Clinical trial NCT05279859: A Study of Anti-Cancer Therapies Targeting the MAPK Pathway in Patients With Hematologic Malignancies
Official title: A Phase 1b/2 Master Protocol of Agents Targeting the Mitogen-Activated Protein Kinase Pathway in Patients With Hematologic Malignancies
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE1
PHASE2
Conditions: Acute Myeloid Leukemia
Keywords: AML
FLT3
mutation
relapsed
refractory
gilteritinib
Xospata
MAPK
SHP2
ERK
Lead sponsor: Erasca, Inc.
Sponsor class: INDUSTRY
First posted: 2022-03-15
Enrollment: 0
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 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: 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.

Eligibility criteria: 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.

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: Antileukemic activity
timeFrame: Assessed up to 24 months from time of first dose
measure: Duration of antileukemic activity
timeFrame: Assessed up to 24 months from time of first dose
measure: Duration of antileukemic activity
timeFrame: Assessed up to 24 months from time of first dose
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Dallas
country: United States
facility: Texas Oncology
state: Texas
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
city: Fairfax
country: United States
facility: NEXT Oncology Virginia
state: Virginia
Study officials:
affiliation: Medical Monitor
name: Les Brail, Ph.D.
role: STUDY_DIRECTOR
References: