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
This clinical research study is made up of 2 parts. Part 1 has been completed. The goal of Part 1 of this study was to find the highest tolerable dose of GSK525762 that can be given to patients with refractory or relapsed leukemia. The safety of this drug was also studied. In this part of the study, Part 2, researchers will continue testing the recommended dose from Part 1 in refractory or relapsed leukemia as well as myelodysplastic syndromes (MDS).
Disease Group: Leukemia
Treatment Agent: GSK525762
Treatment Location: Both at MDACC & and Other Sites
Part 1: Primary: To determine the safety, tolerability and maximum tolerated dose (MTD), following once daily (QD) administration, establishing the recommended Phase 2 dose (RP2D) of GSK525762 in adult subjects with acute myeloid leukemia (AML), multiple myeloma (MM), or non-Hodgkin' lymphoma (NHL). Secondary: To evaluate clinical efficacy following QD administration in subjects with AML, MM and NHL. To characterize the Pharmacokinetic (PK) of GSK525762 after single- and repeat-dose administration following QD and/or twice daily (BID) dosing schedules. To evaluate the relationship between GSK525762 exposure and cardiac and other safety parameters following QD and/or BID dosing schedules. To evaluate the relationship between GSK525762 dose/exposure and Pharmacodynamic (PD) response following QD and/or BID dosing schedules. To evaluate the relationship between GSK525762 dose and exposure with clinical activity of GSK525762. Exploratory: To investigate the relationship between genetic variants in candidate genes and the pharmacokinetics (PK) and safety profile of GSK525762 following QD dosing schedules. To investigate the mechanism of action and indicators of sensitivity and resistance to GSK525762 Part 2: Primary: To evaluate clinical efficacy after treatment with GSK525762 in high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) that has evolved from an antecedent MDS ("myeloid cohort"). To evaluate clinical efficacy after treatment with GSK525762 in multiple myeloma (MM) To evaluate clinical efficacy after treatment with GSK525762 in non-Hodgkins' Lymphoma (NHL) Secondary: To characterize the PK of GSK525762 in 3 disease-specific cohorts of subjects with MDS/AML, MM or NHL after repeat-dose administration. To evaluate the exposure response (i.e., PK/PD) relationship between GSK525762 and safety/efficacy parameters in 3 disease-specific cohorts of subjects with MDS/AML. MM or NHL. To evaluate the safety and tolerability of RP2D of GSK525762 in 3 disease-specific cohorts of subjects with MDS/AML, MM or NHL. To determine the clinical activity of GSK525762 in 3 disease-specific cohorts of subjects with MDS/AML, MM or NHL. Exploratory: To investigate the relationship between genetic variants in candidate genes and the pharmacokinetics (PK) and safety profile of GSK525762 To investigate the mechanism of action and indicators of sensitivity and resistance to GSK525762
IRB Review and Approval Date: 04/22/2014
Recruitment Status: Open
Projected Accrual: Part 1, approximately 60-70; Part 2, maximum 110
1) Written informed consent provided.
2) Males and females 18 years old or older.
3) Subjects must have a diagnosis of relapsed or refractory AML, Myelodysplastic Syndrome (MDS), Multiple Myeloma (MM), or non-Hodgkin's Lymphoma (NHL). (Part 1 only) 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. (Part 2 only): Subjects with MDS/AML are eligibile if they have high-risk (defined as intermediate [INT]-2 or higher by International Prognostic Scoring System [IPSS] criteria, or high/very high by IPSS-Revised [IBSS-R] criteria MDS that has relapsed after or been refractory to prior therapy with hypomethylating agent, OR have AML that has arisen from an antecedent MDS (irrespective of IPSS/IPSS-R score). Subjects must have progressed despite, or failed to respond to, prior therapy with hypomethylating agent, AND at least one bone marrow biopsy obtained within 28 days of first dose of GSK525762 must demonstrate a marrow blast percentage of no more than 30%.
4) #3 continued: Note: If marrow blasts exceed 30% on any biopsy within 28 days of first dose, enrollment will only be permitted after discussion with the medical monitor. (Part 1 and Part 2): 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. (Part 1 and Part 2): 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).
5) #3 continued: In Part 2, the NHL cohort will separately enroll 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.
6) Subjects with a prior history of stem cell transplant are allowed if at least 3 months have 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 and there are no signs of graft versus host disease, other than Grade 1 skin involvement.
7) Eastern Cooperative Oncology Group (ECOG) performance status of </=1
8) Subject must be stable enough to be expected to complete dosing through the DLT observation period as assessed by the investigator.
9) 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.
10) A female subject is eligible to participate if she is of: 1) 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 MlU/mL and estradiol < 40 pg/mL (< 140 pmol/L) 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.
11) #9 continued: Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method; 2) 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; 3) Negative serum pregnancy test </= 7 days prior to first study drug dose; 4) 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.
12) Male subjects with a female partner of childbearing potential or who is pregnant 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 least 16 weeks after the last dose of study medication. In addition, male subjects whose partners are or become pregnant must use/continue to use condoms for 16 weeks after last dose of study medication.
13) Adequate organ system function.
14) Ability to comply with dietary and tobacco/alcohol abstinence
1) 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] RNA).
2) History or concurrent malignancy of solid tumours, except for: 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.
3) Currently receiving cancer therapy (chemotherapy, radiation therapy, immuno- therapy, biologic therapy, hormonal therapy, surgery, and/or tumour embolization). Note: 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.).
4) #3 continued: Note: 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.
5) Evidence of severe or uncontrolled infection.
6) 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.
7) 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.
8) 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.
9) Symptomatic or untreated CNS disease. Subjects with a history of CNS diease (leukemia, lymphoma or myeloma) are permitted to enroll 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 the study.
10) 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.
11) Any of the following ECG findings or assessments including: Baseline QTcF interval >/= 450 msec.; Clinically significant ECG assessments should be reviewed by the site cardiologist prior to study entry.
12) 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.
13) Evidence of pulmonary hemoptysis within the last 7 days.
14) History of major gastrointestinal bleeding within the last 3 months or any evidence of active gastrointestinal bleeding excludes the subject
15) Presence of gastrointestinal disease that would significantly affect compound absorption.
Information and next steps
Phase I/Phase II
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