Phase 1
Completed N=65
A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of GSK525762 in Subjects With NUT Midline Carcinoma (NMC) and Other Cancers
Carcinoma, Midline
Source: ClinicalTrials.gov NCT01587703 ↗
Enrolled (actual)
65
Serious AEs
54.1%
Results posted
Mar 2020
Primary outcomePrimary: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Part 1 QD — 3; 4; 1; 3 Participants
Summary
This study is divided into two parts; Part 1 of the study is a dose escalation phase to select the recommended dose for Part 2 based on the safety, pharmacokinetic, and pharmacodynamic profiles observed after oral administration of GSK525762 in the following subjects: NMC, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), neuroblastoma (NB), castration resistant prostate cancer (CRPC), triple negative breast cancer (TNBC), estrogen receptor positive (ER positive) breast cancer, and MYCN driven solid tumor subjects. Part 2 of the study will explore the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of the recommended dose from Part 1 in cohorts comprised of NMC, small cell lung cancer (SCLC), castration resistant prostate cancer (CRPC), triple negative breast cancer (TNBC), and estrogen receptor positive (ER positive) breast cancer subjects. Approximately 60 subjects will be enrolled in the Part 1 and approximately 150 subjects will be enrolled in Part 2. A sub-study will be opened in Part 1 to approximately 10-12 subjects in the United States to investigate the relative bioavailability of the besylate tablet compared to the amorphous free-base tablet at the maximum tolerated dose (MTD) or recommended phase 2 dosing (RP2D), the effect of high-fat high-calorie meal on the bioavailability of the besylate tablet at the MTD or RP2D and the dose proportionality of 2 doses of GSK525762 administered as besylate tablet.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)-Part 1 QD |
3; 4; 1; 3; 3; 9 | — |
| PRIMARY Number of Participants With AEs and SAEs-Part 1 BID |
4; 10; 5; 0; 4; 2 | — |
| PRIMARY Number of Participants With AEs and SAEs-Part 2 |
11; 14; 23; 19; 21; 13 | — |
| PRIMARY Number of Participants With Dose Reductions or Delays-Part 1 QD |
0; 0; 0; 0; 0; 2 | — |
| PRIMARY Number of Participants With Dose Reductions or Delays-Part 1 BID |
0; 3; 1 | — |
| PRIMARY Number of Participants With Dose Reductions or Delays-Part 2 |
7; 4; 11; 6; 6; 4 | — |
| PRIMARY Number of Participants With Dose Reductions or Delays-Besylate Sub-study |
3; 1 | — |
| PRIMARY Number of Participants Withdrawn Due to Toxicities-Part 1 QD |
0; 1; 0; 0; 0; 2 | — |
| PRIMARY Number of Participants Withdrawn Due to Toxicities-Part 1 BID |
0; 2; 2 | — |
| PRIMARY Number of Participants Withdrawn Due to Toxicities-Part 2 |
1; 3; 6; 4; 6; 2 | — |
| PRIMARY Number of Participants Withdrawn Due to Toxicities-Besylate Sub-study |
0; 0 | — |
| PRIMARY Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Part 1 QD |
0; 2; 1; 3; 2; 7 | — |
| PRIMARY Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Part 1 BID |
1; 9; 5; 1; 3; 1 | — |
| PRIMARY Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Part 2 |
10; 10; 20; 16; 18; 9 | — |
| PRIMARY Number of Participants With Grade Change From Baseline in Clinical Chemistry Data-Besylate Sub-study |
4; 5; 0; 0; 0; 0 | — |
| PRIMARY Number of Participants With Grade Change From Baseline in Hematology Data-Part 1 QD |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Number of Participants With Grade Change From Baseline in Hematology Data-Part 1 BID |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Number of Participants With Grade Change From Baseline in Hematology Data-Part 2 |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Number of Participants With Grade Change From Baseline in Hematology Data-Besylate Sub-study |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Number of Participants With Maximum Urinalysis Change From Baseline-Part 1 QD |
0; 1; 1; 1; 0; 1 | — |
| PRIMARY Number of Participants With Maximum Urinalysis Change From Baseline Data-Part 1 BID |
