A Dose Escalation/Expansion Study of ERAS-601 in Patients With Advanced or Metastatic Solid Tumors

Study Overview
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Brief Summary
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To evaluate the safety and tolerability of escalating doses of ERAS-601 when administered as a monotherapy and in combination with other cancer therapies in study participants with advanced or metastatic solid tumors. To determine the Maximum Tolerated Dose (MTD) and/or recommended dose (RD) of ERAS-601 when administered as a monotherapy and in combination with other cancer therapies. To characterize the pharmacokinetic (PK) profile of ERAS-601 when administered as a monotherapy and in combination with other cancer therapies. To evaluate the antitumor activity of ERAS-601 when administered as a monotherapy and in combination with other cancer therapies.

Detailed Description
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This is a first-in-human, Phase 1/1b, open-label, multicenter clinical study of ERAS-601 as a monotherapy and in combination with other cancer therapies. The study will commence with dose escalation of ERAS-601 monotherapy, followed by dose escalation of ERAS-601 in combination with other cancer therapies. Once the monotherapy MTD and/or RD has been determined, then dose expansion of ERAS-601 monotherapy may commence with enrollment of study participants with advanced or metastatic solid tumors harboring specific molecular alterations. Once the combination therapy MTD and/or RD has been determined, then dose expansion of that combination may commence with enrollment of study participants with advanced or metastatic solid tumors harboring specific molecular alterations.

Official Title
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An Open-Label, Multi-Center Phase 1/1b Dose Escalation and Expansion Study of ERAS-601 SHP2 Inhibitor as a Monotherapy and in Combination With Other Anti-Cancer Therapies in Patients With Advanced or Metastatic Solid Tumors

Conditions
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Advanced or Metastatic Solid Tumors

Intervention / Treatment
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* Drug: ERAS-601
* Drug: Cetuximab
* Drug: Pembrolizumab


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 advanced or metastatic solid tumor There is no available standard systemic therapy available for the patient's tumor histology and/or molecular biomarker profile; or standard therapy is intolerable, not effective, or not accessible; or patient has refused standard therapy Able to swallow oral medication Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 Adequate cardiovascular, hematological, liver, and renal function Willing to comply with all protocol-required visits, assessments, and procedures Exclusion Criteria: Previous treatment with a SHP2 inhibitor Documented PTPN11 mutations Is currently receiving another study therapy or has participated in a study of an investigational agent and received study therapy within 4 weeks of the first dose of ERAS-601 Received prior palliative radiation within 7 days of Cycle 1, Day 1 Have primary central nervous system (CNS) disease or known active CNS metastases and/or carcinomatous meningitis Prior surgery (e.g., gastric bypass surgery, gastrectomy) or gastrointestinal dysfunction (e.g., Crohn's disease, ulcerative colitis, short gut syndrome) that may affect drug absorption Active, clinically significant interstitial lung disease or pneumonitis History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to the first dose of study treatment History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO Have any underlying medical condition, psychiatric condition, or social situation that, in the opinion of the Investigator, would compromise study administration as per protocol or compromise the assessment of AEs Are pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial

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 A): ERAS-601 monotherapy<br>ERAS-601 monotherapy will be administered in sequential ascending doses to study participants with advanced or metastatic solid tumors until unacceptable toxicity, disease progression, or withdrawal of consent. | Drug: ERAS-601<br>* Administered orally<br>|
| Experimental: Dose Escalation (Part B): ERAS-601 monotherapy<br>ERAS-601 monotherapy will be administered in sequential ascending doses to study participants with advanced or metastatic solid tumors until unacceptable toxicity, disease progression, or withdrawal of consent. | Drug: ERAS-601<br>* Administered orally<br>|
| Experimental: Dose Escalation (Part C): ERAS-601 monotherapy<br>ERAS-601 will be administered in sequential ascending doses to study participants with advanced or metastatic solid tumors until unacceptable toxicity, disease progression or withdrawal of consent. | Drug: ERAS-601<br>* Administered orally<br>|
| Experimental: Dose Escalation and Dose Expansion (Part D): ERAS-601 in combination with cetuximab<br>ERAS-601 will be administered in sequential ascending doses with cetuximab to study participants with advanced metastatic solid tumors until unacceptable toxicity, disease progression or withdrawal of consent. Once the combination therapy recommended dose has been determined, this will be administered to study participants with HPV negative advanced or metastatic head and neck squamous cell carcinoma (HNSCC) or colorectal cancer (CRC). | Drug: ERAS-601<br>* Administered orally<br>Drug: Cetuximab<br>* Administered via intravenous infusion<br>* Other names: Erbitux;|
| Experimental: Dose Escalation and Dose Expansion (Part E): ERAS-601 in combination with pembrolizumab<br>ERAS-601 will be administered in sequential ascending doses with pembrolizumab to study participants with advanced metastatic solid tumors until unacceptable toxicity, disease progression or withdrawal of consent. Once the combination therapy recommended dose has been determined, this will be administered to study participants with HPV negative advanced or metastatic head and neck squamous cell carcinoma (HNSCC) or non small cell lung cancer (NSCLC). | Drug: ERAS-601<br>* Administered orally<br>Drug: Pembrolizumab<br>* Administered via intravenous infusion<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicities (DLT) | Based on toxicities observed | Study Day 1 up to Day 29 | 
| Maximum tolerated dose (MTD) | Based on toxicities observed | Study Day 1 up to Day 29 | 
| Recommended dose (RD) | Based on toxicities observed | Study Day 1 up to Day 29 | 
| Adverse Events | Incidence and severity of treatment-emergent AEs and serious AEs | Assessed up to 24 months from time of first dose | 
| Plasma concentration (Cmax) | Maximum plasma concentration of ERAS-601 and cetuximab or pembrolizumab (if applicable) | Study Day 1 up to Day 29 | 
| Time to achieve Cmax (Tmax) | Time to achieve maximum plasma concentration of ERAS-601 and cetuximab or pembrolizumab (if applicable) | Study Day 1 up to Day 29 | 
| Area under the curve | Area under the plasma concentration-time curve of ERAS-601 and cetuximab or pembrolizumab (if applicable) | Study Day 1 up to Day 29 | 
| Half-life | Half-life of ERAS-601 and cetuximab or pembrolizumab (if applicable) | Study Day 1 up to Day 29 | 

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 | 
| Time to Response (TTR) | 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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SHP2, PTPN11, solid tumor, advanced solid tumor, metastatic solid tumor, neoplasms, solid malignancies, targeted therapy, colorectal cancer, CRC, head and neck squamous cell carcinoma, HPV Negative HNSCC, molecular alterations, cetuximab, Erbitux, Chordoma