Clinical Trial Results:
A phase Ib/II, multi-center, open-label study to evaluate the efficacy of AUY922 in combination with trastuzumab in patients with locally advanced or metastatic HER2-positive breast cancer that has progressed after or during at least one Trastuzumab-containing regimen
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Summary
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EudraCT number |
2009-015628-27 |
Trial protocol |
SE FR GB DE NL |
Global end of trial date |
11 Sep 2013
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Results information
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Results version number |
v1(current) |
This version publication date |
13 Jul 2016
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First version publication date |
26 Jul 2015
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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 |
CAUY922A2109
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01271920 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Novartis Pharma AG
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Sponsor organisation address |
CH-4002, Basel, Switzerland,
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Public contact |
Clinical Disclosure Office, Novartis Pharma AG, +41 613241111,
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Scientific contact |
Clinical Disclosure Office, 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 |
11 Sep 2013
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
11 Sep 2013
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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 objective of phase Ib: To define the Maximum Tolerated Dose (MTD) and/or the Recommended Phase Two Dose (RPTD) of AUY922 in combination with Trastuzumab when administered intravenously (i.v.) on a once weekly schedule to adult patients with advanced or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancers.
Primary objective of phase II: To evaluate preliminary anti-tumor activity of AUY922 in combination with trastuzumab in adult patients with advanced or metastatic HER2- positive breast cancers.
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Sep 2010
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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 |
Spain: 6
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Country: Number of subjects enrolled |
United Kingdom: 20
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Country: Number of subjects enrolled |
France: 3
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Country: Number of subjects enrolled |
Germany: 2
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Country: Number of subjects enrolled |
Italy: 4
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Country: Number of subjects enrolled |
Singapore: 7
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Country: Number of subjects enrolled |
United States: 3
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Worldwide total number of subjects |
45
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EEA total number of subjects |
35
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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) |
40
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From 65 to 84 years |
5
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85 years and over |
0
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Recruitment
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Recruitment details |
- | |||||||||||||||||||||
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Pre-assignment
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Screening details |
Subjects were screened over a period of 2 weeks. | |||||||||||||||||||||
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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 | |||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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55 mg/m2 AUY922 + 2 mg/kg trastuzumab | |||||||||||||||||||||
Arm description |
AUY922 was to be administered in combination with trastuzumab. In the Phase Ib component, patients received escalating doses of AUY922 combined with a standard dose of trastuzumab until the Maximum Tolerated Dose (MTD) and/or Recommended Phase Two Dose (RP2D) had been determined. For the Phase Ib part of the study, the starting dose of AUY922 was 55 mg/m2. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
AUY922
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
AUY922 was diluted to the appropriate concentration (according to patient body surface area [BSA]) in a 500 mL infusion bag containing 5% dextrose or glucose (with a maximum infusion volume of 500 mL) prior to administration. The drug could be administered using a central line or via peripheral vein. For the Phase Ib part of the study, the starting dose of AUY922 was 55 mg/m2, administered i.v. once weekly (Days 1, 8, 15, and 22 of each treatment cycle) in combination with the standard trastuzumab therapy (2 mg/kg once weekly or a loading dose of 4 mg/kg at Cycle 1, Day 1 if felt necessary by the investigator). It was possible for some dose levels to be skipped or additional, intermediate doses added during the course of the study. Dose escalation was not to exceed a 100% increase from the current dose being studied. In no case was the AUY922 infusion to start later than 24 hours after trastuzumab infusion.
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Investigational medicinal product name |
Trastuzumab
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Investigational medicinal product code |
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Other name |
Herceptin
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Pharmaceutical forms |
Powder for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Trastuzumab was dosed on a mg/kg basis, using the patient weight at the beginning of each cycle. Administered dose was 2 mg/kg.
