A Study of ERAS-007 in Patients With Advanced Gastrointestinal Malignancies (HERKULES-3)

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

• 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.

Study Overview

• Status: Completed
• Conditions: Metastatic Colorectal Cancer; Metastatic Pancreatic Ductal Adenocarcinoma
• Intervention / Treatment: Drug: Cetuximab; Drug: ERAS-007; Drug: Encorafenib; Drug: Palbociclib

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 101
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham (O'Neal Comprehensive Cancer Center)
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Orange, California, United States, 92868
      • University of California Irvine College of Medicine
    • San Francisco, California, United States, 94158
      • UCSF Mount Zion Medical Ctr
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • The Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Massachusetts General Hospital
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Cancer Institute
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University (Siteman Cancer Center)
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Cancer Institute
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Stephenson Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute (Tennessee Oncology)
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists
  • Washington
    • Seattle, Washington, United States, 98109
      • University of Washington - Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 95 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 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.

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

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Escalation (Parts A1a, A2a, or A3a): ERAS-007 in combination with encorafenib and cetuximab; 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: Cetuximab; Administered via intravenous infusion; Other Names: Erbitux; Drug: ERAS-007; Administered orally; Drug: Encorafenib; Administered orally; Other Names: Braftovi
Experimental: Dose Escalation (Parts B1a, B2a, B3a or B4a): ERAS-007 in combination with palbociclib; 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; Administered orally; Drug: Palbociclib; Administered orally; Other Names: Ibrance
Experimental: Dose Expan (Parts A1b, A1c, A2b, A2c, A3b, or A3c): ERAS-007 in combo with encorafenib & cetuximab; 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: Cetuximab; Administered via intravenous infusion; Other Names: Erbitux; Drug: ERAS-007; Administered orally; Drug: Encorafenib; Administered orally; Other Names: Braftovi
Experimental: Dose Expansion (Parts B1b, B2b, B3b, and B4b): ERAS-007 in combination with palbociclib; 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; Administered orally; Drug: Palbociclib; Administered orally; Other Names: Ibrance

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 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

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 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

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2021
• Primary Completion (Actual): August 15, 2025
• Study Completion (Actual): January 26, 2026

Study Registration Dates

• First Submitted: September 1, 2021
• First Submitted That Met QC Criteria: September 1, 2021
• First Posted (Actual): September 9, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2026
• Last Update Submitted That Met QC Criteria: March 23, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: colorectal cancer; mutation; EGFR; ERK; MAPK; KRAS; CRC; cetuximab; Erbitux; Pancreas Cancer; BRAF; NRAS; PDAC; Ibrance; encorafenib; palbociclib; CDK4/6; V600E; Braftovi; GI neoplasm; gastrointestinal neoplasm
• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Intestinal Diseases; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Colonic Diseases; Colorectal Neoplasms; Pancreatic Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Cetuximab; encorafenib; palbociclib
• Other Study ID Numbers: ERAS-007-03

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