Clinical Trial - NCT03614728

Study to Investigate the Safety and Clinical Activity of GSK3326595 and Other Agents to Treat Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)

Recruiting

Sponsor: GlaxoSmithKline

Collaborators:

Information provided by (Responsible party): Sponsor

ClinicalTrials.gov Identifier: NCT03614728

Protocol Info

Short Description: GSK3326595 in Acute Myeloid Leukaemia + Myelodysplastic
Long Description: A Phase I/II study to investigate the safety and clinical activity of GSK3326595 and other agents in subjects with myelodysplastic syndrome and acute myeloid leukaemia
MGH Status: Open
Sponsor: GlaxoSmithKline
Disease Program: Leukemia

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.




Purpose

GSK3326595 is a potent, selective, reversible inhibitor of the protein arginine methyltransferase 5 (PRMT5)/Methylosome protein 50 (MEP50) complex that is being tested as an oral treatment for human participants with cancer. Myelodysplastic syndrome and acute myeloid leukemia are bone marrow neoplasms for which novel, effective therapies are desperately needed. This is an open-label, multicenter, multi-part study to evaluate the safety, tolerability, and clinical activity of GSK3326595 in participants with relapsed and refractory MDS, chronic myelomonocytic leukemia (CMML), and hypoproliferative AML that has evolved from an antecedent MDS. The study will be conducted in two parts and at the end of Part 1, if pre-specified criteria are met, then the study will be expanded with three additional parts that will be opened in parallel (Part 2A, 2B and 2C). Part 1 is composed of a single-arm dose expansion cohort to determine the clinical benefit rate of GSK3326595. Part 2A is a randomized head-to-head Phase II evaluation of GSK3326595 compared to investigator's choice of best available care (BAC). Part 2B is composed of an abbreviated series of dose escalation cohorts followed by a single-arm dose expansion cohort to determine the overall response rate of the combination of GSK3326595 plus 5-azaciditine in newly-diagnosed MDS. Part 2C is a single-arm dose expansion study to evaluate the clinical activity of single-agent GSK3326595 in participants with AML whose disease contains mutations in spliceosome proteins.
Condition Title Intervention Phase
Neoplasms GSK3326595 5-azacitidine Best available care Phase 1
Study Type Interventional
Official Title A Phase I/II Study to Investigate the Safety and Clinical Activity of GSK3326595 and Other Agents in Subjects With Myelodysplastic Syndrome and Acute Myeloid Leukaemia

Primary Outcome Measures

Part 1: Percentage of participants with clinical benefit rate (CBR) [Time Frame: Up to 4 years] [Designated as safety issue: ]

Part 2A: Time to overall survival [Time Frame: Up to 4 years] [Designated as safety issue: ]

Part 2B: Percentage of participants achieving overall response rate [Time Frame: Up to 4 years] [Designated as safety issue: ]

Part 2C: Percentage of participants achieving overall response rate [Time Frame: Up to 4 years] [Designated as safety issue: ]


Secondary Outcome Measures

Part 1 and Part 2 (A, B and C): Number of participants with adverse events (AEs) and serious adverse events (SAEs) [Time Frame: Up to 4 years] [Designated as safety issue: ]

Part 1 and Part 2 (A, B and C): Time to progression free survival [Time Frame: Up to 4 years] [Designated as safety issue: ]

Part 1 and Part 2A: Percentage of participants achieving overall response rate [Time Frame: Up to 4 years] [Designated as safety issue: ]

Part 1 and Part 2C: Time to overall survival [Time Frame: Up to 4 years] [Designated as safety issue: ]

Part 1 and Part 2B: Number of participants achieving dose limiting toxicities (DLTs) [Time Frame: Up to 28 days] [Designated as safety issue: ]

Part 1: Maximum Observed Plasma Concentration (Cmax) of GSK3326595 in plasma following single- (Day 1) and repeat-dose administration [Time Frame: Pre-dose, 5, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours on Day 1 and Day 15; within 1 hour pre-dose on Day 1 of Weeks 5, 7, Week 9 and every 4 weeks thereafter] [Designated as safety issue: ]

Part 1: Time of maximum concentration observed (Tmax) of GSK3326595 in plasma following single- (Day 1) and repeat-dose administration [Time Frame: Pre-dose, 5, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours on Day 1 and Day 15; within 1 hour pre-dose on Day 1 of Weeks 5, 7, Week 9 and every 4 weeks thereafter] [Designated as safety issue: ]