0; 0; 1; 1; 0; 1 | — |
| PRIMARY Number of Participants With Maximum Urinalysis Change From Baseline-Part 2 |
0; 0; 0; 1; 0; 0 | — |
| PRIMARY Number of Participants With Maximum Urinalysis Change From Baseline-Besylate Sub-study |
1; 1; 1; 0; 1; 1 | — |
| PRIMARY Number of Participants With Changes in Pulse Rate From Baseline-Part 1 QD |
0; 1; 0; 1; 0; 1 | — |
| PRIMARY Number of Participants With Changes in Pulse Rate From Baseline-Part 1 BID |
0; 0; 0; 3; 4; 2 | — |
| PRIMARY Number of Participants With Changes in Pulse Rate From Baseline-Part 2 |
0; 1; 0; 0; 1; 1 | — |
| PRIMARY Number of Participants With Changes in Pulse Rate From Baseline-Besylate Sub-study |
0; 0; 3; 1; 2; 4 | — |
| PRIMARY Number of Participants With Increase in Blood Pressure From Baseline-Part 1 QD |
2; 1; 0; 0; 0; 3 | — |
| PRIMARY Number of Participants With Increase in Blood Pressure From Baseline-Part 1 BID |
2; 4; 1; 0; 4; 1 | — |
| PRIMARY Number of Participants With Changes in Blood Pressure From Baseline-Part 2 |
2; 3; 8; 5; 4; 3 | — |
| PRIMARY Number of Participants With Increase in Blood Pressure From Baseline-Besylate Sub-study |
1; 1; 2; 1; 0; 0 | — |
| PRIMARY Number of Participants With Changes in Temperature From Baseline-Part 1 QD |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Number of Participants With Changes in Temperature From Baseline-Part 1 BID |
0; 0; 0; 4; 9; 5 | — |
| PRIMARY Number of Participants With Changes in Temperature From Baseline-Part 2 |
1; 0; 0; 0; 1; 0 | — |
| PRIMARY Number of Participants With Changes in Temperature From Baseline-Besylate Sub-study |
0; 0; 4; 5; 1; 0 | — |
| PRIMARY Overall Response Rate-Part 1 QD |
0; 25; 0; 0; 0; 0 | — |
| PRIMARY Overall Response Rate-Part 1 BID |
0; 0; 0 | — |
| PRIMARY Overall Response Rate-Part 2 |
8; 0; 4; 0; 0; 0 | — |
| PRIMARY Overall Response Rate-Besylate Sub-study |
— | — |
| PRIMARY Number of Participants With Prostate Specific Antigen (PSA)50 Response-Part 1 QD |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Number of Participants With PSA50 Response Rate-Part 1 BID |
0; 0; 0 | — |
| PRIMARY Number of Participants With PSA50 Response-Part 2 |
0; 0; 0; 0; 0; 0 | — |
| PRIMARY Number of Participants With PSA50 Response-Besylate Sub-study |
0; 0 | — |
| PRIMARY Area Under the Concentration-time Curve (AUC) From Time Zero to 24 Hours(AUC[0 to 24]); AUC From Time 0 to Last Quantifiable Concentration (AUC [0 to t]) and AUC Extrapolated to Infinity (AUC[0 to Inf]) of GSK525762-Besylate Sub-study |
6954.3; 7377.9; 2977.3; 9123.8; 7292.0; 7703.4 | — |
| PRIMARY Maximum Observed Concentration (Cmax) of GSK525762-Besylate Sub-study |
1431.41; 1483.21; 655.33; 1305.59 | — |
| PRIMARY Apparent Terminal Phase Elimination Rate Constant (Lambda z) for GSK525762-Besylate Sub-study |
5.628; 5.176; 5.088; 5.954 | — |
| PRIMARY Time to Reach Cmax (Tmax) for GSK525762-Besylate Sub-study |
0.5833; 0.8083; 0.8333; 2.0000 | — |
| PRIMARY Number of Participants With Non-serious AEs and SAEs-Besylate Sub-study |
5; 5; 3; 3 | — |
| SECONDARY Number of Participants With Increase in QT Interval Corrected for Heart Rate According to Fridericia's Formula (QTcF)-Part 1 QD |
1; 0; 0; 1; 4; 4 | — |
| SECONDARY Number of Participants With Increase in QTcF-Part 1 BID |
3; 4; 2; 3; 0; 0 | — |
| SECONDARY Number of Participants With Increase in QTcF-Part 2 |
1; 2; 6; 1; 2; 0 | — |
| SECONDARY Number of Participants With Increase in QTcF-Besylate Sub-study |
2; 0; 0; 0; 0; 0 | — |
| SECONDARY Progression Free Survival-Part 1 QD |
0.3; 4.1; 2.2; 9.1; 3.8; 3.6 | — |
| SECONDARY Progression Free Survival-Part 1 BID |
7.7; 5.6; 8.0 | — |
| SECONDARY Progression Free Survival-Part 2 |
4.8; 2.2; 8.0; 2.4; 4.7; 3.4 | — |
| SECONDARY Progression Free Survival-Besylate Sub-study |
3.5 | — |
| SECONDARY Time to Response-Part 1 QD |
— | — |
| SECONDARY Time to Response-Part 1 BID |
— | — |
| SECONDARY Time to Response-Part 2 |
— | — |
