Clinical Trial Results:
An Open-Label Phase I/II Study of GSK2110183 in Combination with Carboplatin and Paclitaxel in Subjects with Platinum-Resistant Ovarian Cancer
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Summary
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EudraCT number |
2012-002483-27 |
Trial protocol |
GB |
Global end of trial date |
01 Jul 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
01 Mar 2017
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First version publication date |
01 Mar 2017
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
PKB116611
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01653912 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Accenture
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Sponsor organisation address |
1160 W Swedesford Road, Berwyn, United States, PA 19312
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Public contact |
Study Director, Novartis Pharma AG, 41 613241111,
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Scientific contact |
Study Director, Novartis Pharma AG, 41 613241111,
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
24 Nov 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
01 Jul 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
01 Jul 2015
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Primary Phase I
To determine the safety and tolerability of GSK2110183 administered in combination with carboplatin and paclitaxel in subjects with ovarian cancer--which will be used to identify the dosing regimen to be evaluated in Phase II.
Primary Phase II
To evaluate the clinical efficacy (as measured by overall response rate) of GSK2110183 administered in combination with carboplatin and paclitaxel in subjects with recurrent platinum-resistant ovarian cancer.
To evaluate the clinical efficacy (as measured by overall response rate) of GSK2110183 administered in combination with carboplatin and paclitaxel in subjects with platinum refractory ovarian cancer.
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Protection of trial subjects |
This clinical study was designed and implemented and reported in accordance with the International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), with applicable local regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 21, and with the ethical principles laid down in the Declaration of Helsinki.
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Background therapy |
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Evidence for comparator |
- | ||
Actual start date of recruitment |
31 Jul 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 26
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Country: Number of subjects enrolled |
Russian Federation: 5
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Country: Number of subjects enrolled |
Australia: 28
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Worldwide total number of subjects |
59
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EEA total number of subjects |
26
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
33
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From 65 to 84 years |
26
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85 years and over |
0
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Recruitment
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Recruitment details |
Subjects were enrolled at 10 centers in 3 countries (United Kingdom, Australia, and Russia) | ||||||||||||
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Pre-assignment
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Screening details |
A total of 59 subjects (29 subjects in Phase I and 30 subjects in Phase II) | ||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||
Blinding implementation details |
This was an open-label study
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Arms
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Arm title
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GSK2110183, Carboplatin and Paclitaxel | ||||||||||||
Arm description |
Subjects will be treated with a maximum of 6 doses of carboplatin + paclitaxel in combination with continuous daily GSK2110183 followed by GSK2110183 at the single-agent Maximum Tolerated Dose (MTD) of 125 mg or above by mouth daily. GSK2110183 in combination with carboplatin and paclitaxel: Phase I is a dose escalation evaluation of increasing doses of GSK2110183 administered on a continuous daily schedule in combination with carboplatin Area Under the Curve (AUC) 5 and paclitaxel 175 mg/m2 given every 3 weeks for a maximum 6 cycles. The dosing regimen identified in Phase I will then be evaluated in Phase II, a single arm study focused on clinical efficacy. Treatment with the 3 drugs regimen will continue for a maximum of 6 x 21 day cycles followed by continuous GSK2110183 at the single agent MTD. Subjects may continue on study drug until progression, death or unacceptable toxicity. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
GSK2110183
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Investigational medicinal product code |
GSK2110183
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Other name |
Afuresertib
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
150 mg capsule by mouth daily for 6 months
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Investigational medicinal product name |
CARBOPLATIN
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Area Under the Curve (AUC) 5
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Investigational medicinal product name |
Paclitaxel
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
175 mg/m2 intravenously every 3 weeks
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Baseline characteristics reporting groups
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Reporting group title |
Overall Study
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Reporting group description |
Subjects will be treated with a maximum of six doses of carboplatin + paclitaxel in combination with continuous daily GSK2110183 followed by single agent GSK2110183 at the single-agent MTD of 125 mg or above oral daily. GSK2110183 in combination with carboplatin and paclitaxel: Phase I is a dose escalation evaluation of increasing doses of GSK2110183 administered on a continuous daily schedule in combination with carboplatin AUC 5 and paclitaxel 175mg/m2 given every three weeks for a maximum 6 cycles. The dosing regimen identified in Phase I will then be evaluated in Phase II, a single arm study focused on clinical efficacy. Treatment with the three drug regimen will continue for a maximum of 6 x 21 day cycles followed by continuous GSK2110183 at the single agent MTD. Subjects may continue on study drug until progression, death or unacceptable toxicity. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
GSK2110183, Carboplatin and Paclitaxel
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Reporting group description |
Subjects will be treated with a maximum of 6 doses of carboplatin + paclitaxel in combination with continuous daily GSK2110183 followed by GSK2110183 at the single-agent Maximum Tolerated Dose (MTD) of 125 mg or above by mouth daily. GSK2110183 in combination with carboplatin and paclitaxel: Phase I is a dose escalation evaluation of increasing doses of GSK2110183 administered on a continuous daily schedule in combination with carboplatin Area Under the Curve (AUC) 5 and paclitaxel 175 mg/m2 given every 3 weeks for a maximum 6 cycles. The dosing regimen identified in Phase I will then be evaluated in Phase II, a single arm study focused on clinical efficacy. Treatment with the 3 drugs regimen will continue for a maximum of 6 x 21 day cycles followed by continuous GSK2110183 at the single agent MTD. Subjects may continue on study drug until progression, death or unacceptable toxicity. | ||
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End point title |
Phase I Tolerability: Number of Subjects With Dose Limiting Toxicity (DLT) Events [1] | ||||||||||||||||||||||||||||||
End point description |
Dose limiting toxicity: An event was considered a DLT if it had a reasonable causal relationship to study drug and occurs within the first 3 weeks of therapy and met at least one of the following criteria:
• Grade 3 or 4 non-hematologic toxicity as described in the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v 4.0, 2009 [NCI, 2009] with the exceptions of Grade 3 electrolyte disturbances that respond to correction within 24 hours; or Grade 3 rash, diarrhea, nausea, vomiting and mucositis that responded to standard medical supportive care within 48 hours).
• Grade 4 neutropenia lasting ≥5 days
• Febrile neutropenia
• Grade 3 thrombocytopenia with bleeding
• Grade 4 thrombocytopenia
• Grade 4 anemia
• Treatment delay of >14 days due to unresolved toxicity
• Alanine aminotransferase (ALT) >3 times upper limit of normal (ULN) with bilirubin >2 times ULN
Analysis Population Description:
All treated Subjects (ATS) in phase I
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End point type |
Primary
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End point timeframe |
Up to Week 3
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Primary endpoint analysis was sequential and was performed adaptively using Bayesian design. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||
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End point title |
Phase I Safety: Number of Subjects Reporting Adverse Events [2] | ||||||||||||||||||||||||||||
End point description |
Study Treatment refers to GSK2110183 with or without Carboplatin and/or Paclitaxel.
Analysis Population Description:
Phase I ATS population
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End point type |
Primary
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End point timeframe |
Up to Week 3
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical hypothesis was tested in Phase I. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
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End point title |
Overall Response Rate (ORR) in Phase II Subjects With Recurrent Platinum-resistant Ovarian Cancer (Cohort A) [3] | ||||||||
End point description |
ORR defined as the percentage of subjects with Investigator confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
Analysis Population Description:
ATS population (Phase II-Cohort A)
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End point type |
Primary
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End point timeframe |
Every 3 weeks up to 6 months
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical hypothesis was tested in Phase I. |
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| No statistical analyses for this end point | |||||||||
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End point title |
ORR in Phase II Subjects With Recurrent Platinum-refractory Ovarian Cancer (Cohort B) [4] | ||||||
End point description |
Due to difficulty in enrolling platinum refractory subjects into Phase II Efficacy-Cohort B, enrollment was stopped prior to having the planned 10-20 subjects enrolled.
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End point type |
Primary
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End point timeframe |
Every 3 weeks up to 6 months
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Primary endpoint analysis was sequential and was performed adaptively using Bayesian design. |
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| Notes [5] - No analysis done due to difficulty in enrolling Platinum refractory subjects in Cohort B. |
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| No statistical analyses for this end point | |||||||
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End point title |
ORR in Phase I Subjects With Recurrent Platinum-resistant Ovarian Cancer | ||||||||
End point description |
Analysis Population Description:
ATS population
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End point type |
Secondary
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End point timeframe |
Up to Week 3
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| No statistical analyses for this end point | |||||||||
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End point title |
Phase II Tolerability: Number of Subjects With DLT Events During the First 3 Weeks of Combination Therapy | ||||||||||||||||||||
End point description |
Analysis Population Description:
ATS population
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End point type |
Secondary
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End point timeframe |
Up to Day 21 (Phase II)
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Phase II Safety: Number of Subjects Reporting Adverse Events | ||||||||||||||||||||||||||||
End point description |
Analysis Population Description:
ATS population
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End point type |
Secondary
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End point timeframe |
Up to Day 51
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||
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End point title |
Phase II: Response Rate (RR) Defined by Gynecologic Cancer Intergroup (GCIG) CA 125 | ||||||||
End point description |
RR as defined by the percentage of phase II subjects with investigator-assessed PR or CR at any time during the study by GCIG cancer antigen (CA) 125
Analysis Population Description:
ATS population
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End point type |
Secondary
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End point timeframe |
From Month 1 to 6
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| No statistical analyses for this end point | |||||||||
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End point title |
Progression Free Survival (PFS) by RECIST or Clinical Symptomatic Progression of Subjects With Recurrent Platinum-resistant Ovarian Cancer (Phase II-Cohort A) | ||||||||
End point description |
PFS is defined as the number of months between date of first GSK2110183 treatment and the earliest date of disease progression by either RECIST or clinical symptomatic progression or death due to any cause whichever is earlier.
