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

Erasca

Status and phase: Withdrawn; Phase 2; Phase 1

Conditions: Acute Myeloid Leukemia

Treatments: Drug: Gilteritinib; Drug: ERAS-007; Drug: ERAS-601

Study type: Interventional

Funder types: Industry

Identifiers

NCT05279859

ERAS-007-04

Details and patient eligibility

About

• 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.

Full 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.

Sex: All

Ages: 18 to 99 years old

Volunteers: No 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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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0 participants in 4 patient groups

Dose Escalation (Part 1): ERAS-007 plus gilteritinib

Experimental group

Description:

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.

Treatment:

Drug: ERAS-007

Drug: Gilteritinib

Dose Escalation (Part 2): ERAS-601 plus gilteritinib

Experimental group

Description:

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.

Treatment:

Drug: ERAS-601

Drug: Gilteritinib

Dose Expansion (Part 3): ERAS-007 plus gilteritinib

Experimental group

Description:

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.

Treatment:

Drug: ERAS-007

Drug: Gilteritinib

Dose Expansion (Part 4): ERAS-601 plus gilteritinib

Experimental group

Description:

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.

Treatment:

Drug: ERAS-601

Drug: Gilteritinib