A Study of Dual-SIgnaling Protein 107 (DSP107) for Patients With Hematological Malignancies

Sponsor

Kahr Medical (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04937166

Collaborator

(none)

Enrollment

Location

Arm

14.6

Anticipated Duration (Months)

2.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study will be divided into two parts, Parts A and B and will enroll patients with relapsed/refractory AML or MDS/chronic myelomonocytic leukemia (CMML) patients who have failed up to 2 prior therapeutic regimens.

Part A is a dose escalation study to explore the safety, efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) profile of DSP107 when administered as monotherapy and in combination with azacitidine (AZA).

Part B is a dose escalation study to explore the safety, efficacy, PK and PD profile of DSP107 when administered in combination with AZA and venetoclax (VEN).

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia Myelodysplastic Syndromes Chronic Myelomonocytic Leukemia	Biological: DSP107 Drug: Azacitidine Drug: Venetoclax	Phase 1

Detailed Description

Part A is a dose escalation study in up to 3 cohorts of patients designed to test the safety and efficacy of DSP107 administered alone and in combination with AZA. The DSP107 starting dose level in Part A will be 0.3 mg/kg based on aggregate safety, PK and PD data from study DSP107_001, an ongoing study exploring the safety of escalating DSP107 doses in patients with advanced solid tumors. There will be separate DLT evaluation periods, lasting at least 28 days, to determine the safety of DSP107 as a single agent and in combination with AZA. The safety, efficacy and PK data will be used to establish a recommended Phase II dose for potential future expansion cohorts and a starting dose for Part B.

Part B is a dose escalation study in 2 cohorts of patients that will test the safety and efficacy of DSP107 in combination with AZA and VEN. The starting dose for Part B will be at least one dose level lower than the DSP107 dose selected in Part A as being safe and effective in combination with AZA. Once a safe, effective dose has been established in Part B, a recommended phase 2 dose for patients with newly diagnosed AML will be agreed with the FDA at an End-of-Phase 1 meeting.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

36 participants

Allocation:

N/A

Intervention Model:

Sequential Assignment

Intervention Model Description:

This study will involve sequential enrolment of approximately 36 patients accrued into five dose cohorts, each testing a different DSP107 dose level as monotherapy and in combination with azacitidine (Part A) or DSP107 in combination with azacitidine and venetoclax (Part B).This study will involve sequential enrolment of approximately 36 patients accrued into five dose cohorts, each testing a different DSP107 dose level as monotherapy and in combination with azacitidine (Part A) or DSP107 in combination with azacitidine and venetoclax (Part B).

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An Open-label Phase Ib Study of DSP107 for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Actual Study Start Date :

Jan 13, 2022

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Apr 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: DSP107 monotherapy and in combination with azacitidine or azacitidine plus venetoclax. DSP107 will be administered by intravenous infusion once weekly during each 28-day cycle to all patients in this study. Azacitidine (75 mg/m2/day) will be administered subcutaneously or intravenously for the first 7 days of every cycle. Patients enrolled in Part B only will also receive venetoclax. During Cycle 1, venetoclax will be dose escalated daily to the goal dose of 400 mg daily. Patients will receive 100 mg on Day 1, 200 mg on Day 2 and 400 mg on Day 3 and onwards.	Biological: DSP107 DSP107 (SIRPα - 4-1BBL) is a bi-functional, trimeric, fusion protein. Drug: Azacitidine Azacitidine is an analog of the pyrimidine nucleoside cytidine. Other Names: Vidaza Drug: Venetoclax Venetoclax is a B-cell lymphoma (BCL)-2 inhibitor Other Names: Venclexta, Venclyxto

Arm

Intervention/Treatment

Experimental: DSP107 monotherapy and in combination with azacitidine or azacitidine plus venetoclax.

DSP107 will be administered by intravenous infusion once weekly during each 28-day cycle to all patients in this study. Azacitidine (75 mg/m2/day) will be administered subcutaneously or intravenously for the first 7 days of every cycle. Patients enrolled in Part B only will also receive venetoclax. During Cycle 1, venetoclax will be dose escalated daily to the goal dose of 400 mg daily. Patients will receive 100 mg on Day 1, 200 mg on Day 2 and 400 mg on Day 3 and onwards.

