A Study of Anti-Cancer Therapies Targeting the MAPK Pathway in Patients With Advanced NSCLC (HERKULES-2)

A Phase 1b Master Protocol of Agents Targeting the Mitogen-Activated Protein Kinase Pathway in Patients With Advanced Non-Small-Cell Lung Cancer

• To evaluate the safety and tolerability of escalating doses of ERAS-007 or ERAS-601 in combination with other cancer therapies in study participants with advanced non-small cell lung cancer (NSCLC).
• To determine the Maximum Tolerated Dose (MTD) and/or Recommended Dose (RD) of ERAS-007 or ERAS-601 administered in combination with other cancer therapies.
• To evaluate the antitumor activity of ERAS-007 or ERAS-601 in combination with other cancer therapies.
• To evaluate the PK profiles of ERAS-007 or ERAS-601 and other cancer therapies when administered in combination.

Study Overview

• Status: Completed
• Conditions: Advanced Non-squamous Non-small-cell Lung Cancer
• Intervention / Treatment: Drug: ERAS-601; Drug: ERAS-007; Drug: Osimertinib; Drug: Sotorasib

Detailed Description

This is a Phase 1b, open-label, multicenter master protocol evaluating safety, tolerability, and antitumor activity of ERAS-007 or ERAS-601 in combination with other cancer therapies in study participants with advanced NSCLC. The study will commence with the following dose escalation cohorts: ERAS-007 plus osimertinib in study participants with advanced NSCLC harboring epidermal growth factor receptor-sensitizing mutation(s) (EGFRm); ERAS-007 or ERAS-601 plus sotorasib in study participants with advanced NSCLC harboring Kirsten rat sarcoma G12C mutation (KRAS G12Cm). Dose expansion will follow and will evaluate ERAS-007 or ERAS-601 drug combinations administered at the RD identified from each respective dose escalation cohort in study participants with advanced EGFRm or KRAS G12Cm NSCLC.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Orange, California, United States, 92868
      • UC Irvine, Chao Family Comprehensive Cancer Center
    • Santa Monica, California, United States, 90404
      • UC Los Angeles
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Research Institute
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center (John Theurer Cancer Center)
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute (Tennessee Oncology)
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years.
• Willing and able to give written informed consent.
• Have histologically or cytologically confirmed NSCLC, with presence of EGFR mutation(s) sensitive to EGFR inhibitors, or KRAS G12C mutation.
• Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
• Adequate bone marrow and organ function.
• Have ECOG performance status of 0 or 1.
• Willing to comply with all protocol-required visits, assessments, and procedures.
• Able to swallow oral medication.

Exclusion Criteria:

