Overview

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.

Eligibility

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.