a study of anti-cancer therapies targeting the mapk pathway in patients with hematologic malignancies

Conditions: Acute Myeloid Leukemia

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.

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.

Keywords: aml flt3 mutation relapsed refractory gilteritinib xospata mapk shp2 erk