• Concurrent treatment with any systemic anticancer therapy for NSCLC, including any approved or investigational agent.
• For participants with EGFRm NSCLC: prior therapy with a RAS, RAF, MEK, or ERK inhibitor.
• For participants with KRAS G12Cm NSCLC: prior therapy with a SHP2, ERK, or KRAS G12C inhibitor (depending on which cohort is being considered for enrollment).
• Palliative radiotherapy within 7 days of enrollment.
• History of unacceptable toxicity to treatment with osimertinib or sotorasib.
• Major surgery within the 28 days of enrollment.
• Unresolved toxicities from prior systemic therapy greater than NCI CTCAE grade 1 at time of enrollment, except for toxicities not considered a safety risk (eg, alopecia, vitiligo, and grade 2 neuropathy due to prior chemotherapy).
• History of another malignancy ≤5 years prior to first dose, except for patients who are disease-free for >2 years after treatment with curative intent or who have carcinoma in situ.
• Symptomatic and unstable brain metastases, or spinal cord compression, except for patients who have completed definitive therapy (surgery or radiotherapy), are not on steroids, and have a stable neurologic status for a least 2 weeks after completion of the definitive therapy and steroids.
• History of or clinically active ILD, drug induced ILD, or radiation pneumonitis that required steroid treatment.
• Impaired cardiovascular function or clinically significant cardiovascular disease.
• History or current evidence of retinal pigment epithelial detachment (RPED), central serous retinopathy, retinal vein occlusion (RVO), or predisposing factors to RPED or RVO.
• Any evidence of severe or uncontrolled systemic disease or evidence of any other significant clinical disorder or laboratory finding that renders the patient inappropriate to participate in the study.
• Pregnant or breastfeeding women.
• Contraindication to osimertinib or sotorasib use as per local label.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Escalation (Part 1): ERAS-007 plus osimertinib; ERAS-007 will be orally administered in combination with osimertinib to study participants with EGFRm NSCLC in sequential ascending doses until unacceptable toxicity, disease progression, or withdrawal of consent.	Drug: ERAS-007; Administered orally; Drug: Osimertinib; Administered orally; Other Names: Tagrisso
Experimental: Dose Escalation (Part 2): ERAS-007 plus sotorasib; ERAS-007 will be orally administered in combination with sotorasib to study participants with KRAS G12Cm NSCLC in sequential ascending doses until unacceptable toxicity, disease progression, or withdrawal of consent.	Drug: ERAS-007; Administered orally; Drug: Sotorasib; Administered orally; Other Names: Lumakras
Experimental: Dose Escalation (Part 3): ERAS-601 plus sotorasib; ERAS-601 will be orally administered in combination with sotorasib to study participants with KRAS G12Cm NSCLC in sequential ascending doses until unacceptable toxicity, disease progression, or withdrawal of consent.	Drug: ERAS-601; Administered orally; Drug: Sotorasib; Administered orally; Other Names: Lumakras
Experimental: Dose Expansion (Part 4): ERAS-007 plus osimertinib; ERAS-007 will be orally administered at the recommended dose (as determined from Part 1) in combination with osimertinib to study participants with EGFRm NSCLC.	Drug: ERAS-007; Administered orally; Drug: Osimertinib; Administered orally; Other Names: Tagrisso
Experimental: Dose Expansion (Part 5): ERAS-007 plus sotorasib; ERAS-007 will be orally administered at the recommended dose (as determined from Part 2) in combination with sotorasib to study participants with KRAS G12Cm NSCLC.	Drug: ERAS-007; Administered orally; Drug: Sotorasib; Administered orally; Other Names: Lumakras
Experimental: Dose Expansion (Part 6): ERAS-601 plus sotorasib; ERAS-601 will be orally administered at the recommended dose (as determined from Part 3) in combination with sotorasib to study participants with KRAS G12Cm NSCLC.	Drug: ERAS-601; Administered orally; Drug: Sotorasib; Administered orally; Other Names: Lumakras

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events	Incidence and severity of treatment-emergent AEs and serious AEs	Assessed up to 24 months from time of first dose
Dose Limiting Toxicities (DLT)	Based on adverse events observed	Study Day 1 up to Day 22
Maximum Tolerated Dose (MTD)	Based on adverse events observed	Study Day 1 up to Day 22
Recommended Dose (RD)	Based on adverse events observed	Study Day 1 up to Day 22

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	Based on assessment of radiographic imaging per RECIST version 1.1	Assessed up to 24 months from time of first dose
Duration of Response (DOR)	Based on assessment of radiographic imaging per RECIST version 1.1	Assessed up to 24 months from time of first dose
Plasma concentration (Cmax)	Maximum plasma concentration of ERAS-007 or ERAS-601 and other cancer therapies	Study Day 1 up to Day 22
Time to achieve Cmax (Tmax)	Time to achieve maximum plasma concentration of ERAS-007 or ERAS-601 and other cancer therapies	Study Day 1 up to Day 22
Area under the curve	Area under the plasma concentration-time curve of ERAS-007 or ERAS-601 and other cancer therapies	Study Day 1 up to Day 22
Half-life	Half-life of ERAS-007 or ERAS-601 and other cancer therapies	Study Day 1 up to Day 22

Collaborators and Investigators

• Sponsor: Erasca, Inc.
• Investigators: Study Director: Joyce Antal, Senior Director, Clinical Development

Study record dates

Study Major Dates

• Study Start (Actual): September 2, 2021
• Primary Completion (Actual): April 27, 2023
• Study Completion (Actual): April 27, 2023

Study Registration Dates

• First Submitted: July 2, 2021
• First Submitted That Met QC Criteria: July 2, 2021
• First Posted (Actual): July 13, 2021

Study Record Updates

• Last Update Posted (Actual): July 25, 2023
• Last Update Submitted That Met QC Criteria: July 24, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: NSCLC; mutation; biomarker; Non-small cell lung cancer; EGFR; Tagrisso; SHP2; ERK; MAPK; KRAS; PTPN11; molecular alterations; Lung neoplasms; osimertinib; Kirsten rat sarcoma; epidermal growth factor receptor; Thoracic neoplasms; sotorasib; Lumakras; G12C; ERAS-601; ERAS-007
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Immune Checkpoint Inhibitors; Osimertinib; Sotorasib
• Other Study ID Numbers: ERAS-007-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No