| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with relapsed and/or refractory haematological malignancies (lymphoma, leukemia, or multiple myeloma) |
|
| E.1.1.1 | Medical condition in easily understood language |
| hematological malignancies |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066481 |
| E.1.2 | Term | Hematological malignancy |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
PART 1
To determine the safety, tolerability and maximum tolerated dose (MTD), following once daily (QD) and/or twice daily (BID) dosing schedules, establishing the recommended Phase 2 dose (RP2D) of GSK525762 in adult subjects with acute leukemia (AML), multiple myeloma (MM), or non-Hodgkin’s lymphoma (NHL).
PART 2
To evaluate clinical efficacy after treatment with GSK525762 in acute myeloid leukemia (AML).
To evaluate clinical efficacy after treatment with GSK525762 in multiple myeloma (MM)
To evaluate clinical efficacy after treatment with GSK525762 in non- Hodgkin’s Lymphoma (NHL) |
|
| E.2.2 | Secondary objectives of the trial |
PART 1
- To characterize the Pharmacokinetic (PK) of GSK525762 after single- and repeat-dose administration following QD and/or 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 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.
PART 2
-To characterize the PK of GSK525762 in 3 disease specific cohorts of subjects with 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 AML, MM, or NHL..
Please see also protocol page 45 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent provided.
2. Males and females 18 years old or older.
3. In Part 1, subjects must have relapsed and/or refractory hematologic malignancies (leukemias, myeloproliferative neoplasms, lymphomas, and myelomas) for which no standard therapies are available or anticipated to result in remission.
In Part 2, subjects must have Acute Myeloid Leukemia (AML), Multiple Myeloma (MM), or non-Hodgkin’s Lymphoma (NHL).
Subjects with AML (Part 1 and Part 2), 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.
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.
4. Subjects with a prior history of stem cell transplant are allowed if
- At least 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
5. Eastern Cooperative Oncology Group (ECOG) performance status of ≤1.
6. Subject must be stable enough to be expected to complete dosing through the DLT observation period as assessed by the investigator.
7. 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.
8. 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 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. 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 (described in section 9.1), 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.
9. 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 while on study medication must continue to use condoms for 7 days after stopping study medications.
10. Adequate organ system function (at both screening and where applicable pre first dose) as defined in Table 5.
11. Ability to comply with dietary and tobacco/alcohol abstinence requirements as defined in Section 9.2.
(Refer to the Protocol on Page 46, for TABLE 5 - Definitions for Adequate Organ Function) |
|
| E.4 | Principal exclusion criteria |
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 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.
3. Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy, surgery, and/or tumour embolization).
Note: the following are allowed:
Hydroxyurea for proliferative disease
Corticosteroids
Use of hematopoetic growthfactors 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.).
Note: the following are NOT allowed:
Investigational anti-cancer drug within 2 weeks (or 5 half-lives of the drug, whichever is longer) 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
4. Evidence of severe of uncontrolled infection.
5. 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.
6. 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 (see Section 8.3). In addition, any subject who is expected to require a QT prolonging medication while on trial should not be enrolled.
7. 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.
8. Symptomatic or untreated 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.
9. 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) [Appendix 2].
-History of acute coronary syndromes (including unstable angina and
myocardial infarction), coronary angioplasty, or stenting within the past 3 months.
10. 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.
11. 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.
12. No evidence of hemoptysis within the last 7 days.
13. History of major gastrointestinal bleeding within the last 3 months or any evidence of active gastrointestinal bleeding excludes the subject (refer to Section 1.5).
14. Presence of gastrointestinal disease that would significantly affect compound absorption. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
PART 1
Adverse Events (AEs), Serious Adverse Events (SAEs), Dose Limiting Toxicity (DLT), dose reductions or delays, withdrawals due to toxicities and changes in safety assessments (e.g., laboratory parameters, vital signs, and cardiac parameters).
PART 2
For AML: Objective response rate (% of subjects achieving Complete Response (CR), Partial Response (PR), CRp (as per CR but platelet count <100 x 10^9/L) or morphologic leukemia-free state) per response criteria.
For MM: Objective response rate (defined as the percentage of subjects that have achieved a CR, VGPR, or PR) per response criteria
For NHL: Objective response rate (defined as the percentage of subjects that have achieved a CR, or PR) per response criteria |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
PART 1
Dose limiting toxicity will be evaluated during the first 3 weeks of treatment but all other safety parameters and adverse events are followed until the patient discontinues the study.
PART 2
The response rate will be assessed until a subject has disease progression or terminates the study.
|
|
| E.5.2 | Secondary end point(s) |
PART 1
GSK525762 PK parameters following single and repeat-dose administration of GSK525762, including Area under concentration-time curve (AUC), Minimum observed concentration (Cmin), Pre-dose (trough) concentration at the end of a dosing interval (CT), Maximum observed concentration (Cmax), Time of maximum concentration (tmax), Apparent terminal half-life (t1/2) (or t1/2, eff), time invariance and accumulation ratio.
Changes in cardiac QT duration corrected for heart rate by Fridericia’s formula (QTcF) and other safety parameters in relation to GSK525762 exposure markers (dose, concentration, Cmax, AUC, following single and repeat-dose oral administration of GSK525762
Dose related change in molecular markers (e.g., gene transcription and/or expression of proteins regulated by Bromodomain [BRD] proteins) in tumor tissue and/or peripheral blood samples.
Assess overall response rate (RR) according to disease specific assessments for leukemia, multiple myeloma, and non-Hodgkin’s lymphoma.
PART 2
Population PK parameters for GSK525762 such as apparent clearance following oral administration (CL/F) and volume of distribution (V/F), and relevant covariates which may influence exposure (e.g., age, weight, or disease associated covariates).
PK/PD relationship between GSK525762 exposure markers and safety and efficacy parameters.
AEs, SAEs, dose reductions or delays, withdrawals due to toxicities and changes in safety assessments (e.g., laboratory parameters, vital signs, and cardiac parameters) at RP2D.
Dose related change in molecular markers (e.g., gene transcription and/or expression of proteins regulated by BRD proteins) in tumor tissue and/or peripheral blood samples.
Overall survival (OS, the time from the treatment start date until death from any cause).
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
PART 1
Subjects will be evaluated for secondary endpoints such as pharmacokinetics for the first 3 weeks, at Week 7 and every 6 weeks for subjects on study longer than 12 weeks.
PART 2
Subjects will be evaluated for secondary endpoints for the first 3 weeks and subsequently at Week 4, Week 7, and Week 10. Subjects will then be evaluated 3 weeks after Week 10, and every 6 weeks thereafter.
In both Part 1 and Part 2, subjects will receive study treatment until disease progression, death or unacceptable adverse event. A subject will be considered to have completed the study 2 years after the last treatment or if the subject dies or is still in follow-up at the time the study is closed or terminated, whichever is sooner.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Dose escalation, safety, PK, PD, clinical activity |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| A subject will be considered to have completed the study 2 years after the last treatment or if the subject dies or is still in follow-up at the time the study is closed or terminated, whichever is sooner. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 24 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 24 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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