Clinical trial NCT05039177: A Study of ERAS-007 in Patients With Advanced Gastrointestinal Malignancies
Official title: A Phase 1b/2 Study of Agents Targeting the Mitogen-Activated Protein Kinase Pathway in Patients With Advanced Gastrointestinal Malignancies (HERKULES-3)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Metastatic Colorectal Cancer
Metastatic Pancreatic Ductal Adenocarcinoma
Keywords: 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
Lead sponsor: Erasca, Inc.
Sponsor class: INDUSTRY
First posted: 2021-09-09
Enrollment: 102
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Dose Limiting Toxicities (DLT)
timeFrame: Study Day 1 up to Day 29
measure: Maximum Tolerated Dose (MTD)
timeFrame: Study Day 1 up to Day 29
measure: Recommended Dose (RD)
timeFrame: Study Day 1 up to Day 29
measure: Adverse Events
timeFrame: Assessed up to 24 months from time of first dose
Secondary outcomes:
measure: Plasma concentration (Cmax)
timeFrame: Study Day 1 up to Day 29
measure: Time to achieve Cmax (Tmax)
timeFrame: Study Day 1 up to Day 29
measure: Area under the curve
timeFrame: Study Day 1 up to Day 29
measure: Half-life
timeFrame: Study Day 1 up to Day 29
measure: Objective Response Rate (ORR)
timeFrame: Assessed up to 24 months from time of first dose
measure: Duration of Response (DOR)
timeFrame: Assessed up to 24 months from time of first dose
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham (O'Neal Comprehensive Cancer Center)
state: Alabama
city: Duarte
country: United States
facility: City of Hope
state: California
city: Orange
country: United States
facility: University of California Irvine College of Medicine
state: California
city: San Francisco
country: United States
facility: UCSF Mount Zion Medical Ctr
state: California
city: Baltimore
country: United States
facility: The Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Cancer Institute
state: Michigan
city: Saint Louis
country: United States
facility: Washington University (Siteman Cancer Center)
state: Missouri
city: Durham
country: United States
facility: Duke Cancer Institute
state: North Carolina
city: Oklahoma City
country: United States
facility: Stephenson Cancer Center
state: Oklahoma
city: Nashville
country: United States
facility: Sarah Cannon Research Institute (Tennessee Oncology)
state: Tennessee
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists
state: Virginia
city: Seattle
country: United States
facility: University of Washington - Seattle Cancer Care Alliance
state: Washington
Study officials:
affiliation: Clinical Development
name: Joyce Antal
role: STUDY_DIRECTOR
References: