Clinical trial NCT01943851: A Dose Escalation Study to Investigate the Safety, Pharmacokinetics (PK), Pharmacodynamics (PD) and Clinical Activity of GSK525762 in Subjects With Relapsed, Refractory Hematologic Malignancies
Official title: A Phase I/II Open-label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of GSK525762 in Subjects With Relapsed, Refractory Hematologic Malignancies
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Neoplasms
Keywords: leukemia
Acute myeloid leukemia
BET inhibitor
lymphoma
Myelodysplastic syndromes
Oncology
multiple myeloma
GSK525762
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-09-17
Enrollment: 111
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is an open-label repeat dose, multicenter, 2-part study to determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) for GSK525762 given once-daily (QD) orally. Part 1 of the study is a dose escalation phase to select the recommended Part 2 dose (RP2D) based on the safety, PK, and PD profiles observed after oral administration of GSK525762. Eligible subjects with select relapsed refractory hematological malignancies (acute myeloid leukemia \[AML\], non-Hodgkin's Lymphoma \[NHL\]and multiple myeloma \[MM\]), will be enrolled in the QD and/or BID dosing cohorts until a MTD is established. Subjects may continue treatment in the study until disease progression, unacceptable toxicity, or withdrawal of consent. . Upon determination of the MTD, twice daily (BID) dosing cohorts may be opened to collect additional safety data and evaluate the preliminary efficacy of GSK525762 administered BID. Part 2 will explore clinical activity at the MTD or RP2D; separate expansion cohorts will be planned for acute myeloid leukemia (AML), non-Hodgkin's Lymphoma (NHL, including an exploratory sub-cohort of subjects with myc and B-Cell Leukemia (BCL)2 and/or BCL6 rearrangements/overexpression \[double- and triple-hit lymphoma\]), and multiple myeloma (MM). This is the first study of this agent to be conducted in subjects with these relapsed and/or refractory hematological malignancies for which no standard therapies are anticipated to result in a durable remission.


Eligibility criteria: Inclusion criteria

* Written informed consent provided.
* Males and females 18 years old or older.
* In Part 1 and, Part 2, subjects must have AML, MM, or NHL. Subjects with AML, are eligible if they • have relapsed and/or refractory disease, OR are\>=65 years of age and not candidates for or have refused standard chemotherapy. Subjects with multiple myeloma are eligible if they have progressed despite therapy with an alkylating agent, proteasome inhibitor, and immunomodulatory agent, either as individual regimens or in combination. Subjects with NHL are eligible if they have received at least two prior lines of systemic therapy, including at least one line of immunochemotherapy with an anti-CD20 antibody (if their tumor expresses CD20).

In Part 2, the NHL cohort will separately enrol subjects with double- and triple hit lymphoma, so that a minimum of 10 subjects with this subset of disease will be enrolled. To be eligible for this sub-cohort, tumor sample from the subject must demonstrate rearrangement and/or overexpression of MYC and either BCL2 and/or BCL6 genes. Evaluation of double- or triple-hit status may be performed via appropriate local testing, and the determination of double- or triple-hit diagnosis will be at the discretion of the investigator and GSK Medical Monitor.

* 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 GSK525762, 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 GSK525762. Topical steroids are permitted
  * there are no signs or symptoms of graft versus host disease, other than Grade 1 skin involvement.
* Eastern Cooperative Oncology Group (ECOG) performance status of \<=1.
* Subject must be stable enough to be expected to complete dosing through the DLT observation period as assessed by the investigator.
* Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
* A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea \[in questionable cases, a blood sample with simultaneous follicle stimulating hormone (FSH) \> 40 milli-International units per milliliter and estradiol \< 40 picograms per milliliter (\< 140 picomole per liter) is confirmatory\]. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods defined in protocol if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. For most forms of HRT, at least two to four weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method; Child-bearing potential and agrees to use one of the contraception methods for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until at least 7 months after the last dose of study medication; Negative serum pregnancy test \<= 7 days prior to first study drug dose; Female subjects who are lactating must discontinue nursing prior to the first dose of study treatment and must refrain from nursing throughout the treatment period and for 5 half-lives of GSK525762 or at least 28 days (whichever is longer) following the last dose of study treatment.
* Male subjects must agree to use one of the methods of contraception specified. This method must be used from the time of the first dose of study medication until 16 weeks after the last dose of study medication. In addition, male subjects whose partners are or become pregnant must continue to use condoms for 7 days after stopping study medications.
* Adequate organ system function.
* Ability to comply with dietary and tobacco/alcohol abstinence requirements.

Exclusion Criteria

* Haematological malignancy associated with human immunodeficiency virus (HIV) infection or solid organ transplant or history of known Hepatitis B Antigen or positive Hepatitis C antibody (confirmed by Recombinant ImmunoBlot Assay \[RIBA\], if available or alternately confirmed by Hepatitis C Virus \[HCV\] Ribonucleic acid \[RNA\]).
* History or concurrent malignancy of solid tumours, except for below. Exception: Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. Subjects with second malignancies that are indolent or definitively treated may be enrolled even if less than 5 years have elapsed since treatment. Consult the GSK Medical Monitor if unsure whether second malignancies meet requirements specified above.
* Currently receiving cancer therapy (chemotherapy, radiation therapy, immuno- therapy, biologic therapy, hormonal therapy, surgery, and/or tumour embolization).The following are allowed: Hydroxyurea for proliferative disease, Corticosteroids, Use of hematopoetic growth factors is permitted at the discretion of the investigator according to published guidelines (e.g., National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), American Society of Hematology (ASH), etc.). The following are NOT allowed: Investigational anti cancer drug within 2 weeks prior to the first dose of GSK525762; Major surgery, radiotherapy, or immunotherapy within 4 weeks of GSK525762 Chemotherapy regimens with delayed toxicity within the last 4 weeks. Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within the last 2 weeks.

Nitrosourea or mitomycin C within the last 6 weeks

* Evidence of severe of uncontrolled infection.
* Use of anticoagulants (e.g., warfarin, heparin) at therapeutic levels within 7 days prior to the first dose of GSK525762. Low dose (prophylactic) low molecular weight heparin (LMWH) is permitted. In addition, INR must be monitored in accordance with local institutional practices, as appropriate.
* Current use of a prohibited medication or requires any of these medications during treatment with the investigational drugs. This includes excluding current medications known or suspected to be associated QT prolongation. In addition, any subject who is expected to require a QT prolonging medication while on trial should not be enrolled.
* Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal, cardiac disease, or clinically significant bleeding episodes). Any serious and/or unstable pre-existing medical (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures, in the opinion of the investigator.
* Symptomatic or untreated Central nervous system (CNS) disease, Subjects with a history of CNS disease (leukemia, lymphoma or myeloma) are permitted to enrol if they have previously received appropriate therapy and CNS remission has been documented. Subject with primary CNS lymphoma (defined as isolated CNS lymphoma without systemic involvement) are excluded from study.
* Cardiac abnormalities as evidenced by any of the following: History or current clinically significant uncontrolled arrhythmias or hypertension; Clinically significant conduction abnormalities or arrhythmias, subjects with Bundle Branch Block; Presence of cardiac pacemaker; History or evidence of current \>=Class II congestive heart failure as defined by New York Heart Association (NYHA); History of acute coronary syndromes (including unstable angina and myocardial infarction), coronary angioplasty, or stenting within the past 3 months.
* Any of the following ECG findings or assessments including: Baseline QTcF interval \>=450 milliseconds; Clinically significant ECG assessments should be reviewed by the site cardiologist prior to study entry.
* GSK525762 is a benzodiazepine class molecule. Any serious known immediate or delayed hypersensitivity reaction(s) to GSK525762 or idiosyncrasy to drugs chemically related to the investigational drug.
* Evidence of hemoptysis within the last 7 days.
* History of major gastrointestinal bleeding within the last 3 months or any evidence of active gastrointestinal bleeding excludes the subject.
* Presence of gastrointestinal disease that would significantly affect compound absorption.

Primary outcomes:
measure: Part 1: Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs) and AE Leading to Discontinuation (AELD)
timeFrame: Up to 86.9 weeks
measure: Part 1: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: Up to 3 weeks
measure: Part 1: Number of Participants With Dose Reductions
timeFrame: Up to 86.9 weeks
measure: Part 1: Number of Participants With Any Dose Interruptions or Delays
timeFrame: Up to 86.9 weeks
measure: Part 1: Number of Participants With Grade Change From Baseline in Clinical Chemistry Parameters
timeFrame: Up to 86.9 weeks
measure: Part 1: Number of Participants With Grade Change From Baseline in Hematology Parameters
timeFrame: Up to 86.9 weeks
measure: Part 1: Number of Participants With Worst-case Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method
timeFrame: Up to 86.9 weeks
measure: Part 1: Number of Participants With Worst Case Vital Signs Results Relative to Baseline: Pulse Rate and Body Temperature
timeFrame: Up to 86.9 weeks
measure: Part 1: Number of Participants With Increase to Grade 3 From Baseline in Vital Signs: Diastolic Blood Pressure (DBP) and Systolic Blood Pressure (SBP)
timeFrame: Up to 86.9 weeks
measure: Part 1: Number of Participants With Worst-case Post-Baseline Abnormal Electrocardiogram (ECG) Findings (Investigator Reading)
timeFrame: Up to 86.9 weeks
measure: Part 2: Objective Response Rate (ORR) (MDS Cohort)
timeFrame: Up to 36.4 weeks
measure: Part 2: Objective Response Rate Lasting at Least 4 Months (ORR4) (CTCL Cohorts)
timeFrame: Up to 36.4 weeks
Secondary outcomes:
measure: Part 1: Overall Response Rate (ORR)- Investigator Assessment
timeFrame: Up to 86.9 weeks
measure: Part 1: Area Under the Concentration-time Curve (AUC) From Time Zero to 24 Hours(AUC[0-24]) and AUC Extrapolated to Infinity (AUC[0-inf]) of GSK525762 Following Single Dose Administration
timeFrame: Week 1 Day 1: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
measure: Part 1: AUC(0-24) and Area Under the Concentration-time Curve Over the Dosing Interval (AUC[0-tau]) of GSK525762 Following Repeat Dose Administration
timeFrame: Week 2 Day 7: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
measure: Part 1: Maximum Observed Concentration (Cmax) and Minimum Plasma Concentration (Cmin) of GSK525762 Following Single Dose Administration
timeFrame: Week 1 Day 1: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
measure: Part 1: Cmax and Cmin of GSK525762 Following Repeat Dose Administration
timeFrame: Week 2 Day 7: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
measure: Part 1: Trough Concentration (Ctau) of GSK525762 Following Repeat Dose Administration
timeFrame: Week 2 Day 7: Pre-dose on Days 4, 6 and 7
measure: Part 1: Time of Maximum Concentration (Tmax) of GSK525762 Following Single Dose Administration
timeFrame: Week 1 Day 1: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
measure: Part 1: Tmax of GSK525762 Following Repeat Dose Administration
timeFrame: Week 2 Day 7: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
measure: Part 1: Terminal Half Life (T1/2) of GSK525762 Following Single Dose Administration
timeFrame: Week 1 Day 1: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
measure: Part 1: T1/2 of GSK525762 Following Repeat Dose Administration
timeFrame: Week 2 Day 7: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
measure: Part 1: Time Invariance (RS) of GSK525762
timeFrame: Week 1 Day 1: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose; Week 2 Day 7: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
measure: Part 1: Accumulation Ratio (RO) of GSK525762
timeFrame: Week 1 Day 1: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose; Week 2 Day 7: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
measure: Part 2: Apparent Clearance (CL/F) of GSK525762 After Single Dose Administration
timeFrame: Week 1 Day 1: pre-dose and at 0.5 - 2 hour, 4 - 8 hours post-dose
measure: Part 2: Apparent Clearance (CL/F) of GSK525762 After Repeat Dose Administration
timeFrame: Week 3 Day 1: pre-dose and at 0.5 - 2 hour, 4 - 8 hours post-dose
measure: Part 2: Apparent Central Volume of Distribution (V1/F) of GSK525762 Following Single Dose Administration
timeFrame: Week 1 Day 1: pre-dose and at 0.5 - 2 hour, 4 - 8 hours post-dose
measure: Part 2: Apparent Central Volume of Distribution (V1/F) of GSK525762 Following Repeat Dose Administration
timeFrame: Week 3 Day 1: pre-dose and at 0.5 - 2 hour, 4 - 8 hours post-dose
measure: Part 1: AUC(0-24) and AUC[0-inf] of GSK3529246 (Active Metabolite) Following Single Dose Administration
timeFrame: Week 1 Day 1: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
measure: Part 1: AUC(0-24) and AUC(0-tau) of GSK3529246 (Active Metabolite) Following Repeat Dose Administration
timeFrame: Week 2 Day 7: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
measure: Part 1: Cmax and Cmin of GSK3529246 (Active Metabolite) Following Single Dose Administration
timeFrame: Week 1 Day 1: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
measure: Part 1: Cmax and Cmin of GSK3529246 (Active Metabolite) Following Repeat Dose Administration
timeFrame: Week 2 Day 7: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
measure: Part 1: Trough Concentration (Ctau) of GSK3529246 (Active Metabolite) Following Repeat Dose Administration
timeFrame: Week 2 Day 7: Pre-dose on Days 4, 6 and 7
measure: Part 1: Tmax of GSK3529246 (Active Metabolite) Following Single Dose Administration
timeFrame: Week 1 Day 1: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
measure: Part 1: Tmax of GSK3529246 (Active Metabolite) Following Repeat Dose Administration
timeFrame: Week 2 Day 7: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
measure: Part 1: T1/2 of GSK3529246 (Active Metabolite) Following Single Dose Administration
timeFrame: Week 1 Day 1: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
measure: Part 1: T1/2 of GSK3529246 (Active Metabolite) Following Repeat Dose Administration
timeFrame: Week 2 Day 7: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
measure: Part 1: Time Invariance (RS) of GSK3529246 (Active Metabolite)
timeFrame: Week 1 Day 1: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose; Week 2 Day 7: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
measure: Part 1: Accumulation Ratio (RO) of GSK3529246 (Active Metabolite)
timeFrame: Week 1 Day 1: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose; Week 2 Day 7: pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post-dose
measure: Part 2: Apparent Clearance (CL/F) of GSK3529246 (Active Metabolite) Following Single Dose Administration
timeFrame: Week 1 Day 1: pre-dose and at 0.5 - 2 hours, 4 - 8 hours post-dose
measure: Part 2: Apparent Clearance (CL/F) of GSK3529246 (Active Metabolite) Following Repeat Dose Administration
timeFrame: Week 3 Day 1: pre-dose and at 0.5 - 2 hours, 4 - 8 hours post-dose
measure: Part 2: Apparent Central Volume of Distribution (V1/F) of GSK3529246 (Active Metabolite) Following Single Dose Administration
timeFrame: Week 1 Day 1: pre-dose and at 0.5 - 2 hours, 4 - 8 hours post-dose
measure: Part 2: Apparent Central Volume of Distribution (V1/F) of GSK3529246 (Active Metabolite) Following Repeat Dose Administration
timeFrame: Week 3 Day 1: pre-dose and at 0.5 - 2 hours, 4 - 8 hours post-dose
measure: Part 2: Change From Baseline in Skindex-29 Domain Scores (Emotional, Functioning and Symptoms Score) for CTCL Cohort
timeFrame: Baseline (pre-dose Week1 Day1) and Week 3, Week 7, Week 10, Week 16 and Week 24
measure: Part 2: Number of Participants With Non-serious AEs and SAEs and AELDs
