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A Phase 1, Open Label Study of Intravenous GSK3745417 to Evaluate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Determine RP2D & Schedule in Participants With Relapsed or Refractory Myeloid Malignancies Including AML and HR MDS

Primary Purpose

Leukemia, Myeloid, Acute

Status
Recruiting
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
GSK3745417
Sponsored by
GlaxoSmithKline
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Leukemia, Myeloid, Acute focused on measuring GSK3745417, Acute myeloid leukemia, AML, high-risk myelodysplastic syndrome, HR-MDS

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Participants must be ≥18 years of age and ≤75 years of age at the time of signing the informed consent for dose escalation and >18 years of age at the time of signing the informed consent for the dose expansion.
  • Participants must be capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol.
  • Participants must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • Participants with AML/HR MDS are eligible for participation in Part 1 and Part 2 if they have:

    1. A diagnosis of AML according to the World Health Organization 2016 criteria with relapsed or refractory disease and ineligible for or have exhausted standard therapeutic options.
    2. Have high-risk or high/very high by Revised International Prognostic Scoring System (IPSS-R) for MDS (restricted to Part 1) that has relapsed after or been refractory to prior therapy with hypomethylating agent.
  • Participants with a prior history of stem cell transplant (autologous and/or allogeneic) are allowed if:

No clinical signs or symptoms of graft versus host disease (other than Grade 1 GVHD (<25% skin surface affected) and the participant is off all systemic immunosuppression. (Note: topical steroids for G1 skin GVHD are permitted on study)

  • Participants must agree to abide by the gender specific contraceptive requirements below:

Female participants are eligible to participate if they are not either pregnant or breastfeeding, and at least one of the following conditions applies:

  1. Is not a woman of childbearing potential (WOCBP), or
  2. Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), The effectiveness of the contraceptive method will be evaluated by the investigator in relationship to the first dose of study treatment.

Exclusion Criteria:

  • Diagnosis of acute promyelocytic leukemia (APML or t(15;17) PML-RARA fusion). Patients with biphenotypic disease are excluded.
  • Active central nervous system (CNS) involvement or disorder; and well controlled with ongoing treatment
  • Participants with Immediate life-threatening, severe complications of leukemia (sepsis, hemorrhage).
  • Participants with extramedullary disease as the sole site of AML
  • Participants with active severe or uncontrolled infection,
  • Participants with active autoimmune disease that has required systemic disease modifying or immunosuppressive treatment within the last 2 years.
  • Participants with concurrent medical condition requiring the use of systemic immunosuppressive treatment within 28 days before the first dose of study treatment.
  • Participants with history of vasculitis at any time prior to study treatment.
  • Participant with a history of other malignancies less than 2 years prior to study entry,
  • Participants with QT interval corrected using Fridericia's formula (QTcF) >450 millisecond (msec) for male participants, >470 msec for female participants, or >480 msec for participants with bundle branch block.
  • Participants with recent history of allergen desensitization therapy within 4 weeks of starting study treatment.
  • Participants with history or evidence of cardiovascular (CV) risk history of immune myocarditis or pericarditis.
  • Participants with prior STING therapy.
  • Participants with prior solid organ transplantation.
  • Participants with recent prior therapy defined as follows: any non-monoclonal anti-cancer therapy within 14 days or 5 half-lives, whichever is longer, prior to start of study treatment; prior therapy with biological agents (including monoclonal antibodies) within 28 days prior to start of study treatment; any radiotherapy or major surgery within 14 days prior to start of study treatment; currently receiving investigational therapy in a clinical trial
  • Participants with immune-related toxicity related to prior treatment that has not resolved to Grade ≤1 (except alopecia, hearing loss or Grade ≤2 neuropathy or endocrinopathy managed with replacement therapy).

Sites / Locations

  • GSK Investigational SiteRecruiting
  • GSK Investigational SiteRecruiting
  • GSK Investigational SiteRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Part 1: Dose escalation

Part 2: Dose expansion

Arm Description

Part 1 will evaluate a dosing schedule for a total of 28 days in each cycle. The starting dose for Cycle 1 will be escalated in the next dose escalation cohort until MTD is reached.

