Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03614728
Recruitment Status : Recruiting
First Posted : August 3, 2018
Last Update Posted : October 29, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
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 subjects with cancer. Myelodysplastic syndrome and acute myeloid leukaemia are bone marrow neoplasms for which novel, effective therapies are desperately needed. This is an open-label, multicentre, multi-part study to evaluate the safety, tolerability, and clinical activity of GSK3326595 in subjects with relapsed and refractory MDS, chronic myelomonocytic leukaemia (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 subjects with AML whose disease contains mutations in spliceosome proteins.

Condition or disease Intervention/treatment Phase
Neoplasms Drug: GSK3326595 Drug: 5-azacitidine Drug: Best available care Phase 1

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 302 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : October 16, 2018
Estimated Primary Completion Date : December 15, 2022
Estimated Study Completion Date : December 15, 2022


Arm Intervention/treatment
Experimental: Part 1: GSK3326595
Subjects 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 25 and 100 mg strengths 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
Subjects in this treatment arm will start at the dose identified as the myeloid monotherapy dose in Part 1 of the study.
Drug: GSK3326595
GSK3326595 is available as 25 and 100 mg strengths 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: Best available care
Best available care will be the treatment of choice as 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)
Subjects 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: GSK3326595
GSK3326595 is available as 25 and 100 mg strengths 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.

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
Subjects in this treatment arm 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.
Drug: GSK3326595
GSK3326595 is available as 25 and 100 mg strengths 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.




Primary Outcome Measures :
  1. Part 1: Percentage of subjects with clinical benefit rate (CBR) [ Time Frame: Up to 4 years ]
    CBR is defined as the percentage of subjects achieving a complete remission (CR), complete marrow remission (mCR), partial remission (PR), stable disease (SD) lasting at least 8 weeks, or hematologic improvement (HI), per International Working Group (IWG) criteria.

  2. Part 2A: Time to overall survival [ Time Frame: Up to 4 years ]
    Overall survival is defined as time from randomization to death due to any cause.

  3. Part 2B: Percentage of subjects achieving overall response rate [ Time Frame: Up to 4 years ]
    Overall response rate is defined as the percentage of subjects achieving a CR, mCR, or PR, per IWG criteria.

  4. Part 2C: Percentage of subjects achieving overall response rate [ Time Frame: Up to 4 years ]
    Overall response rate is defined as the percentage of subjects achieving a CR, complete remission with incomplete platelet recovery (CRp), complete remission with incomplete count recovery (CRi), or PR per standard criteria.


Secondary Outcome Measures :
  1. Part 1: Number of subjects with adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Up to 4 years ]
    An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity and is a congenital anomaly/birth defect.

  2. Part 1: Number of subjects achieving dose limiting toxicities (DLTs) [ Time Frame: Up to 4 years ]
    An event is considered to be a DLT if the event occurs within the first 28 days of treatment and meets the Non-hematologic toxicity, hematologic toxicity and other toxicity criteria unless it can be clearly established that the event is unrelated to treatment.

  3. Part 1: Percentage of subjects achieving overall response rate [ Time Frame: Up to 4 years ]
    Overall response rate is defined as the percentage of subjects achieving a CR, mCR, or PR, per IWG criteria.

  4. Part 1: Time to progression free survival [ Time Frame: Up to 4 years ]
    Progression free survival is defined as time from first dose to disease progression, as defined by IWG criteria, or death due to any cause, whichever occurs earlier.

  5. Part 1: Time to overall survival [ Time Frame: Up to 4 years ]
    Overall survival is defined time from first dose to death due to any cause.

  6. 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 ]
    Blood samples will be collected to determine Cmax of GSK3326595.

  7. Part 1: Time of maximum concentration observed (Tmax) and 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 ]
    Blood samples will be collected to determine Tmax and t1/2 of GSK3326595.

  8. Part 1: Area under the Concentration-time Curve from time zero (pre-dose) to last time of quantifiable concentration within a subject across all treatments (AUC[0-t]) and AUC 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 ]
    Blood samples will be collected to determine AUC(0-t) and AUC(0-inf) of GSK3326595.

