Zotatifin: Study of eFT226 in Subjects With Selected Advanced Solid Tumor Malignancies
Study Details
Study Description
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. The study will evaluate weekly 1-hour intravenous (IV) administration of Zotatifin (eFT226). Treatment and study subject evaluations will be performed in 21 day cycles.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1/Phase 2 |
Detailed Description
Part 1 (Dose Escalation): Phase Completed; Recommended Phase 2 Dose (RP2D) and Maximum Tolerated Dose (MTD) identified
Part 2 (Expansion Cohort) provides defined expansion cohorts to further explore the safety, pharmacology, and clinical activity of eFT226 monotherapy in subjects with previously treated advanced solid tumor malignancies.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Part 1: Sequential escalation (Completed) eFT226 administered IV weekly in 21-day cycles; dose escalated in sequential cohorts after subjects enrolled in a given cohort have completed DLT evaluation period. |
Drug: eFT226
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).
Other Names:
|
| Experimental: Part 2: Cohort Expansion, Monotherapy, NSCLC, KRAS (EMNK) Cohort EMNK |
Drug: eFT226
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).
Other Names:
|
| Experimental: Part 2: Cohort Expansion, Monotherapy, Breast, FGFR (EMBF) Cohort EMBF |
Drug: eFT226
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).
Other Names:
|
| Experimental: Part 2: Cohort Expansion, Monotherapy, Breast, HER2 (EMBH) Cohort EMBH |
Drug: eFT226
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).
Other Names:
|
| Experimental: Part 2: Cohort Expansion, Combination, Breast, Fulvestrant (ECBF) Cohort ECBF; Combination therapy partner administered per SOC at the approved dose. |
Drug: Fulvestrant
500 mg administered intramuscularly on Days 1, 15, 29, and once monthly thereafter
Other Names:
|
| Experimental: Part 2: Cohort Expansion, Combination, NSCLC, Sotorasib (ECNS) Cohort ECNS; Combination therapy partner administered per SOC at the approved dose. |
Drug: Sotorasib
Recommended dosage: 960 mg orally once daily
Other Names:
|
| Experimental: Part 2: Cohort Expansion, Combination, Breast, Fulvestrant+Abemaciclib (ECBF+A) Cohort ECBF+A; Combination therapy partner administered per SOC at the approved dose. |
Drug: Fulvestrant
500 mg administered intramuscularly on Days 1, 15, 29, and once monthly thereafter
Other Names:
Drug: Abemaciclib
Dose in combination with fulvestrant: 150 mg twice daily
Other Names:
|
| Experimental: Part 2: Cohort Expansion, Combination, Breast, Trastuzumab (ECBT) Cohort ECBT; Combination therapy partner administered per SOC at the approved dose. |
Drug: Trastuzumab
600 mg every 3 weeks
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Part 2: Objective Response Rate- Efficacy [Through study completion, on average 12 months]
defined as confirmed Complete Response (CR) or Partial Response (PR)
- Part 2: (Combination Cohorts) Determine MTD [Through study completion, on average 12 months]
determined by occurrence of first cycle Dose Limiting Toxicities (DLTs) within the study design
- Part 2: (Combination Cohorts) Determine RP2D [Through study completion, on average 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: (Combination Cohorts) Incidence, type, and severity of AEs and SAEs [Through study completion, on average 12 months]
via adverse event monitoring
- Percent change in tumor dimensions of target lesions- Efficacy [Through study completion, on average 12 months]
calculated by the percentage change from baseline in the sum of the LD of target lesions
- Time to Response (TTR)- Efficacy [Through study completion, on average 12 months]
defined as the interval from the start of study therapy to the first documentation of an objective response
- Duration of Response (DOR)- Efficacy [Through study completion, on average 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
Secondary Outcome Measures
- Part 2: (Monotherapy and Combination Cohorts) Incidence and severity of AEs, SAEs, and additional safety parameters [Through study completion, on average 12 months]
via adverse event monitoring
- Part 2: Progression Free Survival [Through study completion, on average 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, on average 12 months]
including area under the plasma concentration-time curve
- Evaluate plasma Pharmacokinetic (PK) parameters of eFT226 [Through study completion, on average 12 months]
including maximum concentration
- Evaluate plasma Pharmacokinetic (PK) parameters of eFT226 [Through study completion, on average 12 months]
including terminal phase rate constant
- Evaluate plasma Pharmacokinetic (PK) parameters of eFT226 [Through study completion, on average 12 months]
including estimated steady-state volume of distribution [Vss]
- Evaluate plasma Pharmacokinetic (PK) parameters of eFT226 [Through study completion, on average 12 months]
including half-life (t½)
- Evaluate plasma Pharmacokinetic (PK) parameters of eFT226 [Through study completion, on average 12 months]
including total body clearance
Eligibility Criteria
Criteria
Key Criteria:
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.
-
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.
-
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.
-
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Southern California | Los Angeles | California | United States | 90033 |
| 2 | Stanford University | Palo Alto | California | United States | 94304 |
| 3 | Hoag Memorial Hospital Presbyterian | Tustin | California | United States | 92782 |
| 4 | START Midwest | Grand Rapids | Michigan | United States | 49546 |
| 5 | Memorial Sloan Kettering Cancer Center | Middletown | New Jersey | United States | 07748 |
| 6 | Memorial Sloan Kettering Cancer Center | Harrison | New York | United States | 10604 |
| 7 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | 10021 |
| 8 | University of Toledo | Toledo | Ohio | United States | 43614 |
| 9 | MD Anderson Cancer Center | Houston | Texas | United States | 77030 |
| 10 | Virginia Cancer Specialists | Fairfax | Virginia | United States | 22031 |
Sponsors and Collaborators
- Effector Therapeutics
Investigators
- Study Director: Robert Sikorski, MD, PhD, Effector Therapeutics
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- eFT226-0002