Part 2 will evaluate efficacy after an induction phase. The induction phase consists of a treatment regimen at RP2D determined in Part 1.

Outcomes

Primary Outcome Measures

Part 1: Number of participants with Adverse Events (AEs) and number of participants per severity grade of AE in total population
Severity for each AE will be reported during the study and will assign a grade according to the National Cancer Institute - Common Toxicity Criteria for Adverse Events (NCI-CTCAE) v5.0.
Part 1: Number of participants with Serious Adverse Events (SAEs) and number of participants per severity grade of SAE in total population
Severity for each SAE will be reported during the study and will assign a grade according to the NCI-CTCAE v5.0.
Part 1: Number of participants with Dose limiting toxicities (DLT) and number of participants per severity grade of DLT
An AE will be considered a DLT if the investigator considers it to be clinically relevant and attributed (definitely, probably, or possibly) to the study intervention and meets at least 1 of the DLT criteria. Severity for DLT will be reported according to the NCI-CTCAE v5.0.
Part 1: Number of participants with withdrawals due to AEs
Part 2: Overall response rate (ORR) after the daily dosing induction period of GSK3745417
ORR is defined as the percentage of participants with a complete remission (CR), CR with incomplete platelet recovery (CRp), CR with incomplete count recovery (CRi), or a partial remission (PR) as per response criteria for AML and HR MDS respectively.
Part 2: Number of participants with AEs and number of participants per severity grade of AE in total population during maintenance dosing
Severity for each AE will be reported during the study and will assign a grade according to the NCI-CTCAE v5.0.
Part 2: Number of participants with SAEs and number of participants per severity grade of SAE in total population during maintenance dosing
Severity for each SAE will be reported during the study and will assign a grade according to the NCI-CTCAE v5.0.
Part 2: Number of participants with DLT and number of participants per severity grade of DLT during maintenance dosing
An AE will be considered a DLT if the investigator considers it to be clinically relevant and attributed (definitely, probably, or possibly) to the study intervention and meets at least 1 of the DLT criteria. Severity for DLT will be reported according to the NCI-CTCAE v5.0.
Part 2: Number of participants with withdrawals due to AEs during maintenance dosing

Secondary Outcome Measures

Part 1: Maximum concentration (Cmax) following administration of GSK3745417
Part 1: Area under the concentration-time curve AUC(0-t) following administration of GSK3745417
Part 1: AUC (0-tau) following administration of GSK3745417 Part 1: AUC(0-infinity) following repeated dose administration of GSK3745417
Part 1: AUC(0-infinity) following repeated dose administration of GSK3745417
Part 1: AUC(0-infinity) following single dose administration of GSK3745417
Part 1: Terminal phase elimination rate constant (Lambda Z) following administration of GSK3745417
Part 1: Terminal phase half-life (t1/2) following single dose administration of GSK3745417
Part 1: Systemic clearance of parent drug (CL) following administration of GSK3745417
Part 1: Volume of distribution (V) following administration of GSK3745417
Part 2: Number of participants with AEs, leading to dose modification and dose delays
Part 2: Number of participants with SAEs and AESIs leading to dose modification and dose delays
Part 2: Cmax following administration of GSK3745417
Part 2: AUC(0-t) following administration of GSK3745417
Part 2: AUC (0-tau) following administration of GSK3745417
Part 2: AUC(0-infinity) following repeated dose of GSK3745417
Part 2: AUC(0-infinity) following administration of single dose GSK3745417
Part 2: Lambda Z following administration of GSK3745417
Part 2: t1/2 following administration of single dose GSK3745417
Part 2: CL following administration of GSK3745417
Part 2: V following administration of GSK3745417

Full Information

First Posted
June 15, 2022
Last Updated
October 4, 2022
Sponsor
GlaxoSmithKline
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1. Study Identification