Part 1: Apparent terminal phase half-life (t1/2) of GSK3326595 in plasma following single- (Day 1) and repeat-dose administration [Time Frame: Pre-dose, 5, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours on Day 1 and Day 15; within 1 hour pre-dose on Day 1 of Weeks 5, 7, Week 9 and every 4 weeks thereafter] [Designated as safety issue: ]

Part 1: Area under Concentration-time Curve from time zero (pre-dose) to last time of quantifiable concentration within participant across all treatments (AUC[0-t]) of GSK3326595 [Time Frame: Pre-dose, 5, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours on Day 1 and Day 15; within 1 hour pre-dose on Day 1 of Weeks 5, 7, Week 9 and every 4 weeks thereafter] [Designated as safety issue: ]

Part 1: AUC from 0 hours to the time of next dosing (AUC[0-tau]) of GSK3326595 [Time Frame: Pre-dose, 5, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours on Day 1 and Day 15; within 1 hour pre-dose on Day 1 of Weeks 5, 7, Week 9 and every 4 weeks thereafter] [Designated as safety issue: ]

Part 1: AUC(0-inf) from time zero to infinity (AUC[0-inf]) of GSK3326595 [Time Frame: Pre-dose, 5, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours on Day 1 and Day 15; within 1 hour pre-dose on Day 1 of Weeks 5, 7, Week 9 and every 4 weeks thereafter] [Designated as safety issue: ]

Part 1: Oral clearance (CL/F) of GSK3326595 in plasma following single- (Day 1) and repeat-dose administration [Time Frame: Pre-dose, 5, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours on Day 1 and Day 15; within 1 hour pre-dose on Day 1 of Weeks 5, 7, Week 9 and every 4 weeks thereafter] [Designated as safety issue: ]

Part 1: Time invariance (TI) of GSK3326595 in plasma following single- (Day 1) and repeat-dose administration [Time Frame: Pre-dose, 5, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours on Day 1 and Day 15; within 1 hour pre-dose on Day 1 of Weeks 5, 7, Week 9 and every 4 weeks thereafter] [Designated as safety issue: ]

Part 1: Accumulation ratio (AR) of GSK3326595 in plasma following single- (Day 1) and repeat-dose administration [Time Frame: Pre-dose, 5, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours on Day 1 and Day 15; within 1 hour pre-dose on Day 1 of Weeks 5, 7, Week 9 and every 4 weeks thereafter] [Designated as safety issue: ]

Part 2A: Change from Baseline in quality of life as measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) [Time Frame: Baseline and up to 4 years] [Designated as safety issue: ]

Part 2A: Change from Baseline in quality of life as measured by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (FACIT-F) [Time Frame: Baseline and up to 4 years] [Designated as safety issue: ]

Part 2B: Cmax of GSK3326595 and 5-azacitidine in plasma following single- (Day 1) and repeat-dose administration [Time Frame: Pre-dose, 5, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours on Day 1 and Day 15; within 1 hour pre-dose on Day 1 of Weeks 5, 7, Week 9 and every 4 weeks thereafter] [Designated as safety issue: ]

Part 2B: Tmax of GSK3326595 and 5-azacitidine in plasma following single- (Day 1) and repeat-dose administration [Time Frame: Pre-dose, 5, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours on Day 1 and Day 15; within 1 hour pre-dose on Day 1 of Weeks 5, 7, Week 9 and every 4 weeks thereafter] [Designated as safety issue: ]

Part 2B: t1/2 of GSK3326595 and 5-azacitidine in plasma following single- (Day 1) and repeat-dose administration [Time Frame: Pre-dose, 5, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours on Day 1 and Day 15; within 1 hour pre-dose on Day 1 of Weeks 5, 7, Week 9 and every 4 weeks thereafter] [Designated as safety issue: ]

Part 2B: AUC(0-t) of GSK3326595 and 5-azacitidine in plasma following single- (Day 1) and repeat-dose administration [Time Frame: Pre-dose, 5, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours on Day 1 and Day 15; within 1 hour pre-dose on Day 1 of Weeks 5, 7, Week 9 and every 4 weeks thereafter] [Designated as safety issue: ]

