a safety study of sea-cd70 in patients with myeloid malignancies

Conditions: Myelodysplastic Syndrome; Acute Myeloid Leukemia

Summary: this trial will look at a drug called sea-cd70 with and without azacitidine, to find out if it is safe for participants with myelodysplastic syndrome (mds) and acute myeloid leukemia (aml). it will study sea-cd70 to find out what its side effects are and if it works for aml and mds. a side effect is anything the drug does besides treating cancer. this study will have seven groups or "parts." * part a will find out how much sea-cd70 should be given to participants * part b will use the dose found in part a to find out how safe sea-cd70 is and if it works to treat participants with mds. * part c will use the dose found in part a to find out how safe sea-cd70 is and if it works to treat participants with aml. * part d will find out how much sea-cd70 with azacitidine should be given to participants * part e will use the dose found in part d to find out how safe sea-cd70 with azacitidine is and if it works to treat participants with mds or mds/aml that has not been treated. * part f will use the dose found in part d to find out how safe sea-cd70 with azacitidine is and if it works to treat participants with mds or mds/aml. * part g will find out how much sea-cd70 with azacitidine and with venetoclax should be given to participants with aml. also, to evaluate safety and tolerability of pf-08046040 in combination with azacitidine and venetoclax in participants with previously untreated aml who are unfit for standard induction chemotherapy.

this is a phase 1, open-label, multicenter, dose-finding, and dose expansion study designed to evaluate the safety, tolerability, pharmacokinetics (pk), and antitumor activity of sea-cd70 monotherapy and sea-cd70 in combination with azacitidine in adults with myeloid malignancies. the study will be conducted in up to 6 parts. * part a is a dose-escalation cohort designed to identify the mtd or recommended expansion dose of sea-cd70 monotherapy in participants with relapsed/refractory (hypomethylating agent \[hma\]-failure) mds. * part b is an expansion cohort designed to evaluate the safety and tolerability of sea-cd70 monotherapy in participants with relapsed/refractory (hma-failure) mds. * part c is an expansion cohort designed to evaluate the safety and tolerability of sea-cd70 monotherapy in participants with relapsed/refractory aml. * part d contains dose-finding/dose optimization cohorts designed to evaluate the safety/tolerability and identify the recommended expansion dose of sea-cd70 in combination with azacitidine in participants with 1) relapsed/refractory (hma-failure) mds or mds/aml, and 2) previously untreated higher-risk per ipss-m (moderate high, high or very high) mds or mds/aml. * part e is an expansion cohort designed to evaluate the safety and tolerability of sea-cd70 in combination with azacitidine in participants with previously untreated higher-risk per ipss-m (moderate high, high, or very high) mds or mds/aml. * part f is an expansion cohort designed to evaluate the safety and tolerability of sea-cd70 in combination with azacitidine in participants with relapsed/refractory (hma-failure) mds or mds/aml. * part g will find out how much sea-cd70 with azacitidine and with venetoclax should be given to participants with previously untreated aml who are unfit for standard of care induction chemotherapy

Eligibility criteria:
part a inclusion criteria * participants with cytologically/histologically confirmed mds (2016 world health organization (who) classification) with * measurable disease per who mds with excess blasts criteria * mds that is relapsed or refractory and must not have other therapeutic options * treatment failure after prior hypomethylating agent (hma) therapy for mds * eastern cooperative oncology group (ecog) performance status of 0-1 part b inclusion criteria * participants with cytologically/histologically confirmed mds (who classification) with: * measurable disease per who mds with excess blasts (mds-eb) criteria * mds that is relapsed or refractory and must not have other therapeutic options * treatment failure after prior hma therapy for mds * ecog performance status of 0-2 part c inclusion criteria * participants with relapsed or refractory aml (icc 2022) (except for acute promyelocytic leukemia \[apl\]): * who have received either 2 or 3 previous regimens * who have received 1 previous regimen to treat active disease and have at least one of the following: * age \> 60 and ≤75 years. * primary resistant aml or secondary aml * first cr duration \<6 months * adverse-risk per european leukemia network genetic risk stratification * age 18-75 years * ecog performance status of 0-2 parts d and f inclusion criteria * participants with diagnosis of mds or mds/aml (icc 2022 criteria) * disease which has relapsed, failed to respond after minimum of 6 cycles, or progressed following an hma in the immediately preceding line of therapy. * eligible for continued therapy with azacitidine * ecog performance status 0-2 parts d and e inclusion criteria * participants with diagnosis of mds or mds/aml (icc 2022 criteria), previously untreated. * participants with higher-risk per ipss-m mds and mds/aml * ecog performance status 0-2 part g inclusion criteria * participants with diagnosis of aml (icc 2022 criteria), previously untreated and ineligible for standard induction chemotherapy. * age ≥18 years. * ecog performance status of 0-2. exclusion criteria (all parts) * previous exposure to cd70-targeted agents * prior allogeneic hematopoietic stem cell transplant, for any condition * central nervous system leukemia * history of clinically significant sickle cell anemia, autoimmune hemolytic anemia, or idiopathic thrombocytopenic purpura * parts d, f and g only: prior oral hma or oral hma-combinations * part g: conditions that preclude enteral route of administration; concomitant use of strong/moderate cyp3a inducers; history of myeloproliferative neoplasm

Keywords: seattle genetics