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Arm title
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70 mg/m2 AUY922 + 2 mg/kg trastuzumab | |||||||||||||||||||||
Arm description |
AUY922 was to be administered in combination with trastuzumab. Once the MTD and/or RP2D was confirmed, this MTD and/or RP2D cohort was to be expanded to a total of 40 patients as the Phase 2 part. In the Phase 2 part of the trial, the starting dose for AUY922 was 70 mg/m2. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
AUY922
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
AUY922 was diluted to the appropriate concentration (according to patient body surface area [BSA]) in a 500 mL infusion bag containing 5% dextrose or glucose (with a maximum infusion volume of 500 mL) prior to administration. The drug could be administered using a central line or via peripheral vein. In the Phase 2 part of the trial, the starting dose for AUY922 was 70 mg/m2 administered i.v. once weekly (Days 1, 8, 15, and 22 of each treatment cycle) in combination with the standard trastuzumab therapy (2 mg/kg once weekly or a loading dose of 4 mg/kg at Cycle 1, Day 1 if felt necessary by the investigator). In no case was the AUY922 infusion to start later than 24 hours after trastuzumab infusion.
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Investigational medicinal product name |
Trastuzumab
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Investigational medicinal product code |
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Other name |
Herceptin
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Pharmaceutical forms |
Powder for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Trastuzumab was dosed on a mg/kg basis, using the patient weight at the beginning of each cycle. Administered dose was 2 mg/kg.
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Baseline characteristics reporting groups
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Reporting group title |
55 mg/m2 AUY922 + 2 mg/kg trastuzumab
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Reporting group description |
AUY922 was to be administered in combination with trastuzumab. In the Phase Ib component, patients received escalating doses of AUY922 combined with a standard dose of trastuzumab until the Maximum Tolerated Dose (MTD) and/or Recommended Phase Two Dose (RP2D) had been determined. For the Phase Ib part of the study, the starting dose of AUY922 was 55 mg/m2. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
70 mg/m2 AUY922 + 2 mg/kg trastuzumab
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Reporting group description |
AUY922 was to be administered in combination with trastuzumab. Once the MTD and/or RP2D was confirmed, this MTD and/or RP2D cohort was to be expanded to a total of 40 patients as the Phase 2 part. In the Phase 2 part of the trial, the starting dose for AUY922 was 70 mg/m2. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
55 mg/m2 AUY922 + 2 mg/kg trastuzumab
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Reporting group description |
AUY922 was to be administered in combination with trastuzumab. In the Phase Ib component, patients received escalating doses of AUY922 combined with a standard dose of trastuzumab until the Maximum Tolerated Dose (MTD) and/or Recommended Phase Two Dose (RP2D) had been determined. For the Phase Ib part of the study, the starting dose of AUY922 was 55 mg/m2. | ||
Reporting group title |
70 mg/m2 AUY922 + 2 mg/kg trastuzumab
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Reporting group description |
AUY922 was to be administered in combination with trastuzumab. Once the MTD and/or RP2D was confirmed, this MTD and/or RP2D cohort was to be expanded to a total of 40 patients as the Phase 2 part. In the Phase 2 part of the trial, the starting dose for AUY922 was 70 mg/m2. | ||
Subject analysis set title |
Dose Determining Set (DDS)
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The DDS consisted of all patients from the safety set (at least within the dose-escalation part) who either experienced dose-limiting toxicity (DLT) within Cycle 1, or if not experiencing DLT had completed the safety assessments as requested in the protocol during this treatment and observation period of at least 28 days in Cycle 1 and met the following minimum exposure criterion:
• A patient in the Phase Ib part receiving AUY922 and trastuzumab was considered to have met the minimum exposure criterion if they received three of the four planned doses of AUY922 and at least three of the four planned trastuzumab doses within Cycle 1.
