a phase 1, open label study of intravenous gsk3745417 to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics and determine rp2d & schedule in participants with relapsed or refractory myeloid malignancies including aml and hr mds

Conditions: Leukemia, Myeloid, Acute

Summary: this is a phase 1, open label, two-part study to determine recommended phase 2 dose (rp2d) and schedule of gsk3745417 administration in participants with relapsed/refractory aml or hr-mds.


Eligibility criteria:
inclusion criteria: * participants must be ≥18 years of age and ≤75 years of age at the time of signing the informed consent for dose escalation and \>18 years of age at the time of signing the informed consent for the dose expansion. * participants must be capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (icf) and in the protocol. * participants must have eastern cooperative oncology group (ecog) performance status of 0 or 1. * participants with aml/hr mds are eligible for participation in part 1 and part 2 if they have: 1. a diagnosis of aml according to the world health organization 2016 criteria with relapsed or refractory disease and ineligible for or have exhausted standard therapeutic options. 2. have high-risk or high/very high by revised international prognostic scoring system (ipss-r) for mds (restricted to part 1) that has relapsed after or been refractory to prior therapy with hypomethylating agent. * participants with a prior history of stem cell transplant (autologous and/or allogeneic) are allowed if: no clinical signs or symptoms of graft versus host disease (other than grade 1 gvhd (\<25% skin surface affected) and the participant is off all systemic immunosuppression. (note: topical steroids for g1 skin gvhd are permitted on study) * participants must agree to abide by the gender specific contraceptive requirements below: female participants are eligible to participate if they are not either pregnant or breastfeeding, and at least one of the following conditions applies: 1. is not a woman of childbearing potential (wocbp), or 2. is a wocbp and using a contraceptive method that is highly effective (with a failure rate of \<1% per year), the effectiveness of the contraceptive method will be evaluated by the investigator in relationship to the first dose of study treatment. exclusion criteria: * diagnosis of acute promyelocytic leukemia (apml or t(15;17) pml-rara fusion). patients with biphenotypic disease are excluded. * active central nervous system (cns) involvement or disorder; and well controlled with ongoing treatment * participants with immediate life-threatening, severe complications of leukemia (sepsis, hemorrhage). * participants with extramedullary disease as the sole site of aml * participants with active severe or uncontrolled infection, * participants with active autoimmune disease that has required systemic disease modifying or immunosuppressive treatment within the last 2 years. * participants with concurrent medical condition requiring the use of systemic immunosuppressive treatment within 28 days before the first dose of study treatment. * participants with history of vasculitis at any time prior to study treatment. * participant with a history of other malignancies less than 2 years prior to study entry, * participants with qt interval corrected using fridericia's formula (qtcf) \>450 millisecond (msec) for male participants, \>470 msec for female participants, or \>480 msec for participants with bundle branch block. * participants with recent history of allergen desensitization therapy within 4 weeks of starting study treatment. * participants with history or evidence of cardiovascular (cv) risk history of immune myocarditis or pericarditis. * participants with prior sting therapy. * participants with prior solid organ transplantation. * participants with recent prior therapy defined as follows: any non-monoclonal anti-cancer therapy within 14 days or 5 half-lives, whichever is longer, prior to start of study treatment; prior therapy with biological agents (including monoclonal antibodies) within 28 days prior to start of study treatment; any radiotherapy or major surgery within 14 days prior to start of study treatment; currently receiving investigational therapy in a clinical trial * participants with immune-related toxicity related to prior treatment that has not resolved to grade ≤1 (except alopecia, hearing loss or grade ≤2 neuropathy or endocrinopathy managed with replacement therapy).

Keywords: gsk3745417 acute myeloid leukemia aml high-risk myelodysplastic syndrome hr-mds