Acute Myeloid Leukemia, Myelodysplastic Syndrome
Conditions
Keywords
Seattle Genetics
Brief 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 compared to azacitidine alone 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.
Detailed 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 vs 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
Interventions
DRUGSEA-CD70
Given into the vein (IV; intravenously) on Days 1 and 15 of each treatment cycle
DRUGazacitidine
75mg/m\^2 injected under the skin (SC; subcutaneous) or given into the vein (IV; intravenously) on Days 1 through 7 of each treatment cycle.
DRUGVenetoclax
400 mg /day PO, continuously; administered with ramping
Sponsors
Seagen, a wholly owned subsidiary of Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Parts B and C may enroll in parallel after enrollment of Part A is complete. Part D will enroll after Part A is complete. Parts E, F and Part G will enroll in parallel once Part D is complete.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with adverse events (AEs) | Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years | Any untoward medical occurrence in a clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. |
| Number of participants with laboratory abnormalities | Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years | To be summarized using descriptive statistics. |
| Number of participants with a dose-limiting toxicity (DLT) at each dose level (Parts A and D only) | Though end of DLT evaluation period; up to approximately 4 weeks | To be summarized using descriptive statistics. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete remission with incomplete blood count recovery (CRi) rate | Up to approximately 4 years | Proportion of participants with AML who achieve CRi |
| Complete remission with limited count recovery (CRL) rate for participants with MDS or MDS/AML | Up to approximately 4 years | Proportion of participants with MDS or MDS/AML who achieve CRL |
| Complete remission with partial hematologic recovery (CRh) rate | Up to approximately 4 years | Proportion of participants with AML, MDS/AML, or MDS who achieve CRh |
| Hematologic response (HI) rate | Up to approximately 4 years | Proportion of participants with MDS or MDS/AML with HI |
| T1/2 - Terminal elimination half-life | Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years | To be summarized using descriptive statistics. |
| AUC - Area under the plasma concentration-time curve | Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years | To be summarized using descriptive statistics. |
| Tmax - Time to maximum concentration attained | Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years | To be summarized using descriptive statistics. |
| Cmax - Maximum observed plasma concentration | Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years | To be summarized using descriptive statistics. |
| Ctrough - Minimum plasma concentration per dosing interval | Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years | To be summarized using descriptive statistics. |
| Duration of remission (DOR) | Up to approximately 4 years | For AML, the time from first CR/CRi/CRh/PR response to the first documentation of disease progression, start of new anticancer therapy, or death due to any cause. For MDS, the time from first CR (or Req)/CRL/CRh/PR to the first documentation of disease progression, start of new anticancer therapy, or death due to any cause |
| Overall survival (OS) | Up to approximately 4 years | Time from start of study treatment to the date of death due to any cause |
| Event-free survival (EFS) | Up to approximately 4 years | Time from first dose to the first documentation of progression, failure to achieve remission within 6 months of study entry, disease relapse, or death due to any cause, whichever comes first. |
| Progression-free survival (PFS) | Up to approximately 4 years | Time from first dose to the first documentation of progression, disease relapse, or death from any cause, whichever comes first |
| MRD-negative ORR | Up to approximately 4 years | Proportion of participants with AML or MDS who achieve MRD-negative ORR |
| Time to response (TTR) | Up to approximately 4 years | Time from start of study treatment to the first documentation of objective response |
| Rate of conversion to transfusion independence (TI) | Up to approximately 4 years | Proportion of participants who convert from transfusion dependence at baseline to TI post-baseline |
| Overall response rate (ORR) | Up to approximately 4 years | For AML, the proportion of participants who achieve a best response of CR, CRi, CRh, or partial response (PR). For MDS, the proportion of participants who achieve a best response of CR, CReq, CRL, CRh, PR, or HI |
| Rate of TI maintenance | Up to approximately 4 years | Proportion of participants who were TI at baseline and maintain TI post-baseline |
| Incidence of antidrug antibodies (ADA) | Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years | To be summarized using descriptive statistics. |
| Complete remission (CR) Rate and complete remission equivalent (CReq) rate | Up to approximately 4 years | Proportion of participants with AML, MDS/AML or MDS who achieve CR or CReq |
Countries
Japan, Netherlands, United States
Contacts
STUDY_DIRECTORPfizer CT.gov Call Center
Pfizer
Outcome results
None listed