Analysis Population Description:
ATS population
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End point type |
Secondary
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End point timeframe |
After first dose up to Month 6
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| No statistical analyses for this end point | |||||||||
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End point title |
PFS by RECIST of Subjects With Recurrent Platinum-resistant Ovarian Cancer (Phase II-Cohort A) | ||||||||
End point description |
PFS is defined as the number of months between date of first GSK2110183 treatment and the earliest date of disease progression by RECIST or death due to any cause whichever is earlier.
Analysis Population Description:
ATS population
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End point type |
Secondary
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End point timeframe |
After first dose up to Month 6
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Up to Day 51
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.1
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Reporting groups
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Reporting group title |
GSK2110183, Carboplatin and Paclitaxel
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Reporting group description |
Subjects will be treated with a maximum of 6 doses of carboplatin + paclitaxel in combination with continuous daily GSK2110183 followed by GSK2110183 at the single-agent Maximum Tolerated Dose (MTD) of 125 mg or above by mouth daily. GSK2110183 in combination with carboplatin and paclitaxel: Phase I is a dose escalation evaluation of increasing doses of GSK2110183 administered on a continuous daily schedule in combination with carboplatin Area Under the Curve (AUC) 5 and paclitaxel 175mg/m2 given every 3 weeks for a maximum 6 cycles. The dosing regimen identified in Phase I will then be evaluated in Phase II, a single arm study focused on clinical efficacy. Treatment with the 3 drugs regimen will continue for a maximum of 6 x 21 day cycles followed by continuous GSK2110183 at the single agent MTD. Subjects may continue on study drug until progression, death or unacceptable toxicity. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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12 Oct 2012 |
Amendment 1:
Addition of EudraCT number; Addition of safety evaluation to objectives and endpoints for Phase II; Addition of ability to increase afuresertib dose beyond 125 mg in dose escalation based on emerging data from afuresertib program which resulted in an increase in the number of subjects that could potentially enroll the Phase I part of the study; Removal of eligibility criteria based on restriction of number of prior therapies; Clarification of timing of select assessments in Time and Events Table; Removal of bone scans as method of disease assessment; Clarification of formula for calculation of creatinine clearance; Update of recommendations for managing hyperglycemia; Clarification of monitoring required for carboplatin and paclitaxel specific toxicities; Clarification of carboplatin and paclitaxel sourcing, Addition of specific dose modification guidelines for conduction disorders; Additional QTc stopping criteria added; Insulin monitoring added; Clarification of birth control requirements. |
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16 May 2013 |
Amendment 2:
Addition of secondary efficacy objectives and endpoints for Phase I; Clarification of cohort 1.5; Removal of requirement for documented response on platinum therapy prior to enrolment for Phase II; Addition of window for time period of progression after most recent therapy for patients eligible for Phase II; Clarification on exclusion criteria for electrocardiogram (ECG) abnormalities; Clarification on Paclitaxel and Carboplatin sourcing; Clarification that Fridericia’s formula should be used for QTc; Clarification of timing for 1,5 Ag, PK and CA 125 assessments in Time and Events Table; Removal of urinalysis for lab assessments. |
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19 Nov 2013 |
Amendment 3:
Addition of platinum-refractory patient population includes changes in the introduction, objectives, endpoints, study design, number of study subjects, eligibility criteria, data analysis and specifications; Update of data for study PKB115125 to justify use of 150 mg dose of afuresertib in maintenance portion of study drug administration; Addition of optional fresh tumor biopsies for exploratory pharmacodynamic analysis includes changes to objectives, endpoint, time and events table, assessments and data analysis; Update of eligibility criteria focused on enrolment of diabetic subjects based on evaluation of emerging safety data; Update of afuresertib dosage and administration to allow study drug to be taken in the fed or fasted state on non – PK days; Clarification of dose modification recommendations; Update on management of mucositis recommendations; Update of hyperglycemia supportive care recommendations based on review of currently available safety data; Update on dyspepsia supportive care recommendations to include the ability to take afuresertib with a meal; Addition of rash supportive care management guidelines based on review of currently available safety data; Update of meals and dietary recommendations to allow administration of afuresertib with food. Clarification on adverse event (AE) and serious adverse event (SAE) reporting and follow up time period as well as updated SAE Email address and Fax number. |
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20 Mar 2014 |
Amendment 4:
Change in target overall response rate for platinum resistant ovarian cancer patient population based on review of published literature evaluating clinical efficacy in similar patient populations. Addition of details regarding interim analysis of median PFS at 6 months. Modification of eligibility criteria for Cohort A to facilitate enrolment. Modification of dispensing of afuresertib every 3 weeks throughout the study. Clarification of how changes in eligibility criteria for Cohort B will be communicated to sites and the study team. Clarification of fasting instructions for subjects undergoing PK sampling to correct internal protocol inconsistencies. Correction of internal consistencies regarding references to investigational product, i.e., replacement of afuresertib with GSK2110183. Clarification of timing of circulating biomarker sample collection so that subjects in Phase II don’t have to return to clinic on Cycle 1, Days 8 and 15 just for biomarker sampling. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