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End point title |
Determination of The Maximum Tolerated Dose (MTD): Number of Subjects Experiencing Dose-limiting Toxicity (DLT) During Phase Ib [1] | ||||||
End point description |
The number of subjects experiencing a DLT was used to identify the MTD of AUY922 when administered intravenously once a week in combination with the standard trastuzumab therapy. A DLT was defined as an adverse event (AE) or abnormal laboratory value assessed as clinically relevant, occurring ≤ 28 days following the first administration of AUY922 (Cycle 1) in combination with the standard trastuzumab therapy.
The MTD was determined as follows: The distribution of the DLT rate for each AUY922 dose and the starting dose level summarized the probability that the true rate of DLT for each dose lay in the following categories:
1. [0, 16%) under-dosing
2. [16%, 33%) targeted toxicity
3. [33%, 100%] excessive toxicity
The escalation with overdose control (EWOC) principle mandated that any dose of AUY922 in combination with the standard trastuzumab therapy that had more than a 25% chance of being in the excessive toxicity category was not considered for the next dose cohort.
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End point type |
Primary
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End point timeframe |
4 weeks
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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: No statistical analysis was planned for this outcome measure. |
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| No statistical analyses for this end point | |||||||
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End point title |
Overall Response Rate: Percentage of Participants With Best Overall Response of Complete Response or Partial Response by Investigator Review Based on Response Evaluation Criteria in Solid Tumors (RECIST) [2] [3] | ||||||||
End point description |
Overall response rate (ORR) was defined as the percentage of patients with a best overall response of Complete Response (CR) or Partial Response (PR) as defined by the Response Evaluation Criteria In Solid Tumors (RECIST) criteria. CR was defined as the disappearance of target and non-target lesions; at least 2 determinations of CR were required at least 4 weeks apart before progression. PR was defined as at least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters; at least 2 determinations of PR or better were required at least 4 weeks apart before progression (and not qualifying for a CR).
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End point type |
Primary
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End point timeframe |
Every 8 weeks for the first 24 weeks and every 12 weeks thereafter
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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 analysis was planned for this primary outcome measure. [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: No statistical analysis was planned for this outcome measure. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Plasma Concentration of AUY922 Over Time | ||||||||||||||||||||||||||||||||||||||||||
End point description |
Pharmacokinetic analysis was used to measure the concentration of AUY922 in serum collected at intervals over 8 days post-dose.
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End point type |
Secondary
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End point timeframe |
8 days post-dose
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||
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End point title |
Plasma Concentration of BJP762 Over Time | ||||||||||||||||||||||||||||||||||||||||||
End point description |
Pharmacokinetic analysis was used to measure the concentration of BJP762 in serum collected at intervals over 8 days post-dose.
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End point type |
Secondary
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End point timeframe |
8 days post-dose
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||
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End point title |
Progression Free Survival (PFS) by Investigator Review at The Recommended Phase Two Dose (RPTD) [4] | ||||||||
End point description |
As defined by the RECIST criteria, PFS is the time from date of randomization/start of treatment to the date of event defined as the first documented progression or death due to any cause. Progression was defined as an increase of at least 20% in the sum of the longest diameter of all measured
target lesions, taking as reference the smallest sum of longest diameter of all
target lesions recorded at or after baseline. If a subject did not have an event, PFS was censored at the date of last adequate tumor assessment. A subject was considered to be censored when data on time to event was missing due to the subject being lost to follow-up before the completion of the trial.
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End point type |
Secondary
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End point timeframe |
Every 3 months until 24 months after the last patient has been enrolled
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| Notes [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: No statistical analysis was planned for this outcome measure. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall Survival (OS) at The RPTD [5] | ||||||||
End point description |
As defined by the RECIST criteria, OS is the time from date of randomization/start of treatment to date of death due to any cause. If a patient was not known to have died, survival was censored at the date of last contact.
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End point type |
Secondary
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End point timeframe |
Every 3 months until 24 months after the last patient has been enrolled
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| Notes [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: No statistical analysis was planned for this outcome measure. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Subjects With Adverse Events | |||||||||||||||
End point description |
Adverse events (AEs) were assessed according to the Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0.
