A Study of ERAS-007 in Patients With Advanced Gastrointestinal Malignancies

Study Overview
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Brief Summary
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To evaluate the safety and tolerability of escalating doses of ERAS-007 in combination with other cancer therapies in study participants with advanced GI malignancies. To determine the Maximum Tolerated Dose (MTD) and/or Recommended Dose (RD) of ERAS-007 administered in combination with other cancer therapies. To evaluate the antitumor activity of ERAS-007 in combination with other cancer therapies. To evaluate the PK profiles of ERAS-007 and other cancer therapies when administered in combination.

Detailed Description
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This is a Phase 1b/2, open-label, multicenter clinical study evaluating ERAS-007 in combination with other cancer therapies in study participants with GI malignancies. This study will serve as a platform study, allowing for evaluation of safety/tolerability and efficacy of ERAS-007 in combination with other cancer therapies. The study will initially commence with dose escalation of ERAS-007 administered in combination with encorafenib and cetuximab in study participants with metastatic colorectal cancer (CRC) harboring B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E mutation; and dose escalation of ERAS-007 administered in combination with palbociclib in study participants with metastatic CRC harboring Kirsten rat sarcoma (KRAS) or neuroblastoma rat sarcoma (NRAS) mutations and metastatic pancreatic adenocarcinoma with (PDAC) KRAS mutation. Dose expansion will follow and will test ERAS-007 administered at the RD identified from each dose escalation arm in study participants with metastatic CRC.

Official Title
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A Phase 1b/2 Study of Agents Targeting the Mitogen-Activated Protein Kinase Pathway in Patients With Advanced Gastrointestinal Malignancies (HERKULES-3)

Conditions
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Metastatic Colorectal Cancer, Metastatic Pancreatic Ductal Adenocarcinoma

Intervention / Treatment
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* Drug: ERAS-007
* Drug: Encorafenib
* Drug: Cetuximab
* Drug: Palbociclib


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 metastatic CRC harboring applicable mutation(s) (e.g., BRAF V600E; KRAS or NRAS mutations) or metastatic PDAC harboring KRAS mutation based on an analytically validated assay performed on tumor tissue in a certified testing laboratory. 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: Prior therapy with a RAS, MEK, or ERK inhibitor. Depending on which treatment arm the patient is assigned, other therapies could also be prohibitive. Anti-cancer therapy ≤ 21 days or 4 half-lives prior to first dose of study drug, whichever is shorter. Palliative radiation ≤ 7 days prior to first dose of study drug. Symptomatic brain metastasis or leptomeningeal disease. Gastrointestinal conditions that may affect absorption of oral medications Active infection requiring systemic therapy, or a known history of HIV infection, hepatitis B virus, or hepatitis C virus. History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤ 12 months prior to first study drug dose. Active, clinically significant interstitial lung disease or pneumonitis. Impaired cardiovascular function or clinically significant cardiovascular disease. History of thromboembolic or cerebrovascular events ≤ 6 months prior to first dose. Major surgery within 28 days of enrollment, or anticipation of major surgery during study treatment. Known intolerance or contraindication to encorafenib, cetuximab, or palbociclib. Pregnant or breastfeeding women. 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.

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 (Parts A1a, A2a, or A3a): ERAS-007 in combination with encorafenib and cetuximab<br>ERAS-007 will be orally administered in combination with encorafenib and cetuximab to study participants with BRAFm CRC in sequential ascending doses until unacceptable toxicity, disease progression, or withdrawal of consent. | Drug: ERAS-007<br>* Administered orally<br>Drug: Encorafenib<br>* Administered orally<br>* Other names: Braftovi;Drug: Cetuximab<br>* Administered via intravenous infusion<br>* Other names: Erbitux;|
| Experimental: Dose Escalation (Parts B1a, B2a, B3a or B4a): ERAS-007 in combination with palbociclib<br>ERAS-007 will be orally administered in combination with palbociclib to study participants with KRASm or NRASm CRC and KRASm PDAC in sequential ascending doses until unacceptable toxicity, disease progression, or withdrawal of consent. | Drug: ERAS-007<br>* Administered orally<br>Drug: Palbociclib<br>* Administered orally<br>* Other names: Ibrance;|
| Experimental: Dose Expan (Parts A1b, A1c, A2b, A2c, A3b, or A3c): ERAS-007 in combo with encorafenib & cetuximab<br>ERAS-007 will be orally administered at the recommended dose (as determined from Parts A1a, A2a or A3a) in combination with encorafenib and cetuximab to study participants with BRAFm CRC. | Drug: ERAS-007<br>* Administered orally<br>Drug: Encorafenib<br>* Administered orally<br>* Other names: Braftovi;Drug: Cetuximab<br>* Administered via intravenous infusion<br>* Other names: Erbitux;|
| Experimental: Dose Expansion (Parts B1b, B2b, B3b, and B4b): ERAS-007 in combination with palbociclib<br>ERAS-007 will be orally administered at the recommended dose (as determined from Parts B1a, B2a, B3a or B4a) in combination with palbociclib to study participants with KRASm or NRASm CRC. | Drug: ERAS-007<br>* Administered orally<br>Drug: Palbociclib<br>* Administered orally<br>* Other names: Ibrance;|

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 during dose escalation | Study Day 1 up to Day 29 | 
| Maximum Tolerated Dose (MTD) | Based on adverse events observed during dose escalation | Study Day 1 up to Day 29 | 
| Recommended Dose (RD) | Based on adverse events observed during dose escalation | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentration (Cmax) | Maximum plasma or serum concentration of ERAS-007 and other cancer therapies | Study Day 1 up to Day 29 | 
| Time to achieve Cmax (Tmax) | Time to achieve maximum plasma or serum concentration of ERAS-007 and other cancer therapies | Study Day 1 up to Day 29 | 
| Area under the curve | Area under the plasma concentration-time curve of ERAS-007 and other cancer therapies | Study Day 1 up to Day 29 | 
| Half-life | Half-life of ERAS-007 and other cancer therapies | Study Day 1 up to Day 29 | 
| 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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ERK, BRAF, V600E, KRAS, NRAS, mutation, Braftovi, encorafenib, Erbitux, cetuximab, Ibrance, palbociclib, MAPK, CDK4/6, CRC, colorectal cancer, EGFR, GI neoplasm, gastrointestinal neoplasm, PDAC, Pancreas Cancer