Part 2B: AUC(0-inf) of GSK3326595 and 5-azacitidine in plasma following single- (Day 1) and repeat-dose administration [Time Frame: Pre-dose, 5, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours on Day 1 and Day 15; within 1 hour pre-dose on Day 1 of Weeks 5, 7, Week 9 and every 4 weeks thereafter] [Designated as safety issue: ]

Part 2B: AUC(0-tau) of GSK3326595 and 5-azacitidine in plasma following single- (Day 1) and repeat-dose administration [Time Frame: Pre-dose, 5, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours on Day 1 and Day 15; within 1 hour pre-dose on Day 1 of Weeks 5, 7, Week 9 and every 4 weeks thereafter] [Designated as safety issue: ]

Part 2B: CL/F of GSK3326595 and 5-azacitidine in plasma following single- (Day 1) and repeat-dose administration [Time Frame: Pre-dose, 5, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours on Day 1 and Day 15; within 1 hour pre-dose on Day 1 of Weeks 5, 7, Week 9 and every 4 weeks thereafter] [Designated as safety issue: ]

Part 2B: TI of GSK3326595 and 5-azacitidine in plasma following single- (Day 1) and repeat-dose administration [Time Frame: Pre-dose, 5, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours on Day 1 and Day 15; within 1 hour pre-dose on Day 1 of Weeks 5, 7, Week 9 and every 4 weeks thereafter] [Designated as safety issue: ]

Part 2B: AR of GSK3326595 and 5-azacitidine in plasma following single- (Day 1) and repeat-dose administration [Time Frame: Pre-dose, 5, 30 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours on Day 1 and Day 15; within 1 hour pre-dose on Day 1 of Weeks 5, 7, Week 9 and every 4 weeks thereafter] [Designated as safety issue: ]

Estimated Enrollment: 302
Study Start Date: October 2018
Estimated Study Completion Date: March 2023
Estimated Primary Completion Date: March 2023
Arms Assigned Interventions

Experimental:Part 1: GSK3326595

Participants will receive GSK3326595 400 mg oral capsule once a day. The dose may be reduced due to toxicity in the myeloid population, or escalated if required.
Drug:GSK3326595
GSK3326595 is available as 100 mg strength as free-base drug substance to be administered orally with water with no food or antacids for 1 hour before and 2 hour after each dose.

Experimental:Part 2A: GSK3326595

Participants in this treatment arm will start at the dose identified as the myeloid monotherapy dose in Part 1 of the study.

Experimental:Part 2A: Best available care

Participants will receive BAC as treatment of choice considered by the investigator.
Drug:Best available care
Best available care will be the treatment of choice as considered by the investigator.

Experimental:Part2B:GSK3326595+5-azacitidine(dose escalation and expansion)

Participants with newly-diagnosed MDS will receive GSK3326595 oral capsule once a day along with 5-azacitidine administered at a dose of 75 mg/meter square (m^2) seven days in a 28-day cycle. The initial dose of GSK3326595 administered in Part 2B of this study will be reduced by two dose levels from the recommended myeloid monotherapy dose, as determined in Part 1, and escalate up to the Recommended Myeloid Monotherapy Dose.
Drug:5-azacitidine
5-azacitidine is available as Lyophilized powder in 100 mg single-dose vials administered 75 mg/m2 subcutaneously or intravenously for 7 days out of a 28 day cycle, as per local standard.

Experimental:Part 2C: GSK3326595

Participants with relapsed and/or refractory AML will receive GSK3326595 oral capsule at the dose identified as the myeloid monotherapy dose in Part 1 of the study, until progression, unacceptable toxicity, or withdrawal of consent.

Eligibility

Ages Eligible for Study: N/A-N/A

Genders Eligible for Study: All

Accepts Healthly Volunteers: No

Inclusion Criteria:

  • Males and females >=18 years of age (at the time consent is obtained).
  • Capable of giving signed informed consent.
  • Able to swallow, retain, and absorb orally-administered medication.
  • Eastern cooperative oncology group (ECOG) performance status of 0, 1, or 2.
  • Diagnosis of one of the following:

Part 1:

