HERKULES-4: A Study of Anti-Cancer Therapies Targeting the MAPK Pathway in Patients With Hematologic Malignancies

Sponsor

Erasca, Inc. (Industry)

Overall Status

Withdrawn

CT.gov ID

NCT05279859

Collaborator

(none)

Enrollment

Locations

Arms

38.6

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

To evaluate the safety and tolerability of escalating doses of ERAS-007 or ERAS-601 in combination with other cancer therapies in study participants with hematologic malignancies.
To determine the Maximum Tolerated Dose (MTD) and/or Recommended Dose (RD) of ERAS-007 or ERAS-601 administered in combination with other cancer therapies.
To evaluate the preliminary efficacy of ERAS-007 or ERAS-601 in combination with other cancer therapies in study participants with hematologic malignancies.
To evaluate the PK profiles of ERAS-007 or ERAS-601 and other cancer therapies when administered in combination.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: ERAS-007 Drug: ERAS-601 Drug: Gilteritinib	Phase 1/Phase 2

Detailed Description

This is a Phase 1b/2, open-label, multicenter master protocol evaluating safety, tolerability, and preliminary efficacy of ERAS-007 or ERAS-601 in combination with other cancer therapies in study participants with hematologic malignancies. The study will commence with dose escalation cohorts (ERAS-007 plus gilteritinib and ERAS-601 plus gilteritinib) in study participants with relapsed or refractory (R/R) Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3) mutated acute myeloid leukemia (AML). Dose expansion will follow and will evaluate ERAS-007 or ERAS-601 drug combinations administered at the RD identified from each respective dose escalation cohort in study participants with R/R FLT-3 mutated AML.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1b/2 Master Protocol of Agents Targeting the Mitogen-Activated Protein Kinase Pathway in Patients With Hematologic Malignancies

Anticipated Study Start Date :

Mar 15, 2022

Anticipated Primary Completion Date :

Mar 1, 2025

Anticipated Study Completion Date :

Jun 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose Escalation (Part 1): ERAS-007 plus gilteritinib ERAS-007 will be administered in combination with gilteritinib to study participants with R/R FLT3 mutated AML in sequential ascending doses until unacceptable toxicity, disease progression, or withdrawal of consent.	Drug: ERAS-007 Administered orally Drug: Gilteritinib Administered orally Other Names: Xospata
Experimental: Dose Escalation (Part 2): ERAS-601 plus gilteritinib ERAS-601 will be administered in combination with gilteritinib to study participants with R/R FLT3 mutated AML in sequential ascending doses until unacceptable toxicity, disease progression, or withdrawal of consent.	Drug: ERAS-601 Administered orally Drug: Gilteritinib Administered orally Other Names: Xospata
Experimental: Dose Expansion (Part 3): ERAS-007 plus gilteritinib ERAS-007 will be administered at the recommended dose (as determined from Part 1) in combination with gilteritinib to study participants with R/R FLT3 mutated AML.	Drug: ERAS-007 Administered orally Drug: Gilteritinib Administered orally Other Names: Xospata
Experimental: Dose Expansion (Part 4): ERAS-601 plus gilteritinib ERAS-601 will be administered at the recommended dose (as determined from Part 2) in combination with gilteritinib to study participants with R/R FLT3 mutated AML.	Drug: ERAS-601 Administered orally Drug: Gilteritinib Administered orally Other Names: Xospata

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Plasma concentration (Cmax) [Study Day 1 up to Day 29]
Maximum plasma concentration of ERAS-007 or ERAS-601 and other cancer therapies
Time to achieve Cmax (Tmax) [Study Day 1 up to Day 29]
Time to achieve maximum plasma concentration of ERAS-007 or ERAS-601 and other cancer therapies
Area under the curve [Study Day 1 up to Day 29]
Area under the plasma concentration-time curve of ERAS-007 or ERAS-601 and other cancer therapies
Half-life [Study Day 1 up to Day 29]
Half-life of ERAS-007 or ERAS-601 and other cancer therapies
Antileukemic activity [Assessed up to 24 months from time of first dose]
Percentage of Participants With Complete Remission and Complete Remission With Partial Hematological Recovery (CR/CRh); CR rate
Duration of antileukemic activity [Assessed up to 24 months from time of first dose]
Duration of CR/CRh (DOCR/DOCRh)
Duration of antileukemic activity [Assessed up to 24 months from time of first dose]
Duration of CR (DOCR)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 99 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age ≥ 18 years.
Willing and able to give written informed consent.
Diagnosis of primary AML or AML secondary to myelodysplastic syndrome (MDS) according to World Health Organization classification.
Relapsed after or refractory to first-line AML therapy.
Positive for FLT3 mutation in bone marrow or whole blood.
Eastern Cooperative Oncology Group performance status ≤ 2 with no deterioration during screening period.
Adequate hepatic and renal function.
Recovery from non-hematologic AEs associated with prior therapy to baseline CTCAE v5 Grade 0 or 1, except for AEs not considered a safety risk (eg, alopecia or vitiligo).
Able to take oral medication with no medical conditions that prevent swallowing and absorbing oral medications.
Willing to comply with all protocol-required visits, assessments, and procedures.

Exclusion Criteria:

Diagnosis of AML secondary to prior chemotherapy or other neoplasms (except for MDS).
Diagnosis of acute promyelocytic leukemia or BCR-ABL-positive leukemia (chronic myeologenous leukemia in blast crisis).
Clinically active central nervous system leukemia.
Second or later hematologic relapse or prior salvage therapy for refractory disease.
For participants being considered for ERAS-007+gilteritinib treatment: prior therapy with ERK inhibitor.
For participants being considered for ERAS-601+gilteritinib treatment: prior therapy with SHP2 inhibitor.
Anticancer therapy ≤14 days prior to first dose (except hydroxyurea given for controlling blast count), or ≤5 half-lives prior to first dose, whichever is shorter.
Palliative radiation ≤7 days prior to first dose.
Major surgery within 28 days of enrollment.
Contraindication to gilteritinib use as per local label.
Known hypersensitivity to any of the components of ERAS-007 or ERAS-601.
Clinically active infection, requiring systemic therapy.
Impaired cardiovascular function or clinically significant cardiovascular disease.
History of thromboembolic or cerebrovascular events ≤6 months prior to first dose.
History of other malignancy ≤3 years prior to first dose.
History of retinal pigment epithelial detachment (RPED), central serous retinopathy, retinal vein occlusion (RVO), or risk factors to RPED or RVO.
History of or clinically active interstitial lung disease (ILD), drug induced ILD, or radiation pneumonitis that required steroid treatment.
Any evidence of severe or uncontrolled systemic disease or evidence of any other significant clinical disorder or laboratory finding that renders the participant inappropriate to participate in the study.
Pregnant or breastfeeding women.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California San Francisco	San Francisco	California	United States	94143
2	Texas Oncology	Dallas	Texas	United States	75251
3	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
4	NEXT Oncology Virginia	Fairfax	Virginia	United States	22031