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

• ClinicalTrials.gov Identifier: NCT05039177
• Recruitment Status: Recruiting
• First Posted: September 9, 2021
• Last Update Posted: December 1, 2022
• Sponsor: Erasca, Inc.
• Information provided by (Responsible Party): Erasca, Inc.

Study Description

Brief Summary:

• 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.

Condition or disease	Intervention/treatment	Phase
Metastatic Colorectal Cancer; Metastatic Pancreatic Ductal Adenocarcinoma	Drug: ERAS-007; Drug: Encorafenib; Drug: Cetuximab; Drug: Palbociclib	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 200 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1b/2 Study of Agents Targeting the Mitogen-Activated Protein Kinase Pathway in Patients With Advanced Gastrointestinal Malignancies (HERKULES-3)
• Actual Study Start Date: September 20, 2021
• Estimated Primary Completion Date: August 2024
• Estimated Study Completion Date: December 2024

Arms and Interventions

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: ERAS-007; Administered orally; Drug: Encorafenib; Administered orally; Other Name: Braftovi; Drug: Cetuximab; Administered via intravenous infusion; Other Name: Erbitux
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 Name: 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: ERAS-007; Administered orally; Drug: Encorafenib; Administered orally; Other Name: Braftovi; Drug: Cetuximab; Administered via intravenous infusion; Other Name: Erbitux
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 Name: Ibrance

Outcome Measures

Primary Outcome Measures :

1. Dose Limiting Toxicities (DLT) [ Time Frame: Study Day 1 up to Day 29 ]
   Based on adverse events observed during dose escalation
2. Maximum Tolerated Dose (MTD) [ Time Frame: Study Day 1 up to Day 29 ]
   Based on adverse events observed during dose escalation
3. Recommended Dose (RD) [ Time Frame: Study Day 1 up to Day 29 ]
   Based on adverse events observed during dose escalation
4. Adverse Events [ Time Frame: Assessed up to 24 months from time of first dose ]
   Incidence and severity of treatment-emergent AEs and serious AEs

Secondary Outcome Measures :

1. Plasma concentration (Cmax) [ Time Frame: Study Day 1 up to Day 29 ]
   Maximum plasma or serum concentration of ERAS-007 and other cancer therapies
2. Time to achieve Cmax (Tmax) [ Time Frame: Study Day 1 up to Day 29 ]
   Time to achieve maximum plasma or serum concentration of ERAS-007 and other cancer therapies
3. Area under the curve [ Time Frame: Study Day 1 up to Day 29 ]
   Area under the plasma concentration-time curve of ERAS-007 and other cancer therapies
4. Half-life [ Time Frame: Study Day 1 up to Day 29 ]
   Half-life of ERAS-007 and other cancer therapies
5. Objective Response Rate (ORR) [ Time Frame: Assessed up to 24 months from time of first dose ]
   Based on assessment of radiographic imaging per RECIST version 1.1
6. Duration of Response (DOR) [ Time Frame: Assessed up to 24 months from time of first dose ]
   Based on assessment of radiographic imaging per RECIST version 1.1

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 99 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Erasca Clinical Team; +1-858-465-6511; clinicaltrials@erasca.com

Locations

United States, Alabama

University of Alabama at Birmingham (O'Neal Comprehensive Cancer Center); Recruiting

Birmingham, Alabama, United States, 35233

United States, California

City of Hope; Recruiting

Duarte, California, United States, 91010

University of California Irvine College of Medicine; Recruiting

Orange, California, United States, 92868

UCSF Mount Zion Medical Ctr; Recruiting

San Francisco, California, United States, 94158

United States, Maryland

The Johns Hopkins Hospital; Recruiting

Baltimore, Maryland, United States, 21287

United States, Massachusetts

Massachusetts General Hospital; Recruiting

Boston, Massachusetts, United States, 02215

United States, Michigan

Henry Ford Cancer Institute; Recruiting

Detroit, Michigan, United States, 48202

United States, Missouri

Washington University (Siteman Cancer Center); Recruiting

Saint Louis, Missouri, United States, 63110

United States, North Carolina

Duke Cancer Institute; Recruiting

Durham, North Carolina, United States, 27710

United States, Oklahoma

Stephenson Cancer Center; Recruiting

Oklahoma City, Oklahoma, United States, 73104

United States, Tennessee

Sarah Cannon Research Institute (Tennessee Oncology); Recruiting

Nashville, Tennessee, United States, 37203

United States, Texas

The University of Texas MD Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

United States, Virginia

Virginia Cancer Specialists; Recruiting

Fairfax, Virginia, United States, 22031

United States, Washington

University of Washington - Seattle Cancer Care Alliance; Recruiting

Seattle, Washington, United States, 98109

Sponsors and Collaborators

Erasca, Inc.

Investigators

• Study Director: Wei Lin, M.D.; Chief Medical Officer

More Information

• Responsible Party: Erasca, Inc.
• ClinicalTrials.gov Identifier: NCT05039177
• Other Study ID Numbers: ERAS-007-03
• First Posted: September 9, 2021
• Last Update Posted: December 1, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Erasca, Inc.:

BRAF; V600E; KRAS; NRAS; mutation; Braftovi; encorafenib; Erbitux; cetuximab; Ibrance; palbociclib; ERK; MAPK; CDK4/6; CRC; colorectal cancer; EGFR; GI neoplasm; gastrointestinal neoplasm; PDAC; Pancreas Cancer

Additional relevant MeSH terms:

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Cetuximab; Palbociclib; Antineoplastic Agents, Immunological; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action