MDS classified as intermediate, high, or very high risk by International Prognostic Scoring System-Revised [IPSS-R] criteria, or Chronic myelomonocytic leukemia (CMML) classified as intermediate-2 or high risk per CMML-specific prognostic scoring system (CPSS) or clinical/molecular CPSS (CPSS-mol) criteria, or MDS/CMML secondary to prior anti-neoplastic therapy, of any risk score, or AML, which has evolved from an antecedent MDS/Myeloproliferative neoplasms (MPN) of any risk score, provided that the myeloblast percentage in the marrow is <= 30% or the peripheral white blood cell count is less than 20,000 cells/microliter (µL) in the absence of leukoreducing therapy (e.g., hydroxyurea, leukapheresis)

Part 2A:

MDS classified as intermediate, high, or very high risk by IPSS-R criteria, or CMML classified as intermediate-2 or high risk per CPSS or CPSS-mol criteria, or MDS/CMML secondary to prior anti-neoplastic therapy, of any risk score, or AML, which has evolved from an antecedent MDS/MPN of any risk score, provided that the myeloblast percentage in the marrow is <= 30% or the peripheral white blood cell count is less than 20,000 cells/µL in the absence of leukoreducing therapy (e.g., hydroxyurea, leukapheresis).

Part 2B:

MDS classified as high/very high by IPSS-R criteria, or CMML classified as intermediate-2 or high risk per CPSS or CPSS-mol criteria, or MDS/CMML secondary to prior anti-neoplastic therapy, of any risk score

Part 2C:

AML (irrespective of antecedent MDS and myeloblast percentage in the marrow, irrespective of hydroxyurea therapy)

  • Prior therapy Part 1: Participants must have disease that failed to respond to, or progressed despite, treatment at least one systemic therapy Part 2A: Participants must have disease that failed to respond to, or progressed despite, treatment with at least one systemic therapy Part 2B: Participants must have received no prior therapy for their disease, or have completed no more than one cycle of a hypomethylating agent Part 2C: Participants must have disease that has failed to respond to, or progressed despite treatment with, at least one but no more than four prior lines of systemic therapy
  • Molecular markers Part 1: At least 12 Participants must have documented loss-of-function mutation(s) at least one of the following genes/proteins: Splicing factor 3B subunit 1 (SF3B1), Serine and arginine rich splicing factor 2 (SRSF2), U2 Small Nuclear RNA Auxiliary Factor 1 (U2AF1), or Zinc Finger CCCH-Type, RNA Binding Motif and Serine/Arginine Rich 2 (ZRSR2); in addition, at least 12 participants must have documented wild type status of all of these genes/proteins. While enrolment will initially proceed without consideration of mutational status, enrolment may be limited to one group or the other as the study proceeds based on the enrolment rates in each group, in order to ensure this minimum number of mutated and wild type participants.

Part 2A: No specific mutational or molecular requirements Part 2B: No specific mutational or molecular requirements Part 2C: Participants must have a documented loss-of-function mutation(s) at least one of the following genes/proteins: SF3B1, SRSF2, U2AF1, or ZRSR2

  • Participants with a prior history of stem cell transplant (autologous and/or allogeneic) are allowed if: At least 3 months has elapsed from the time of transplant and the participant has recovered from transplant-associated toxicities prior to the first dose of GSK3326595 and For participants with a prior history of allogeneic transplant, the participant has been off systemic immunosuppressive medications (including but not limited to: cyclosporine, tacrolimus, mycophenolate mofetil, or corticosteroids) for at least 1 month prior to the first dose of GSK3326595. Topical steroids are permitted; there are no signs or symptoms of acute graft versus host disease, other than Grade 1 skin involvement; there are no signs or symptoms of chronic graft versus host disease requiring systemic therapy.
  • All prior treatment-related toxicities must be National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 <= Grade 1 (except alopecia [permissible at any Grade] and peripheral neuropathy [which must be <= Grade 2]) at the time of treatment allocation.
  • Adequate organ system functions (at both screening and where applicable pre first

Dose are defined as follows:

For hematologic:

Platelets laboratory values were >=10 X 10^9/Liter (participants may receive transfusion to ensure adequate platelet counts); Prothromin time (PT)/ International normalized ratio (INR) and Partial Thromboplastin Time (PTT) laboratory values were <=1.5 X upper limit of normal (ULN), unless participant is receiving systemic anticoagulation;

For hepatic:

Albumin laboratory values were >=2 grams per deciliter (g/dL); Total bilirubin laboratory values were <=1.5 x ULN. Alanine aminotransferase (ALT) laboratory values were <=2.5 x ULN;

For Renal:

Estimated glomerular filtration rate (eGFR)a laboratory value was >=50 mL/min/1.73m2 (a= EGFR should be calculated using the Chronic Kidney Disease Epidemiology Collaborative (CKD-Epi) method:- Females, serum creatinine >62 µmol/L: 144 x (serum creatinine x 0.0113/0.7)-1.209 x 0.993age; Females, serum creatinine <=62 µmol/L: 144 x (serum creatinine x 0.0113/0.7)-0.329 x 0.993age; Males, serum creatinine >80 µmol/L: 141 x (serum creatinine x 0.0113/0.9)-1.209 x 0.993age; Males, serum creatinine <=80 µmol/L: 141 x (serum creatinine x 0.0113/0.9)-0.411 x 0.993age);

  • Agree to abide by the gender-specific contraceptive requirements

Exclusion Criteria:

  • History of prior solid organ transplant
  • History of a second malignancy, excluding non-melanoma skin cell cancer, within the last three years Participants with second malignancies that were indolent, in situ or definitively treated may be enrolled even if less than three years have elapsed since treatment. Participants with a recent history of ductal carcinoma in situ (DCIS) that has been definitively treated may be enrolled irrespective of the time since diagnosis. Consult the GSK Medical Monitor if second malignancies meet the requirements specified above.
  • Active severe or uncontrolled infection. Controlled infections are permitted.
  • Symptomatic or untreated Central Nervous System (CNS) disease Note that lumbar puncture (LP) is not required for study enrollment unless there is clinical suspicion for CNS disease Participants with a history of CNS disease are permitted to enroll if they have previously received appropriate therapy and CNS remission has been documented. Participants on maintenance intrathecal chemotherapy may be enrolled and continue to receive therapy.
  • Recent prior therapy, defined as follows:

Any non-monoclonal anti-cancer therapy within 14 days or 5 half-lives, whichever is longer, prior to the first dose of Investigational product (IP).

Participants in cohort 2B may enroll during the first cycle of 5-azacitidine and continue cycle 1 in combination with IP, after discussion between the investigator and the medical monitor.

Prior therapy with biologic agents (including monoclonal antibodies) within 28 days prior to the first dose of IP.

Any radiotherapy within 14 days or major surgery within 28 days prior to the first dose of IP.

  • Prior therapy with any Protein arginine methyltransferase 5 (PRMT5) inhibitor
  • Current use of a prohibited medication or planned use of any forbidden medications during treatment with study drug(s)
  • History of known human immunodeficiency virus (HIV) infection, or positive HIV test result at screening.
  • Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test result at screening.
  • Any of the following cardiac abnormalities:

History, within the past 6 months prior to first dose of study drug(s), of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting Baseline Corrected QT (Fridericia's formula) interval (QTcF) >=480 msec. Uncontrolled arrhythmias. Participants with rate-controlled atrial fibrillation prior to first dose of study drug(s) may be eligible.

Class II, III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system.

  • History of sensitivity to any of the study medications, or components thereof, or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT03614728

Locations

  • United States, Alabama
    • GSK Investigational Site Birmingham, Alabama, United States, 35294-3300
  • United States, Florida
    • GSK Investigational Site Miami, Florida, United States, 33136
  • United States, Massachusetts
    • GSK Investigational Site Boston, Massachusetts, United States, 02114
    • GSK Investigational Site Boston, Massachusetts, United States, 02215
  • United States, New York
    • GSK Investigational Site New York, New York, United States, 10065
  • United States, Texas
    • GSK Investigational Site Houston, Texas, United States, 77030
  • United States, Wisconsin
    • GSK Investigational Site Milwaukee, Wisconsin, United States, 53226
  • Canada, Ontario
    • GSK Investigational Site Toronto, Ontario, Canada, M5G 2M9

Sponsors and Collaborators

GlaxoSmithKline

More Information

No publications provided

Responsible Party: Sponsor
ClinicalTrials.gov Identifier: NCT03614728
Other Study ID Numbers:
Study First Received:
Last Updated:
Health Authority:

Keywords provided by GlaxoSmithKline:

Acute myeloid leukemia

Myelodysplastic syndrome

GSK3326595

Additional relevant MeSH terms:

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Preleukemia

Myelodysplastic Syndromes

Azacitidine

Next Steps


If you are interested in this protocol or in other treatment options at Massachusetts General Hospital, please Request a Consultation.







ClinicalTrials.gov processed this data on November 12, 2020