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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: ERAS-007
* Drug: ERAS-601
* Drug: Gilteritinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation (Part 1): ERAS-007 plus gilteritinib<br>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<br>* Administered orally<br>Drug: Gilteritinib<br>* Administered orally<br>* Other names: Xospata;|
| Experimental: Dose Escalation (Part 2): ERAS-601 plus gilteritinib<br>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<br>* Administered orally<br>Drug: Gilteritinib<br>* Administered orally<br>* Other names: Xospata;|
| Experimental: Dose Expansion (Part 3): ERAS-007 plus gilteritinib<br>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<br>* Administered orally<br>Drug: Gilteritinib<br>* Administered orally<br>* Other names: Xospata;|
| Experimental: Dose Expansion (Part 4): ERAS-601 plus gilteritinib<br>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<br>* Administered orally<br>Drug: Gilteritinib<br>* Administered orally<br>* Other names: Xospata;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| Adverse Events | Incidence and severity of treatment-emergent AEs and serious AEs | Assessed up to 24 months from time of first dose | 

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, FLT3, mutation, relapsed, refractory, gilteritinib, Xospata, MAPK, SHP2, ERK