  9. 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 ]
    Blood samples will be collected to determine AUC(0-tau) of GSK3326595.

  10. 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 ]
    Blood samples will be collected to determine CL/F of GSK3326595.

  11. 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 ]
    Blood samples will be collected to determine TI of GSK3326595.

  12. Part 1: Accumulation ratio (AR) of GSK3326595 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 ]
    Blood samples will be collected to determine AR of GSK3326595.

  13. Part 2A: Time to progression free survival [ Time Frame: Up to 4 years ]
    Progression free survival is defined as time from randomization to disease progression or death due to any cause, whichever occurs earlier.

  14. Part 2A: Percentage of subjects achieving overall response rate [ Time Frame: Up to 4 years ]
    Overall response rate is defined as percentage of subjects with CR, mCR, or PR, per IWG criteria.

  15. Part 2A: Number of subjects with AEs and SAEs [ Time Frame: Up to 4 years ]
    An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity and is a congenital anomaly/birth defect.

  16. 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 ]
    The EORTC QLQ-C30 is a 30-item questionnaire containing both single- and multi-item measures. These include five functional scales (Physical, Role, Cognitive, Emotional, and Social Functioning), three symptom scales (Fatigue, Pain, and Nausea/Vomiting), a Global Health Status/QOL scale, and six single items (Constipation, Diarrhea, Insomnia, Dyspnea, Appetite Loss, and Financial Difficulties). Scores for each scale and single-item measure are averaged and transformed linearly to a score ranging from 0-100. Change from Baseline will be calculated by subtracting the post-dose value from the Baseline value.

  17. 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 ]
    Subjects will complete a 13-point fatigue questionnaire using the FACIT-Fatigue assessment, a Likert scale from 0 to 4, from "0" (not at all fatigued) to "4" (very much fatigued). This questionnaire provides the level of fatigue with usual daily activities from the previous week. Change from Baseline will be calculated by subtracting the post-dose value from the Baseline value.

  18. Part 2B: Number of subjects with AEs and SAEs [ Time Frame: Up to 4 years ]
    An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity and is a congenital anomaly/birth defect.

  19. Part 2B: Number of subjects achieving DLTs [ Time Frame: Day 1 to Day 22 ]
    An event is considered to be a DLT if the event occurs within the first 28 days of treatment and meets the Non-hematologic toxicity, hematologic toxicity and other toxicity criteria unless it can be clearly established that the event is unrelated to treatment.

  20. 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 ]
    Blood samples will be collected to determine Cmax of GSK3326595 and 5-azacitidine.

  21. Part 2B: Tmax and 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 ]
    Blood samples will be collected to determine Tmax and t1/2 of GSK3326595 and 5-azacitidine.

  22. Part 2B: AUC(0-t), AUC(0-inf) and 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 ]
    Blood samples will be collected to determine AUC(0-t), AUC(0-inf) and AUC(0-tau) of GSK3326595 and 5-azacitidine.

  23. 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 ]
    Blood samples will be collected to determine CL/F of GSK3326595 and 5-azacitidine.

  24. 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 ]
    Blood samples will be collected to determine TI of GSK3326595 and 5-azacitidine.

  25. Part 2B: AR of GSK3326595 of and 5-azacitidineGSK3326595 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 ]
    Blood samples will be collected to determine AR of GSK3326595 and 5-azacitidine.

  26. Part 2B: Time to progression free survival [ Time Frame: Up to 4 years ]
    Progression free survival is defined as time from first dose to disease progression, as defined by standard criteria, or death due to any cause, whichever occurs earlier.

  27. Par 2C: Time to progression free survival [ Time Frame: Up to 4 years ]
    Progression free survival is defined as time from first dose to disease progression, as defined by standard criteria, or death due to any cause, whichever occurs earlier.

  28. Part 2C: Time to overall survival [ Time Frame: Up to 4 years ]
    Overall survival is defined as time from first dose to death from any cause.

  29. Part 2C: Number of subjects with AEs and SAEs [ Time Frame: Up to 4 years ]
    An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. A SAE is defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity and is a congenital anomaly/birth defect.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 leukaemia (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) NOTE: Subjects without a documented history of antecedent MDS/MPN must have AML with myelodysplasia-related changes or recurrent cytogenetic abnormalities per World Health Organization (WHO) criteria

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).