| SECONDARY Time to Response-Besylate Sub-study |
— | — |
| SECONDARY Duration of Response-Part 1 QD |
— | — |
| SECONDARY Duration of Response-Part 1 BID |
— | — |
| SECONDARY Duration of Response-Part 2 |
— | — |
| SECONDARY Duration of Response-Besylate Sub-study |
— | — |
| SECONDARY Overall Survival-Part 1 QD |
0.6; 4.1; 2.2; 9.1; 3.8; 8.9 | — |
| SECONDARY Overall Survival-Part 1 BID |
NA; 6.0; 13.3 | — |
| SECONDARY Overall Survival-Part 2 |
5.0; 2.6; 9.1; 5.0; 8.8; 7.3 | — |
| SECONDARY Overall Survival-Besylate Sub-study |
6.3 | — |
| SECONDARY AUC (0 to t), AUC (0 to 24) and AUC (0 to Inf) of GSK525762-Part 1 QD |
169.2; 354.3; 431.5; 867.9; 3943.2; 4225.0 | — |
| SECONDARY Maximum Observed Concentration for GSK525762-Part 1 QD |
50.95; 70.46; 120.35; 179.45; 603.92; 889.52 | — |
| SECONDARY Lambda z for GSK525762-Part 1 QD |
0.21411; 0.13554; 0.23126; 0.09903; 0.07863; 0.12468 | — |
| SECONDARY Tmax for GSK525762-Part 1 QD |
0.5833; 1.2250; 1.1000; 2.0167; 2.0083; 1.0000 | — |
| SECONDARY Apparent Clearance of GSK525762-Part 1 QD |
11.467; 11.085; 18.470; 18.036; 6.720; 13.769 | — |
| SECONDARY Volume of Distribution of GSK525762-Part 1 QD |
53.56; 81.79; 79.87; 182.13; 85.46; 110.44 | — |
| SECONDARY AUC (0 to Inf), AUC (0 to 24) and AUC (0 to t) of GSK525762-Part 1 BID |
856.1; 3067.0; 2794.4; 981.4; 3261.1; 2607.6 | — |
| SECONDARY Maximum Observed Concentration of GSK525762-Part 1 BID |
231.68; 628.01; 703.31; 166.62; 445.17; 425.76 | — |
| SECONDARY Lambda z for GSK525762-Part 1 BID |
0.23463; 0.19989; 0.23721; 0.21171; 0.14307; 0.18789 | — |
| SECONDARY Tmax for GSK525762-Part 1 BID |
1.5500; 0.9667; 0.5500; 1.9583; 1.9667; 1.9833 | — |
| SECONDARY Apparent Clearance of GSK525762-Part 1 BID |
23.246; 9.621; 14.155; 21.745; 11.057; 16.382 | — |
| SECONDARY Volume of Distribution of GSK525762-Part 1 BID |
99.07; 48.13; 59.67; 116.52; 77.28; 81.11 | — |
Eligibility Criteria
Inclusion Criteria
- Male or female 16 years or older, at the time of signing the informed consent.
- 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).
- 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 .
- 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..
- All prior treatment- related toxicities must be CTCAE (Version 4.0) =1.5 X 10^9/L; Hematologic system: Hemoglobin, Lab values - >=9.5 grams/deciliter (g/dL) (subjects that required transfusion or growth factor need to demonstrate stable haemoglobin for 7 days of 9.5 g/ g/dL); Hematologic system: Platelets, Lab values - >=100 X 10^9/Liter [L] ); Hematologic system: Prothrombin time /International normalized ratio and partial thromboplastin time, Lab values - =50 milliliter (mL)/minute (min); or Renal system: 24-hour urine creatinine clearance>=50 mL/min; Hepatic system: total Bilirubin 1.5 X ULN is acceptable if bilirubin is fractionated and direct bilirubin =2.5 x ULN. Cardiac system: Ejection fraction, lab values - >=lower limit of normal (LLN) by Echocardiogram (ECHO) (minimum of 50%); Cardiac system: Troponin ( T), lab values - =LLN and =LLN. Thyroid system: thyroid stimulating hormone, lab values >=LLN and =8 weeks prior to pre-screening).
- Specific eligibility criteria for Part 2 CRPC expansion cohort: 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
- Specific eligibility criteria for Part 2 CRPC expansion cohort: Ongoing androgen deprivation therapy with a serum testosterone level =2.0 ng/mL. Note: If PSA level has been obtained within 14 days of Screening, this test does not need to be repeated and the result previously obtained may be used for the Screening value.
Exclusion Criteria
- Primary malignancy of the central nervous system or malignancies related to human immunodeficiency virus or solid organ transplant. History of known HIV. History of known Hepatitis B surface antigen or positive Hepatitis C antibody (confirmed by RIBA).
- 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)
Data sourced from ClinicalTrials.gov (NCT01587703). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.