Unique Protocol Identification Number
NCT05424380
Brief Title
A Phase 1, Open Label Study of Intravenous GSK3745417 to Evaluate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Determine RP2D & Schedule in Participants With Relapsed or Refractory Myeloid Malignancies Including AML and HR MDS
Official Title
A Phase 1, Open Label Study of Intravenous GSK3745417 to Evaluate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Determine RP2D and Schedule in Participants With Relapsed or Refractory Myeloid Malignancies Including Acute Myeloid Leukemia (AML) and High-risk Myelodysplastic Syndrome (HR-MDS)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Recruiting
Study Start Date
September 20, 2022 (Actual)
Primary Completion Date
December 1, 2025 (Anticipated)
Study Completion Date
December 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
GlaxoSmithKline

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
This is a Phase 1, open label, two-part study to determine recommended phase 2 dose (RP2D) and schedule of GSK3745417 administration in participants with relapsed/refractory AML or HR-MDS.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Myeloid, Acute
Keywords
GSK3745417, Acute myeloid leukemia, AML, high-risk myelodysplastic syndrome, HR-MDS

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
72 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Part 1: Dose escalation
Arm Type
Experimental
Arm Description
Part 1 will evaluate a dosing schedule for a total of 28 days in each cycle. The starting dose for Cycle 1 will be escalated in the next dose escalation cohort until MTD is reached.
Arm Title
Part 2: Dose expansion
Arm Type
Experimental
Arm Description
Part 2 will evaluate efficacy after an induction phase. The induction phase consists of a treatment regimen at RP2D determined in Part 1.
Intervention Type
Drug
Intervention Name(s)
GSK3745417
Intervention Description
GSK3745417 will be administered
Primary Outcome Measure Information:
Title
Part 1: Number of participants with Adverse Events (AEs) and number of participants per severity grade of AE in total population
Description
Severity for each AE will be reported during the study and will assign a grade according to the National Cancer Institute - Common Toxicity Criteria for Adverse Events (NCI-CTCAE) v5.0.
Time Frame
Up to 36 weeks
Title
Part 1: Number of participants with Serious Adverse Events (SAEs) and number of participants per severity grade of SAE in total population
Description
Severity for each SAE will be reported during the study and will assign a grade according to the NCI-CTCAE v5.0.
Time Frame
Up to 49 weeks
Title
Part 1: Number of participants with Dose limiting toxicities (DLT) and number of participants per severity grade of DLT
Description
An AE will be considered a DLT if the investigator considers it to be clinically relevant and attributed (definitely, probably, or possibly) to the study intervention and meets at least 1 of the DLT criteria. Severity for DLT will be reported according to the NCI-CTCAE v5.0.
Time Frame
Up to 4 weeks
Title
Part 1: Number of participants with withdrawals due to AEs
Time Frame
Up to 36 weeks
Title
Part 2: Overall response rate (ORR) after the daily dosing induction period of GSK3745417
Description
ORR is defined as the percentage of participants with a complete remission (CR), CR with incomplete platelet recovery (CRp), CR with incomplete count recovery (CRi), or a partial remission (PR) as per response criteria for AML and HR MDS respectively.
Time Frame
Up to 12 weeks
Title
Part 2: Number of participants with AEs and number of participants per severity grade of AE in total population during maintenance dosing
Description
Severity for each AE will be reported during the study and will assign a grade according to the NCI-CTCAE v5.0.
Time Frame
Up to 36 weeks
Title
Part 2: Number of participants with SAEs and number of participants per severity grade of SAE in total population during maintenance dosing
Description
Severity for each SAE will be reported during the study and will assign a grade according to the NCI-CTCAE v5.0.
Time Frame
Up to 49 weeks
Title
Part 2: Number of participants with DLT and number of participants per severity grade of DLT during maintenance dosing
Description