Subjects without a documented history of antecedent MDS/MPN must have AML with myelodysplasia-related changes or recurrent cytogenetic abnormalities per WHO criteria

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: Subjects must have disease that failed to respond to, or progressed despite, treatment at least one systemic therapy Part 2A: Subjects must have disease that failed to respond to, or progressed despite, treatment with at least one systemic therapy Part 2B: Subjects must have received no prior therapy for their disease, or have completed no more than one cycle of a hypomethylating agent Part 2C: Subjects 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 subjects 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 subjects 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 subjects.

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

- Subjects 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 subject has recovered from transplant-associated toxicities prior to the first dose of GSK3326595 and For subjects with a prior history of allogeneic transplant, the subject 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.

Subjects with treatment-related toxicities that are unlikely to resolve per the investigator may be enrolled on a case-by-case basis after discussion with the medical monitor

  • 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 (subjects 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 subject 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. NOTE: Isolated bilirubin >1.5 X ULN is acceptable if: bilirubin is fractionated and direct bilirubin <35% OR subject has a diagnosis of Gilbert's syndrome Alanine aminotransferase (ALT) laboratory values were <=2.5 x ULN;

For Renal:

Estimated glomerular filtration rate (eGFR)a laboratory value was >=60 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);

For Cardiac:

Ejection fraction >=Lower limit of normal (LLN) by echocardiogram (minimum of 50%) Troponin (I or T) <= ULN. In situations where laboratory results are outside the permitted range, the investigator may opt to retest the subject and the subsequent within range screening result may be used to confirm eligibility.

  • 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 Subjects with second malignancies that were indolent, in situ or definitively treated may be enrolled even if less than three years have elapsed since treatment. Subjects 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 Subjects with a history of CNS disease are permitted to enroll if they have previously received appropriate therapy and CNS remission has been documented. Subjects 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).

Subjects 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.

Note: subjects receiving hormonal therapy for a definitively-treated malignancy (e.g., adjuvant therapy of localized breast or prostate cancer) may continue to receive adjuvant therapy during study, after discussion with the medical monitor

  • 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.

NOTE: Subjects with positive Hepatitis C antibody due to prior resolved disease can be enrolled only if a confirmatory negative Hepatitis C RNA polymerase chain reaction (PCR) (or comparable test) is obtained.

  • 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. Subjects 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03614728


Contacts
Layout table for location contacts
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 89904466 GSKClinicalSupportHD@gsk.com

Locations
Layout table for location information
United States, Alabama
GSK Investigational Site Recruiting
Birmingham, Alabama, United States, 35294-3300
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Kimo Bachiashvili         
United States, Florida
GSK Investigational Site Recruiting
Miami, Florida, United States, 33136
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Justin Watts         
United States, Massachusetts
GSK Investigational Site Recruiting
Boston, Massachusetts, United States, 02114
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Andrew Brunner         
GSK Investigational Site Recruiting
Boston, Massachusetts, United States, 02215
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Andrew Brunner         
United States, Texas
GSK Investigational Site Recruiting
Houston, Texas, United States, 77030
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Gautam Borthakur         
United States, Wisconsin
GSK Investigational Site Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Sameem Abedin         
Canada, Ontario
GSK Investigational Site Recruiting
Toronto, Ontario, Canada, M5G 2M9
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Centre    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Principal Investigator: Mark Minden         
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Layout table for investigator information
Study Director: GSK Clinical Trials GlaxoSmithKline

Layout table for additonal information
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT03614728     History of Changes
Other Study ID Numbers: 208809
First Posted: August 3, 2018    Key Record Dates
Last Update Posted: October 29, 2019
Last Verified: October 2019
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 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.
URL: http://clinicalstudydatarequest.com

Layout table for additional information
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by GlaxoSmithKline:
Acute myeloid leukaemia
Myelodysplastic syndrome
GSK3326595
Additional relevant MeSH terms:
Layout table for MeSH terms
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors