A Study of ERAS-007 as Monotherapy or in Combination With 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 ERAS-007 monotherapy administered once weekly (QW) and twice daily-once weekly (BID-QW). To determine the Maximum Tolerated Dose (MTD) and/or Recommended Dose (RD) of ERAS-007 monotherapy administered BID-QW. To characterize the pharmacokinetic (PK) profile of ERAS-007 monotherapy. To determine the optimal dose and schedule of ERAS-007 monotherapy. To evaluate antitumor activity of ERAS-007 in various solid tumors. To evaluate the safety and tolerability of ERAS-007 (BID-QW) and ERAS-601 (twice daily for three weeks on and 1 week off (BID 3/1)) when administered in combination. To determine the Maximum Tolerated Dose (MTD) and/or Recommended Dose (RD) of ERAS-007 administered in combination with ERAS-601. To characterize the pharmacokinetic (PK) profile of ERAS-007 and ERAS-601 when administered in combination. To evaluate antitumor activity of ERAS-007 and ERAS-601 when administered in combination in various solid tumors To evaluate antitumor activity of ERAS-007 and ERAS-601 when administered in combination in various solid tumors

Detailed Description
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This is a Phase 1b/2, open-label, multicenter clinical study of ERAS-007 monotherapy (QW or BID-QW) administered either QW or BID-QWand ERAS-007 (BID-QW) in combination with ERAS-601 (BID 3/1). The monotherapy RD on a weekly schedule has been determined to be 250 mg QW in a previous study. The dose escalation phases of this study will test ERAS-007 monotherapy administered BID-QW as a monotherapy or in combination with ERAS-601 in participants with any solid tumor. The monotherapy RD on a weekly schedule has been determined to be 250 mg QW in a previous study. In parallel, the dose expansion phase of this study will test ERAS-007 monotherapy administered at the RD of 250 mg QW in participants with advanced or metastatic solid tumors harboring specific molecular alterations. Once sufficient safety and PK data are available from the BID-QW dose escalation phase, the Sponsor will then determine the optimal dose and schedule of ERAS-007 administered as a monotherapy.

Official Title
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A Phase 1b/2, Open-label, Multi-center Study of ERAS-007 (ERK Inhibitor) Administered as Monotherapy or in Combination With ERAS-601 (SHP2 Inhibitor) in Patients With Advanced or Metastatic Solid Tumors (HERKULES-1)

Conditions
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Advanced or Metastatic Solid Tumors

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


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 with a relevant molecular alteration (as applicable). 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. Recovered from all toxicities associated with prior treatment to acceptable baseline status. Have ECOG performance status of 0 or 1 with an anticipated life expectancy of > 12 weeks. Willing to comply with all protocol-required visits, assessments, and procedures. Able to swallow oral medication. Exclusion Criteria: 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-007. Received previous treatment with an ERK inhibitor. For participants being considered for ERAS-007 + ERAS-601 (Part D): prior treatment with SHP2 inhibitor. For participants being considered for ERAS-007 + ERAS-601 (Part D): documented PTPN11 mutations Received prior antineoplastic therapy within < 21 days or 5 half-lives, whichever is shorter. Received prior palliative radiation within 7 days of first dose of ERAS 007 or ERAS-601, Received previous treatment with a MAPK inhibitor that resulted in discontinuation due to unacceptable toxicity. 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. 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation (Part A): ERAS-007 Monotherapy, BID-QW dosing<br>ERAS-007 monotherapy will be administered BID-QW in sequential ascending doses to participants with advanced or metastatic solid tumors until unacceptable toxicity, disease progression, or withdrawal of consent. | Drug: ERAS-007<br>* ERAS-007 will be administered orally as specified in Arm description.<br>|
| Experimental: Dose Expansion (Part B): ERAS-007 Monotherapy, QW dosing<br>ERAS-007 monotherapy will be administered at 250 mg QW to participants with advanced or metastatic solid tumors that harbor specific molecular alterations. | Drug: ERAS-007<br>* ERAS-007 will be administered orally as specified in Arm description.<br>|
| Experimental: Dose Expansion (Part C): ERAS-007 Monotherapy, BID-QW dosing (if necessary)<br>Depending on data generated from Part A, ERAS-007 monotherapy may be administered at the BID-QW RD to participants with advanced or metastatic solid tumors that harbor specific molecular alterations. | Drug: ERAS-007<br>* ERAS-007 will be administered orally as specified in Arm description.<br>|
| Experimental: Dose Escalation (Part D): ERAS-007 BID-QW dosing in combination with ERAS-601<br>Experimental: Dose Escalation (Part D): ERAS-007 BID-QW dosing in combination with ERAS-601 ERAS-007 will be administered BID-QW in combination with ERAS-601 administered BID 3/1 to study participants with advanced or metastatic solid tumors that harbor specific molecular targets in sequential ascending doses until unacceptable toxicity, disease progression, or withdrawal of consent. | Drug: ERAS-007<br>* ERAS-007 will be administered orally as specified in Arm description.<br>Drug: ERAS-601<br>* ERAS-601 will be administered orally as specified in Arm description.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate safety and tolerability of escalating doses of ERAS-007 BID-QW | Based on adverse events observed | 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 29 | 
| Maximum tolerated dose (MTD) | Based on adverse events observed | Study Day 1 up to Day 29 | 
| Recommended dose (RD) | Based on adverse events 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-007 | Study Day 1 up to Day 29 | 
| Time to achieve Cmax (Tmax) | Time to achieve maximum plasma concentration of ERAS-007 and ERAS-601 | Study Day 1 up to Day 29 | 
| Area under the curve | Area under the plasma concentration-time curve of ERAS-007 and ERAS-601 | Study Day 1 up to Day 29 | 
| Half-life | Half-life of ERAS-007 and ERAS-601 | 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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ERK, solid tumor, advanced solid tumor, metastatic solid tumor, neoplasms, solid malignancies, MAPK, SHP2