Overview
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.
Description
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
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