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

Official title

A Phase 1 Study of SEA-CD70 in Myeloid Malignancies

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.

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 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

• Drug SEA-CD70
  Given into the vein (IV; intravenously) on Days 1 and 15 of each treatment cycle
• Drug azacitidine
  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.
• Drug Venetoclax
  400 mg /day PO, continuously; administered with ramping

Primary outcome measures

• Number of participants with adverse events (AEs) [Time frame: Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years]
• Number of participants with laboratory abnormalities [Time frame: Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years]
• Number of participants with a dose-limiting toxicity (DLT) at each dose level (Parts A and D only) [Time frame: Though end of DLT evaluation period; up to approximately 4 weeks]

Secondary outcome measures (12)

• AUC - Area under the plasma concentration-time curve [Time frame: Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years]
• Tmax - Time to maximum concentration attained [Time frame: Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years]
• Cmax - Maximum observed plasma concentration [Time frame: Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years]
• Ctrough - Minimum plasma concentration per dosing interval [Time frame: Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years]
• T1/2 - Terminal elimination half-life [Time frame: Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years]
• Incidence of antidrug antibodies (ADA) [Time frame: Through 30-37 days following last dose of SEA-CD70; up to approximately 2 years]
• Complete remission (CR) Rate and complete remission equivalent (CReq) rate [Time frame: Up to approximately 4 years]
• Complete remission with incomplete blood count recovery (CRi) rate [Time frame: Up to approximately 4 years]
• Complete remission with limited count recovery (CRL) rate for participants with MDS or MDS/AML [Time frame: Up to approximately 4 years]
• Complete remission with partial hematologic recovery (CRh) rate [Time frame: Up to approximately 4 years]
• Hematologic response (HI) rate [Time frame: Up to approximately 4 years]
• Overall response rate (ORR) [Time frame: Up to approximately 4 years]

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 48 centers

• University of Alabama at Birmingham — Birmingham
• University of Alabama at Birmingham — Birmingham
• Dept. of Medicine, UAB ONeal Comprehensive Cancer Center — Birmingham
• City of Hope (City of Hope National Medical Center, City of Hope Medical Center) — Duarte
• IP Address: City of Hope Investigational Drug Services(IDS) — Duarte
• Ronald Reagan UCLA Medical Center — Los Angeles
• UCLA Hematology-Oncology Clinic — Los Angeles
• Colorado Blood Cancer Institute, Lab — Denver
• … and 40 more centers

Japan · 3 centers

• National Cancer Center Hospital East — Kashiwa
• Nippon Medical School Hospital — Bunkyo-ku
• Yamagata University Hospital — Yamagata

Netherlands · 2 centers

• Pharmacy - UMC Utrecht t.a.v. Apotheek KGO — Utrecht
• University Medical Center (UMC) Utrecht — Utrecht

Publications

• Dewulf J, Flieswasser T, Delahaye T, Vangestel C, Miranda A, de Haard H, Jacobs J, Smits E, Van den Wyngaert T, Elvas F. Site-specific 68Ga-labeled nanobody for PET imaging of CD70 expression in preclinical tumor models. EJNMMI Radiopharm Chem. 2023 Apr 24;8(1):8. doi: 10.1186/s41181-023-00194-3. PMID 37093350

Identifiers

NCT: NCT04227847 · SGNS70-101 · C5781001 · 2023-506945-42-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