An AE will be considered a DLT if the investigator considers it to be clinically relevant and attributed (definitely, probably, or possibly) to the study intervention and meets at least 1 of the DLT criteria. Severity for DLT will be reported according to the NCI-CTCAE v5.0.
Time Frame
Up to 4 weeks
Title
Part 2: Number of participants with withdrawals due to AEs during maintenance dosing
Time Frame
Up to 36 weeks
Secondary Outcome Measure Information:
Title
Part 1: Maximum concentration (Cmax) following administration of GSK3745417
Time Frame
Up to 36 weeks
Title
Part 1: Area under the concentration-time curve AUC(0-t) following administration of GSK3745417
Time Frame
Up to 36 weeks
Title
Part 1: AUC (0-tau) following administration of GSK3745417 Part 1: AUC(0-infinity) following repeated dose administration of GSK3745417
Time Frame
Up to 36 weeks
Title
Part 1: AUC(0-infinity) following repeated dose administration of GSK3745417
Time Frame
Up to 36 weeks
Title
Part 1: AUC(0-infinity) following single dose administration of GSK3745417
Time Frame
Up to 36 weeks
Title
Part 1: Terminal phase elimination rate constant (Lambda Z) following administration of GSK3745417
Time Frame
Up to 36 weeks
Title
Part 1: Terminal phase half-life (t1/2) following single dose administration of GSK3745417
Time Frame
Up to 36 weeks
Title
Part 1: Systemic clearance of parent drug (CL) following administration of GSK3745417
Time Frame
Up to 36 weeks
Title
Part 1: Volume of distribution (V) following administration of GSK3745417
Time Frame
Up to 36 weeks
Title
Part 2: Number of participants with AEs, leading to dose modification and dose delays
Time Frame
Up to 36 weeks
Title
Part 2: Number of participants with SAEs and AESIs leading to dose modification and dose delays
Time Frame
Up to 49 weeks
Title
Part 2: Cmax following administration of GSK3745417
Time Frame
Up to 36 weeks
Title
Part 2: AUC(0-t) following administration of GSK3745417
Time Frame
Up to 36 weeks
Title
Part 2: AUC (0-tau) following administration of GSK3745417
Time Frame
Up to 36 weeks
Title
Part 2: AUC(0-infinity) following repeated dose of GSK3745417
Time Frame
Up to 36 weeks
Title
Part 2: AUC(0-infinity) following administration of single dose GSK3745417
Time Frame
Up to 36 weeks
Title
Part 2: Lambda Z following administration of GSK3745417
Time Frame
Up to 36 weeks
Title
Part 2: t1/2 following administration of single dose GSK3745417
Time Frame
Up to 36 weeks
Title
Part 2: CL following administration of GSK3745417
Time Frame
Up to 36 weeks
Title
Part 2: V following administration of GSK3745417
Time Frame
Up to 36 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Participants must be ≥18 years of age and ≤75 years of age at the time of signing the informed consent for dose escalation and >18 years of age at the time of signing the informed consent for the dose expansion. Participants must be capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol. Participants must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Participants with AML/HR MDS are eligible for participation in Part 1 and Part 2 if they have: A diagnosis of AML according to the World Health Organization 2016 criteria with relapsed or refractory disease and ineligible for or have exhausted standard therapeutic options. Have high-risk or high/very high by Revised International Prognostic Scoring System (IPSS-R) for MDS (restricted to Part 1) that has relapsed after or been refractory to prior therapy with hypomethylating agent. Participants with a prior history of stem cell transplant (autologous and/or allogeneic) are allowed if: No clinical signs or symptoms of graft versus host disease (other than Grade 1 GVHD (<25% skin surface affected) and the participant is off all systemic immunosuppression. (Note: topical steroids for G1 skin GVHD are permitted on study) Participants must agree to abide by the gender specific contraceptive requirements below: Female participants are eligible to participate if they are not either pregnant or breastfeeding, and at least one of the following conditions applies: Is not a woman of childbearing potential (WOCBP), or Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), The effectiveness of the contraceptive method will be evaluated by the investigator in relationship to the first dose of study treatment. Exclusion Criteria: Diagnosis of acute promyelocytic leukemia (APML or t(15;17) PML-RARA fusion). Patients with biphenotypic disease are excluded. Active