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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Advanced Non-squamous Non-small-cell Lung Cancer

Intervention / Treatment
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* Drug: ERAS-007
* Drug: ERAS-601
* Drug: Osimertinib
* Drug: Sotorasib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation (Part 1): ERAS-007 plus osimertinib<br>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<br>* Administered orally<br>Drug: Osimertinib<br>* Administered orally<br>* Other names: Tagrisso;|
| Experimental: Dose Escalation (Part 2): ERAS-007 plus sotorasib<br>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<br>* Administered orally<br>Drug: Sotorasib<br>* Administered orally<br>* Other names: Lumakras;|
| Experimental: Dose Escalation (Part 3): ERAS-601 plus sotorasib<br>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<br>* Administered orally<br>Drug: Sotorasib<br>* Administered orally<br>* Other names: Lumakras;|
| Experimental: Dose Expansion (Part 4): ERAS-007 plus osimertinib<br>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<br>* Administered orally<br>Drug: Osimertinib<br>* Administered orally<br>* Other names: Tagrisso;|
| Experimental: Dose Expansion (Part 5): ERAS-007 plus sotorasib<br>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<br>* Administered orally<br>Drug: Sotorasib<br>* Administered orally<br>* Other names: Lumakras;|
| Experimental: Dose Expansion (Part 6): ERAS-601 plus sotorasib<br>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<br>* Administered orally<br>Drug: Sotorasib<br>* Administered orally<br>* Other names: Lumakras;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Adverse Events | Incidence and severity of treatment-emergent AEs and serious AEs | Assessed up to 24 months from time of first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mutation, EGFR, epidermal growth factor receptor, biomarker, NSCLC, Tagrisso, osimertinib, ERK, MAPK, sotorasib, Lumakras, KRAS, G12C, SHP2, PTPN11, molecular alterations, Kirsten rat sarcoma, Non-small cell lung cancer, Lung neoplasms, Thoracic neoplasms, ERAS-601, ERAS-007