Biological: DSP107

DSP107 (SIRPα - 4-1BBL) is a bi-functional, trimeric, fusion protein.

Drug: Azacitidine

Azacitidine is an analog of the pyrimidine nucleoside cytidine.

Other Names:

Vidaza

Drug: Venetoclax

Venetoclax is a B-cell lymphoma (BCL)-2 inhibitor

Other Names:

Venclexta, Venclyxto

Outcome Measures

Primary Outcome Measures

Adverse Events (AEs) [Duration of the study, estimated to be 12 months]
An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
Dose Limiting Toxicities (DLT) [At the end of Treatment Cycle 2 (within 2 months of treatment initiation)]
A DLT is defined as a clinically significant AE or laboratory abnormality that is related to DSP107 or the combination of DSP107 and AZA, but is unrelated to disease progression, intercurrent illness or concomitant medications
Response Rate (RR) including Complete Remission (CR) and Complete Remission with Incomplete Blood Count Recovery (CRi) [Within 6 months of treatment initiation]
Response rates will be determined by assessing peripheral blood and bone marrow samples.

Secondary Outcome Measures

Overall Response Rate (ORR) [Within 6 months of treatment initiation]
Peripheral and bone marrow samples will be assessed to determine ORR. The ORR will measure the proportion of patients who achieve CR, CRi, complete remission with incomplete hematological recovery (CRh), complete remission with incomplete platelet recovery (CRp) or partial response (PR) within 6 months of treatment initiation, with or without cytogenetic response, hematological improvements and a morphologic leukemia-free state.
Morphologic Leukemia-Free (MLF) Rate [Within 6 months of treatment initiation]
Peripheral and bone marrow samples will be assessed to determine the proportion of patients who are morphologically leukemia-free within 6 months of treatment initiation.
Minimal Residual Disease (MRD) Status [Duration of the study, estimated to be 12 months]
Peripheral and bone marrow samples will be assessed to determine minimal residual disease (MRD) status at response and/or the best MRD response during study participation.
4-week Mortality Rate [Within 4 weeks of treatment initiation]
The proportion of patients who die within 4 weeks of treatment initiation.
DSP107 Serum Concentration [Duration of the study, estimated to be 12 months]
Serum samples will be collected to determine circulating levels of DSP107.
DSP107 anti-drug antibody (ADA) formation [Duration of the study, estimated to be 12 months]
Serum samples will be collected throughout the study for assessment of ADA formation using validated assay.
Change in Phenotypic and Activation Profiles of Peripheral Blood Mononuclear Cells [Duration of the study, estimated to be 12 months]
Whole blood samples will be collected throughout the study for immunophenotyping by flow cytometry and/or mass cytometry.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
White Blood Cell count < 20 x 109/L.
Adequate organ function
Relapsed/refractory AML or MDS/CMML patients who have failed up to 2 prior therapeutic regimens.

Exclusion Criteria:

Acute Promyelocytic leukemia
Symptomatic central nervous system (CNS) leukemia or patients with poorly controlled CNS leukemia
Life-threatening (grade 4) immune-mediated adverse event related to prior immunotherapy
Immune-mediated adverse reaction that required discontinuation of prior immunotherapy
Past or current history of autoimmune disease or immune deficiency
History of severe interstitial lung disease or severe pneumonitis or active pneumonitis
Clinically significant and poorly compensated liver disease
Prior organ allografts (such as renal transplant) requiring active immunosuppression
Active graft versus host disease
Treatment with systemic immunostimulatory within 4 weeks prior to initiation of study treatment
Treatment with any CD47/SIRPα targeting agent or immune agonists
Known allergy or hypersensitivity to any of the test compounds, materials or contraindication to test product
Received live, attenuated vaccine within 4 weeks prior to first dose of study treatment
Active Hepatitis B or C infection
History or evidence of any other clinically unstable/uncontrolled disorder, condition, or disease
Pregnant or breast feeding or planning to become pregnant while enrolled in the study