timeFrame: Up to 36.4 weeks
measure: Part 2: Number of Participants With Dose Reductions
timeFrame: Up to 36.4 weeks
measure: Part 2: Number of Participants With Dose Interruptions/Delays
timeFrame: Up to 36.4 weeks
measure: Part 2: Number of Participants With Grade Change From Baseline in Clinical Chemistry Parameters
timeFrame: Up to 36.4 weeks
measure: Part 2: Number of Participants With Grade Change From Baseline in Hematology Parameters
timeFrame: Up to 36.4 weeks
measure: Part 2: Number of Participants With Worst-case Urinalysis Results Post-Baseline Relative to Baseline by Dipstick Method
timeFrame: Up to 36.4 weeks
measure: Part 2: Number of Participants With Worst Case Vital Signs Results Relative to Baseline: Pulse Rate and Body Temperature
timeFrame: Up to 36.4 weeks
measure: Part 2: Number of Participants With Increase to Grade 3 From Baseline in Vital Signs: DBP and SBP
timeFrame: Up to 36.4 weeks
measure: Part 2: Number of Participants With Worst-case Post-Baseline Abnormal Electrocardiogram (ECG) Findings (Investigator Reading)
timeFrame: Up to 36.4 weeks
measure: Part 2: Progression Free Survival (PFS)
timeFrame: Up to 36.4 weeks
measure: Part 2: Duration of Response (DOR)
timeFrame: Up to 36.4 weeks
measure: Part 2: Overall Survival (OS)
timeFrame: Up to 36.4 weeks
Other outcomes:
measure: Part 2: Time to Progression (TTP) for Participants With MM
timeFrame: Up to 36.4 weeks
measure: Part 1: Changes in Cardiac QT Duration Corrected for Heart Rate by Fridericia's Formula (QTcF) and Other Safety Parameters in Relation to GSK525762 PK Concentrations
timeFrame: Up to 86.9 weeks
measure: Part 1: Number of Participants With Dose /Exposure Markers Related Change in Molecular Markers in Tumor Tissue and/or Peripheral Blood Samples
timeFrame: Up to 86.9 weeks
measure: Part 2: Plasma Concentrations of GSK525762 in Relationship With Safety and Efficacy Parameters Derived From Pharmacokinetic/Pharmacodynamic (PK/PD) Model
timeFrame: Up to 36.4 weeks
measure: Part 2: Number of Participants With Dose /Exposure Markers Related Change in Molecular Markers in Tumor Tissue and/or Peripheral Blood Samples
timeFrame: Up to 36.4 weeks
measure: Part 1: Overall Survival (OS)
timeFrame: Up to 86.9 weeks
Locations:
city: Little Rock
country: United States
facility: GSK Investigational Site
state: Arkansas
city: Aurora
country: United States
facility: GSK Investigational Site
state: Colorado
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Philadelphia
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: East Melbourne
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Málaga
country: Spain
facility: GSK Investigational Site
city: Salamanca
country: Spain
facility: GSK Investigational Site
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Bell C; Fennell K; Chan YC; Rambow F; Yeung M; Vassiliadis D; Lara L; Yeh P; Martelotto L; Rogiers A; Kremer B; Barbash O; Mohammad H; Johanson T; Burr M; Dhar A; Karpinich N; Tian L; Tyler D; MacPherson L; Shi J; Pinnawala N; Fong CY; Papenfuss A; Grimmond S; Dawson SJ; Allan R; Kruger R; Vakoc C; Goode D; Naik S; Gilan O; Lam E; Marine JC; Prinjha R; and Dawson M.Enhancer remodeling overcomes therapeutic resistance driven by epigenetic evolution in cancer.Nature.2019;
citation: Dawson MA, Borthakur G, Huntly BJP, Karadimitris A, Alegre A, Chaidos A, Vogl DT, Pollyea DA, Davies FE, Morgan GJ, Glass JL, Kamdar M, Mateos MV, Tovar N, Yeh P, Delgado RG, Basheer F, Marando L, Gallipoli P, Wyce A, Krishnatry AS, Barbash O, Bakirtzi E, Ferron-Brady G, Karpinich NO, McCabe MT, Foley SW, Horner T, Dhar A, Kremer BE, Dickinson M. A Phase I/II Open-Label Study of Molibresib for the Treatment of Relapsed/Refractory Hematologic Malignancies. Clin Cancer Res. 2023 Feb 16;29(4):711-722. doi: 10.1158/1078-0432.CCR-22-1284.