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
Study Details
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 |
|---|---|---|
| Phase 1 |
Study Design
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
- Part 1: Number of participants with Adverse Events (AEs) and number of participants per severity grade of AE in total population [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.
- Part 1: Number of participants with Serious Adverse Events (SAEs) and number of participants per severity grade of SAE in total population [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.
- Part 1: Number of participants with Dose limiting toxicities (DLT) and number of participants per severity grade of DLT [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.
- Part 1: Number of participants with withdrawals due to AEs [Up to 36 weeks]
- Part 2: Overall response rate (ORR) after the daily dosing induction period of GSK3745417 [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.
- Part 2: Number of participants with AEs and number of participants per severity grade of AE in total population during maintenance dosing [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.
- Part 2: Number of participants with SAEs and number of participants per severity grade of SAE in total population during maintenance dosing [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.
- Part 2: Number of participants with DLT and number of participants per severity grade of DLT during maintenance dosing [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.
- Part 2: Number of participants with withdrawals due to AEs during maintenance dosing [Up to 36 weeks]
Secondary Outcome Measures
- Part 1: Maximum concentration (Cmax) following administration of GSK3745417 [Up to 36 weeks]
- Part 1: Area under the concentration-time curve AUC(0-t) following administration of GSK3745417 [Up to 36 weeks]
- Part 1: AUC (0-tau) following administration of GSK3745417 Part 1: AUC(0-infinity) following repeated dose administration of GSK3745417 [Up to 36 weeks]
- Part 1: AUC(0-infinity) following repeated dose administration of GSK3745417 [Up to 36 weeks]
- Part 1: AUC(0-infinity) following single dose administration of GSK3745417 [Up to 36 weeks]
- Part 1: Terminal phase elimination rate constant (Lambda Z) following administration of GSK3745417 [Up to 36 weeks]
- Part 1: Terminal phase half-life (t1/2) following single dose administration of GSK3745417 [Up to 36 weeks]
- Part 1: Systemic clearance of parent drug (CL) following administration of GSK3745417 [Up to 36 weeks]
- Part 1: Volume of distribution (V) following administration of GSK3745417 [Up to 36 weeks]
- Part 2: Number of participants with AEs, leading to dose modification and dose delays [Up to 36 weeks]
- Part 2: Number of participants with SAEs and AESIs leading to dose modification and dose delays [Up to 49 weeks]
- Part 2: Cmax following administration of GSK3745417 [Up to 36 weeks]
- Part 2: AUC(0-t) following administration of GSK3745417 [Up to 36 weeks]
- Part 2: AUC (0-tau) following administration of GSK3745417 [Up to 36 weeks]
- Part 2: AUC(0-infinity) following repeated dose of GSK3745417 [Up to 36 weeks]
- Part 2: AUC(0-infinity) following administration of single dose GSK3745417 [Up to 36 weeks]
- Part 2: Lambda Z following administration of GSK3745417 [Up to 36 weeks]
- Part 2: t1/2 following administration of single dose GSK3745417 [Up to 36 weeks]
- Part 2: CL following administration of GSK3745417 [Up to 36 weeks]
- Part 2: V following administration of GSK3745417 [Up to 36 weeks]
Eligibility Criteria
Criteria
Inclusion Criteria:
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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.
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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.
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Participants must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
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Participants with AML/HR MDS are eligible for participation in Part 1 and Part 2 if they have:
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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.
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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:
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Is not a woman of childbearing potential (WOCBP), or
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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:
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Diagnosis of acute promyelocytic leukemia (APML or t(15;17) PML-RARA fusion). Patients with biphenotypic disease are excluded.
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Active central nervous system (CNS) involvement or disorder; and well controlled with ongoing treatment
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Participants with Immediate life-threatening, severe complications of leukemia (sepsis, hemorrhage).
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Participants with extramedullary disease as the sole site of AML
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Participants with active severe or uncontrolled infection,
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Participants with active autoimmune disease that has required systemic disease modifying or immunosuppressive treatment within the last 2 years.
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Participants with concurrent medical condition requiring the use of systemic immunosuppressive treatment within 28 days before the first dose of study treatment.
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Participants with history of vasculitis at any time prior to study treatment.
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Participant with a history of other malignancies less than 2 years prior to study entry,
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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.
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Participants with recent history of allergen desensitization therapy within 4 weeks of starting study treatment.
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Participants with history or evidence of cardiovascular (CV) risk history of immune myocarditis or pericarditis.
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Participants with prior STING therapy.
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Participants with prior solid organ transplantation.
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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
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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
No locations specified.Sponsors and Collaborators
- GlaxoSmithKline
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 209809