| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| NUT Midline Carcinoma and other solid tumors |
|
| E.1.1.1 | Medical condition in easily understood language |
| NUT Midline Carcinoma and other solid tumors |
|
| 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 | 10007284 |
| E.1.2 | Term | Carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- To determine the safety, tolerability and maximum tolerated dose (MTD) of GSK525762 in subjects 16 years or older following QD and/or BID dosing schedules.
- To evaluate the clinical activity of GSK525762 in NMC and other solid tumors.
- [US Clinical sites only] To evaluate, after single dose administration, the relative bioavailability of the GSK525762 besylate tablet compared to the amorphous free-base tablet, the effect of high-fat high-calorie meal on the bioavailability of the besylate tablet and the dose proportionality of two doses of GSK525762 administered as the besylate tablets. |
|
| E.2.2 | Secondary objectives of the trial |
- To characterize the pharmacokinetics (PK) of GSK525762 in subjects 16 years or older following QD and/or BID dosing schedules.
- To evaluate cardiac safety, including the potential for QTcF changes with GSK525762 and to assess PK/QTcF relationship following QD and/or BID dosing schedules.
- To evaluate the exposure response (pharmacokinetic/pharmacodynamic [PK/PD]) relationship between GSK525762 and safety and efficacy parameters following QD and/or BID dosing schedules.
- To evaluate the effect of treatment with GSK525762 on tumor growth and survival. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Title: Besylate Sub-Study [US Clinical sites only]
Objective: To determine the relative bioavailability (BA), food effect, and dose proportionality of the besylate formulation of GSK525762 at or near the MTD
Title: Pharmacogenetic Research
Objectives: The objective of the PGx research (if there is a potential unexpected or unexplained variation) is to investigate a possible genetic relationship to handling or response to GSK525762. If at any time it appears there is potential variability in response in this clinical study or in a series of clinical studies with GSK525762 that may be attributable to genetic variations of subjects, the following objectives may be investigated – the relationship between genetic variants and study treatment with respect to:
- Pharmacokinetics and/or pharmacodynamics of study treatment,
- Safety and/or tolerability, and
- Efficacy. |
|
| E.3 | Principal inclusion criteria |
1. Male or female 16 years or older, at the time of signing the informed consent.
2. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. If the subject is less than 18 years old, an Assent form and parental/guardian Consent form (replacing “you will” with “your child will” will be required).
3. Diagnosis of one of the following:
Part 1 Only:
- NUT Midline Carcinoma based on ectopic expression of NUT protein as determined by IHC and/or detection of NUT gene translocation as determined by FISH. Subjects may be treatment naïve or have had prior therapy.
- SCLC, CRC, NB, TNBC, ER positive BC, CRPC, NSCLC, and any other solid tumor which has been confirmed by clinical testing to be MYCN amplified (defined as a MYCN gene copy number gain of ≥5). Subjects should have tumor progression after receiving at least one prior standard/approved chemotherapy, or where there is no approved therapy, or where standard therapy is refused.
Part 2 Only:
- NUT Midline Carcinoma as diagnosed by the Central Laboratory. Subjects may be treatment naïve or have had prior therapy.
- SCLC, CRPC, TNBC and ER+BC
4. Subjects with solid tumors, with the exception of CRPC, must demonstrate measurable disease, per RECIST v1.1. NOTE: Subjects with NMC that do not meet the RECIST v1.1 criteria for measurable disease, but have evaluable disease may be considered for enrollment after discussion with the GSK medical monitor.
5. All prior treatment- related toxicities must be CTCAE (Version 4.0) ≤ Grade 1 (except alopecia and peripheral neuropathy) at the time of treatment allocation.
6. ECOG Performance Status score of 0 to 2 for subjects with NMC; 0-1 for subjects with other tumor types.
7. Adequate organ function as defined in Table 8.
See table in the protocol
8. 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.
9. 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 study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status prior to study enrollment. For most forms of HRT, at least 2 to 4 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 4 weeks 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.
10. 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 least 16 weeks after the last dose of study medication.
Specific Eligibility Criteria for Part 2 CRPC Expansion Cohort:
11. Histologically or cytologically confirmed diagnosis of prostate adenocarcinoma, surgically castrated or continuously medically castrated (for more than or equal to 8 weeks prior to prescreening)
12. Persistent disease with evidence of disease progression following standard therapy(ies) including prior treatment with androgen/androgen receptor directed therapy, including enzalutamide and/or abiraterone
13. Ongoing androgen deprivation therapy with a serum testosterone level <1.7 nmol/L or <50 ng/dL
14. PSA levels more than or equal to 2.0 ng/mL |
|
| E.4 | Principal exclusion criteria |
1. Primary malignancy of the central nervous system, or malignancies related to HIV or solid organ transplant. History of known HIV. History of known Hepatitis B surface antigen or positive Hepatitis C antibody (confirmed by RIBA).
