS-activating mutation; Patients with KRAS G12C mutations are excluded. Cohort EMBF: * Patient has had prior chemotherapy, endocrine therapy, or other therapy as follows: * Minimum of one prior line of therapy for advanced/metastatic disease. * Maximum of five prior lines of therapy for advanced/metastatic disease. * Recurrence or progression on at least one line of endocrine therapy in the advanced/metastatic disease setting, which may include combination therapy (eg, with a CDK4/6 inhibitor). * Tumor is ER+ (defined as ER IHC staining \> 0%) and has FGFR amplification. Cohort EMBH: * Patient has had prior chemotherapy, endocrine therapy, or other therapy as follows: * Minimum of one prior line of therapy for advanced/metastatic disease. * Minimum of one line of HER2-directed therapy Note: Prior treatment with CDK4/6 inhibitors is permitted. * Tumor is ER+ (defined as ER IHC staining \> 0%) and HER2+ (defined as HER2 3+ IHC staining or HER2 2+ and FISH+). Cohort ECNS: * Patient has histologically or cytologically confirmed stage IIIB (pleural or pericardial effusion) or stage IV NSCLC. * Patient has undergone treatment with platinum-based chemotherapy and an anti-PD-1/L1 agent, if appropriate. Note: Patients who have declined approved therapy(ies) or who per treating physician are not eligible for approved therapy(ies) (eg, due to intolerance) may be eligible following discussion with the Medical Monitor. * Tumor has a known G12C KRAS-activating mutation. Note: Patients who have been previously treated with KRAS-specific therapy are excluded. Cohort ECBF: * Patient has had prior chemotherapy, endocrine therapy, or other therapy as follows: * Minimum of one prior line of therapy for advanced/metastatic disease. * Maximum of five prior lines of therapy for advanced/metastatic disease. * Recurrence or progression on at least one line of endocrine therapy in the advanced/metastatic disease setting. * Prior treatment has included a CDK4/6 inhibitor. * Tumor is ER+ (defined as ER IHC staining \> 0%). Cohort ECBF+A: * Patient has had prior chemotherapy, endocrine therapy, or other therapy as follows: * Minimum of one prior line of therapy for advanced/metastatic disease. * Maximum of five prior lines of therapy for advanced/metastatic disease. * Recurrence or progression on at least one line of endocrine therapy in the advanced/metastatic disease setting. * Tumor is ER+ (defined as ER IHC staining \> 0%) and HER2- (defined as absence of HER2 3+ IHC staining and/or absence of FISH+). Cohort ECBT: * Patient has progressed after treatment with at least one approved anti-HER2 agent and has been administered at least one line of chemotherapy. * Tumor is HER2+ (defined as HER2 3+ IHC staining or HER2 2+ and FISH+). Cohorts EMBF, EMBH, ECBF, ECBF+A: There is no limit on the number of lines of prior endocrine therapies. Cohort ECBF-D1: * Patient has metastatic disease or locoregionally recurrent disease which is refractory or intolerant to existing therapy(ies) known to provide clinical benefit. * Patient has had prior chemotherapy, endocrine therapy, or other therapy as follows: * Minimum of one prior line of therapy for advanced/metastatic disease. * Maximum of five prior lines of therapy for advanced/metastatic disease. * Recurrence or progression on at least one line of endocrine therapy in the advanced/metastatic disease setting. * Prior treatment has included a CDK4/6 inhibitor. * Tumor is ER+ (defined as ER IHC staining \> 0%). * Tumor has amplification of Cyclin D1 as determined by next generation sequencing or in situ hybridization.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Time to Response (TTR)- Efficacy | Through study completion, approximately 12 months | defined as the interval from the start of study therapy to the first documentation of an objective response |
| Part 2: Duration of Response (DOR)- Efficacy | Through study completion, approximately 12 months | defined as the interval from the first documentation of objective response to the earlier of the first documentation of disease progression or death from any cause |
| Parts 1a and 1b: MTD | Through study completion, approximately 12 months | determined by occurrence of first cycle DLTs within a 3+3 or 3+3+3 clinical trial design |
| Parts 1a and 1b; incidence of AEs, serious adverse events (SAEs), and DLTs | Through study completion, approximately 12 months | according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) |
| Parts 1a and 1b: RP2D | Through study completion, approximately 12 months | determined by Incidence and type of DLTs |
| Part 2: Objective Response Rate- Efficacy | Through study completion, approximately 12 months | defined as confirmed Complete Response (CR) or Partial Response (PR) |
| Part 2: (Combination Cohorts) Determine MTD | Through study completion, approximately 12 months | determined by occurrence of first cycle Dose Limiting Toxicities (DLTs) within the study design |
| Part 2: (Combination Cohorts) Incidence, type, and severity of AEs and SAEs | Through study completion, approximately 12 months | via adverse event monitoring |
| Part 2: (Combination Cohorts) Determine RP2D | Through study completion, approximately 12 months | determined by incidence and type of DLTs, and incidence, type, and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs) |
| Part 2: Percent change in tumor dimensions of target lesions- Efficacy | Through study completion, approximately 12 months | calculated by the percentage change from baseline in the sum of the LD of target lesions |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Parts 1a and 1b: Objective response | Through study completion, approximately 12 months | determined by confirmed CR or PR |
| Parts 1a and 1b: Percent change in tumor dimensions of target lesions | Through study completion, approximately 12 months | calculated by the percentage change from baseline in the sum of the LD of target lesions |
| Parts 1a and 1b: TTR | Through study completion, approximately 12 months | defined as the interval from the start of study therapy to the first documentation of an objective response |
| Parts 1a and 1b: DOR | Through study completion, approximately 12 months | defined as the interval from the first documentation of objective response to the earlier of the first documentation of disease progression or death from any cause |
| Parts 1a and 1b: PFS | Through study completion, approximately 12 months | defined as the interval from the start of study therapy to the earlier of the first documentation of disease progression or death from any cause |
| Part 2: (Monotherapy and Combination Cohorts) Incidence and severity of AEs, SAEs, and additional safety parameters | Through study completion, approximately 12 months | via adverse event monitoring |
| Part 2: Progression Free Survival | Through study completion, approximately 12 months | defined as the interval from the start of study therapy to the earlier of the first documentation of disease progression or death from any cause |
| Evaluate plasma Pharmacokinetic (PK) parameters of eFT226 | Through study completion, approximately 12 months | including area under the plasma concentration-time curve |
| Evaluate plasma Pharmacokinetic (PK) parameters of eFT226including terminal state volume of distribution | Through study completion, approximately 12 months | including terminal state volume of distribution |
| Evaluate plasma Pharmacokinetic (PK) parameters of eFT226 including terminal phase rate constant | Through study completion, approximately 12 months | including terminal phase rate constant |
Countries
United States
Contacts
Primary ContactMark Densel
Outcome results
None listed