central nervous system (CNS) involvement or disorder; and well controlled with ongoing treatment Participants with Immediate life-threatening, severe complications of leukemia (sepsis, hemorrhage). Participants with extramedullary disease as the sole site of AML Participants with active severe or uncontrolled infection, Participants with active autoimmune disease that has required systemic disease modifying or immunosuppressive treatment within the last 2 years. Participants with concurrent medical condition requiring the use of systemic immunosuppressive treatment within 28 days before the first dose of study treatment. Participants with history of vasculitis at any time prior to study treatment. Participant with a history of other malignancies less than 2 years prior to study entry, Participants with QT interval corrected using Fridericia's formula (QTcF) >450 millisecond (msec) for male participants, >470 msec for female participants, or >480 msec for participants with bundle branch block. Participants with recent history of allergen desensitization therapy within 4 weeks of starting study treatment. Participants with history or evidence of cardiovascular (CV) risk history of immune myocarditis or pericarditis. Participants with prior STING therapy. Participants with prior solid organ transplantation. Participants with recent prior therapy defined as follows: any non-monoclonal anti-cancer therapy within 14 days or 5 half-lives, whichever is longer, prior to start of study treatment; prior therapy with biological agents (including monoclonal antibodies) within 28 days prior to start of study treatment; any radiotherapy or major surgery within 14 days prior to start of study treatment; currently receiving investigational therapy in a clinical trial Participants with immune-related toxicity related to prior treatment that has not resolved to Grade ≤1 (except alopecia, hearing loss or Grade ≤2 neuropathy or endocrinopathy managed with replacement therapy).
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
US GSK Clinical Trials Call Center
Phone
877-379-3718
Email
GSKClinicalSupportHD@gsk.com
First Name & Middle Initial & Last Name or Official Title & Degree
EU GSK Clinical Trials Call Center
Phone
+44 (0) 20 89904466
Email
GSKClinicalSupportHD@gsk.com
Facility Information:
Facility Name
GSK Investigational Site
City
Rotterdam
ZIP/Postal Code
3015 GD
Country
Netherlands
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
US GSK Clinical Trials Call Center
Phone
877-379-3718
Email
GSKClinicalSupportHD@gsk.com
First Name & Middle Initial & Last Name & Degree
EU GSK Clinical Trials Call Centre
Phone
+44 (0) 20 8990 4466
Email
GSKClinicalSupportHD@gsk.com
First Name & Middle Initial & Last Name & Degree
Mojca Jongen-Lavrencic
Facility Name
GSK Investigational Site
City
Madrid
ZIP/Postal Code
28033
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
US GSK Clinical Trials Call Center
Phone
877-379-3718
Email
GSKClinicalSupportHD@gsk.com
First Name & Middle Initial & Last Name & Degree
EU GSK Clinical Trials Call Centre
Phone
+44 (0) 20 8990 4466
Email
GSKClinicalSupportHD@gsk.com
First Name & Middle Initial & Last Name & Degree
Adolfo de la Fuente Burguera
Facility Name
GSK Investigational Site
City
Valencia
ZIP/Postal Code
46026
Country
Spain
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
US GSK Clinical Trials Call Center
Phone
877-379-3718
Email
GSKClinicalSupportHD@gsk.com
First Name & Middle Initial & Last Name & Degree
EU GSK Clinical Trials Call Centre
Phone
+44 (0) 20 8990 4466
Email
GSKClinicalSupportHD@gsk.com
First Name & Middle Initial & Last Name & Degree
Pau Montesinos Fernández

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
IPD for this study will be made available via the Clinical Study Data Request site.
IPD Sharing Time Frame
IPD will be made available within 6 months of publishing the results of the primary endpoints, a key secondary endpoints and safety data of the study.
IPD Sharing Access Criteria
Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Learn more about this trial

A Phase 1, Open Label Study of Intravenous GSK3745417 to Evaluate Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Determine RP2D & Schedule in Participants With Relapsed or Refractory Myeloid Malignancies Including AML and HR MDS

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