2. Prior treatments usage as defined:
a. Use of an investigational anti-cancer drug within 14 days or 5 half-lives, whichever is longer, prior to the first dose of the investigational products.
b. A minimum of 14 days between termination of the investigational drug and administration of GSK525762.
c. Any therapy related toxicities must also have resolved to Grade 1 or less. Note that an investigational drug is defined as a drug without an approved oncologic indication.
d. Chemotherapy, radiotherapy, anti-neoplastic antibody or targeted therapy or immunotherapy within 14 days, major surgery within 28 days (or 42 days for prior nitrosoureas or mitomycin C) prior to the first dose of the investigational product.
e. Anti-androgen (e.g., bicalutamide) therapies for prostate cancer must be stopped 4 weeks prior to enrollment. Second line hormone therapies such as enzalutamide, abiraterone, or orteronel should be stopped 2 weeks prior to enrollement. Subjects with prostate cancer should remain on luteinizing hormone releasing hormone (LHRH) agonists or antagonists. Subjects with prostate cancer may also remain on low-dose prednisone or prednisolone (up to 10 mg/day) and still be eligible for this study.
3. Current 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.
4. Current use of a prohibited medication or requires any of these medications during treatment with the investigational drugs (details will be available in Section 8.3). This includes excluding current medications known or suspected to be associated QT prolongation. In addition, any subject who may require a QT prolonging medication while on trial should not be enrolled.
5. 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.
6. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression.
NOTE: Subjects previously treated for these conditions that have had stable CNS disease (verified with consecutive imaging studies) for >1months, are asymptomatic and off corticosteroids, or are on stable dose of corticosteroids for at least 1 month prior to study Day 1 are permitted. Stability of brain metastases must be confirmed with imaging. Subject treated with gamma knife the can be enrolled 2 weeks postprocedure as long as there are no post-procedure complications/stable. In addition, subjects treated or currently taking enzyme-inducing anticonvulsant (EIAC) are allowed on study.
7. Cardiac abnormalities as evidenced by any of the following:
- History or current untreated clinically significant uncontrolled arrhythmias.
- 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.
8. Any of the following EKG findings:
- Baseline QTcF interval ≥450 msec
- Any clinically significant ECG assessments should be reviewed by the site cardiologist prior to study entry.
9. 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.
10. Hemoptysis > 1 teaspoon in 24 hours within the last 28 days.
11. History of major gastrointestinal bleeding within the last 6 months. Any evidence of active gastrointestinal bleeding excludes the subject.
12. Besylate Sub-Study only [US Clinical sites only]: unable or unwilling to eat the FDA recommended high-fat high-calorie breakfast (two eggs fried in butter, two strips of bacon, 4 oz. of hash brown potatoes and 8 oz of whole milk) within the recommended 30 minutes. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• AEs, SAEs, dose reductions or delays, withdrawals due to toxicities and changes in safety assessments (e.g., laboratory parameters, vital signs, ECG, cardiotoxicity, gastrointestinal, etc) to determine the MTD in subjects 16 years or older
• Assess overall response rate (RR) by RECIST 1.1 in NMC and other solid tumors.
• PK parameter values for GSK525762 following single oral administration as amorphous free-base or besylate tablet |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1: Dose limiting toxicity will be evaluated during the first 4 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) |
• PK parameter values for GSK525762 following single and repeat-dose oral administration in subjects 16 years or older
• Changes in cardiac safety including QTcF following single and repeat-dose oral administration GSK525762.
• Progression free survival (PFS), time to response, duration of response, overall survival (OS), and exploratory analysis for antitumor response by various imaging modalities.
|
|
| 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 4 weeks, at Week 9, and every 8 weeks for subjects on study longer than 13 weeks.
Part 2: Subjects will be evaluated for secondary endpoints for the first 4 weeks and subsequently at Week 5, Week 9, and Week 10. Subjects will then be evaluated 3 weeks after Week 13, and every 4 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.
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|
| 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 | No |
| 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 | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| 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 |
| Australia |
| France |
| Netherlands |
| Spain |
| 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
|
| The end of the study date is defined as last subject last visit (contact). |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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