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End point type |
Secondary
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End point timeframe |
Average 6 months
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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 |
Serious Adverse Events are monitored from date of First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All other adverse events are monitored from First Patient First Treatment until Last Patient Last Visit.
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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 |
15.0
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Reporting groups
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Reporting group title |
70 mg/m2 AUY922 + 2 mg/kg trastuzumab
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Reporting group description |
70 mg/m2 AUY922 + 2 mg/kg trastuzumab | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
55 mg/m2 AUY922 + 2 mg/kg trastuzumab
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Reporting group description |
55 mg/m2 AUY922 + 2 mg/kg trastuzumab | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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05 May 2011 |
This amendment introduced the following changes:
* Removal of FDG-PET imaging assessments. Similar data had been obtained in an ongoing phase II study of HER2+ MBC patients [AUY922A2101], and Novartis considered that additional data would not add further scientific value in understanding the efficacy of
AUY922 in MBC;
* An exploratory objective (effect of AUY922 on the number of circulating tumor cells) was deleted from the Phase II part of the study. Similar data had been obtained in an ongoing phase II study of HER2+ MBC patients [AUY922A2101], and no additional data were needed at this time. Data obtained before the amendment were to be listed.
* Post-Text Supplement 2 “Excluded Medications” was made consistent with Section 6.6.7 of the Study Protocol. Namely, drugs known to be metabolized or to interact with CYP3A4 isoenzymes were not excluded medications, but had to be used with caution as this was the case for drugs known to be metabolized or to interact with CYP2C9, CYP2C19 and CYP2C8;
* Removal of the request for chest x-ray, as all patients were having a CT of the chest performed as a required radiological assessment in this study;
* Clarification that the AUY922 infusion should start as close as possible but no sooner than 10 minutes from the end of the trastuzumab infusion in order to monitor potential allergic reactions to trastuzumab. In no case was the AUY922 infusion to start later than 24 hours from the end of the trastuzumab infusion;
* Updating of Table 6-4 of the Study Protocol to align with the National Cancer Institute CTC version 4 grading of diarrhea. (In the original version of the protocol, Table 6-4 of the Study Protocol was still matching the CTC AE version 3.) |
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14 Dec 2011 |
This amendment introduced the following changes:
* Reduction of the number of biomarkers to be evaluated. Emerging knowledge in the field indicated that, at this time, there was no strong evidence indicating that several of the parameters initially included in this amendment would bring significant value;
* In the already completed Phase Ib part of the trial, the HSP70 biomarker had been analyzed in the blood samples collected to compare the levels of specific biomarkers in pre and post-treatment PBMC samples. Other HSP90 client proteins such as CDK4 had not yet been analyzed in these samples and would not be analyzed in the future as sufficient information had been obtained from the HSP70 analysis;
* In the Phase II part of the trial, plasma and serum biomarker samples had not yet been analyzed and would not be analyzed in the future. With this amendment, no further blood collections were to be done for biomarker assessments.
so far in pre and post fresh tumor biopsy specimens. The changes in HER2 were analyzed as the only PD marker in pre and post fresh tumor biopsy specimens. Also, the collection of paired pre- and post-treatment fresh tumor biopsies became optional;
* In addition, a clarification was made in the imaging Section 7.4.1 of the Study Protocol “Radiological assessment of tumor” for consistency with the Section 5.1 of the Study Protocol (inclusion criteria). Following RECIST, measurable lesions which could not be assessed by CT/MRI (for example skin lesions) were acceptable as target lesions;
* Another clarification was made in Table 7-4 of the Study Protocol: Summary of tumor assessment. The word ‘scintigraphy’ was replaced with ‘scan’;
* The amendment also updated the information about the starting dose for AUY922 at Cycle 1 Day 1. Based on the Dose Escalation Meeting held at the end of the Phase Ib part of the trial on 25-May,the RP2D for AUY922 in the Phase II part of the trial was 70 mg/m2. |
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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 | |||
