A Safety Study of SEA-CD70 in Patients With Myeloid Malignancies

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