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

• ClinicalTrials.gov Identifier: NCT05424380
• Recruitment Status: Active, not recruiting
• First Posted: June 21, 2022
• Last Update Posted: January 26, 2024
• Sponsor: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline

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.

Condition or disease	Intervention/treatment	Phase
Leukemia, Myeloid, Acute	Drug: GSK3745417	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: September 20, 2022
• Estimated Primary Completion Date: March 4, 2024
• Estimated Study Completion Date: March 4, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part 1: Dose escalation; 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.	Drug: GSK3745417; GSK3745417 will be administered
Experimental: Part 2: Dose expansion; Part 2 will evaluate efficacy after an induction phase. The induction phase consists of a treatment regimen at RP2D determined in Part 1.	Drug: GSK3745417; GSK3745417 will be administered

Outcome Measures

Primary Outcome Measures :

1. Part 1: Number of participants with Adverse Events (AEs) and number of participants per severity grade of AE in total population [ Time Frame: Up to 36 weeks ]
   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.
2. Part 1: Number of participants with Serious Adverse Events (SAEs) and number of participants per severity grade of SAE in total population [ Time Frame: Up to 49 weeks ]
   Severity for each SAE will be reported during the study and will assign a grade according to the NCI-CTCAE v5.0.
3. Part 1: Number of participants with Dose limiting toxicities (DLT) and number of participants per severity grade of DLT [ Time Frame: Up to 4 weeks ]
   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.
4. Part 1: Number of participants with withdrawals due to AEs [ Time Frame: Up to 36 weeks ]
5. Part 2: Overall response rate (ORR) after the daily dosing induction period of GSK3745417 [ Time Frame: Up to 12 weeks ]
   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.
6. Part 2: Number of participants with AEs and number of participants per severity grade of AE in total population during maintenance dosing [ Time Frame: Up to 36 weeks ]
   Severity for each AE will be reported during the study and will assign a grade according to the NCI-CTCAE v5.0.
7. Part 2: Number of participants with SAEs and number of participants per severity grade of SAE in total population during maintenance dosing [ Time Frame: Up to 49 weeks ]
   Severity for each SAE will be reported during the study and will assign a grade according to the NCI-CTCAE v5.0.
8. Part 2: Number of participants with DLT and number of participants per severity grade of DLT during maintenance dosing [ Time Frame: Up to 4 weeks ]
   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.
9. Part 2: Number of participants with withdrawals due to AEs during maintenance dosing [ Time Frame: Up to 36 weeks ]

Secondary Outcome Measures :

1. Part 1: Maximum concentration (Cmax) following administration of GSK3745417 [ Time Frame: Up to 36 weeks ]
2. Part 1: Area under the concentration-time curve AUC(0-t) following administration of GSK3745417 [ Time Frame: Up to 36 weeks ]
3. 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 ]
4. Part 1: AUC(0-infinity) following repeated dose administration of GSK3745417 [ Time Frame: Up to 36 weeks ]
5. Part 1: AUC(0-infinity) following single dose administration of GSK3745417 [ Time Frame: Up to 36 weeks ]
6. Part 1: Terminal phase elimination rate constant (Lambda Z) following administration of GSK3745417 [ Time Frame: Up to 36 weeks ]
7. Part 1: Terminal phase half-life (t1/2) following single dose administration of GSK3745417 [ Time Frame: Up to 36 weeks ]
8. Part 1: Systemic clearance of parent drug (CL) following administration of GSK3745417 [ Time Frame: Up to 36 weeks ]
9. Part 1: Volume of distribution (V) following administration of GSK3745417 [ Time Frame: Up to 36 weeks ]
10. Part 2: Number of participants with AEs, leading to dose modification and dose delays [ Time Frame: Up to 36 weeks ]
11. Part 2: Number of participants with SAEs and AESIs leading to dose modification and dose delays [ Time Frame: Up to 49 weeks ]
12. Part 2: Cmax following administration of GSK3745417 [ Time Frame: Up to 36 weeks ]
13. Part 2: AUC(0-t) following administration of GSK3745417 [ Time Frame: Up to 36 weeks ]
14. Part 2: AUC (0-tau) following administration of GSK3745417 [ Time Frame: Up to 36 weeks ]
15. Part 2: AUC(0-infinity) following repeated dose of GSK3745417 [ Time Frame: Up to 36 weeks ]
16. Part 2: AUC(0-infinity) following administration of single dose GSK3745417 [ Time Frame: Up to 36 weeks ]
17. Part 2: Lambda Z following administration of GSK3745417 [ Time Frame: Up to 36 weeks ]
18. Part 2: t1/2 following administration of single dose GSK3745417 [ Time Frame: Up to 36 weeks ]
19. Part 2: CL following administration of GSK3745417 [ Time Frame: Up to 36 weeks ]
20. Part 2: V following administration of GSK3745417 [ Time Frame: Up to 36 weeks ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

  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).

Contacts and Locations

Locations

Canada, Ontario

GSK Investigational Site

Toronto, Ontario, Canada, M5G 2M9

Germany

GSK Investigational Site

Halle, Sachsen-Anhalt, Germany, 06120

GSK Investigational Site

Dresden, Sachsen, Germany, 01307

GSK Investigational Site

Leipzig, Sachsen, Germany, 04103

Italy

GSK Investigational Site

Meldola, Italy, 47014

GSK Investigational Site

Perugia, Italy, 06132

GSK Investigational Site

Roma, Italy, 00168

Netherlands

GSK Investigational Site

Rotterdam, Netherlands, 3015 GD

Spain

GSK Investigational Site

Madrid, Spain, 28033

GSK Investigational Site

Madrid, Spain, 28040

GSK Investigational Site

Valencia, Spain, 46026

Sponsors and Collaborators

GlaxoSmithKline

More Information

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT05424380
• Other Study ID Numbers: 209809
• First Posted: June 21, 2022
• Last Update Posted: January 26, 2024
• Last Verified: January 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• 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.
• 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.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by GlaxoSmithKline:

GSK3745417; Acute myeloid leukemia; AML; high-risk myelodysplastic syndrome; HR-MDS

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases