Clinical Trial Results:
Ixazomib (MLN9708) in combination with carboplatin in pretreated women with advanced triple negative breast cancer (CARIXA)
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Summary
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EudraCT number |
2016-001421-13 |
Trial protocol |
AT |
Global end of trial date |
15 Aug 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
12 Aug 2021
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First version publication date |
12 Aug 2021
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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 |
AGMT_MBC-10 (X16087)
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02993094 | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
AGMT
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Sponsor organisation address |
Gentzgasse 60/21, Vienna, Austria, 1180
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Public contact |
Daniela Wolkersdorfer, AGMT, +43 6626404412, d.wolkersdorfer@agmt.at
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Scientific contact |
Richard Greil, AGMT, +43 5725525801, r.greil@salk.at
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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 Jan 2021
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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 |
15 Aug 2020
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
Phase I: Determination of maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs)
Phase II: Overall response rate (ORR)
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Protection of trial subjects |
Safety assessments were done on a regular basis. All patients having received at least one dose of the study medication have been followed for adverse events for 28 days after discontinuing study treatment or completion of study treatment. In general, concomitant medications and therapies necessary for supportive care and safety of the patient were allowed. Anti-emetic prophylaxis was mandatory, supportive therapy for diarrhoea was defined.
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Background therapy |
In the AGMT_MBC-10 phase I trial a dose escalation of weekly carboplatin from AUC 1.5 to 2.5 for 3 of 4 weeks (according to a dose intensity per week from AUC 1.1 to 1.9) was tested. In phase II the maximum tolerated dose level determined in phase I was administered. | ||
Evidence for comparator |
Not applicable. | ||
Actual start date of recruitment |
16 Feb 2017
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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 |
Austria: 31
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Worldwide total number of subjects |
31
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EEA total number of subjects |
31
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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) |
17
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From 65 to 84 years |
14
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85 years and over |
0
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Recruitment
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Recruitment details |
Between Feb-2017 and Jul-2020 31 patients were enrolled at 11 study sites in Austria. 9 patients were enrolled during phase I and further 22 patients during phase II. | |||||||||||||||||||||
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Pre-assignment
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Screening details |
Female patients with histologically confirmed metastatic or locally advanced (without curative loco-regional treatment options with curative intention) adenocarcinoma of the breast were screened for study participation. | |||||||||||||||||||||
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Period 1
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Period 1 title |
Overall trial (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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Phase I | |||||||||||||||||||||
Arm description |
Accelerated dose-escalation phase: A single-patient cohort per dose level was enrolled, until one dose limiting toxicity (DLT), or 3 moderate toxicities were observed during cycle 1, or until dose level 4 was reached. At this dose level the cohort was expanded to three patients and dose escalation reverted to a conventional 3+3 escalation design. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Ixazomib
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Investigational medicinal product code |
MLN9708
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Ixazomib on days 1, 8, and 15 in combination with carboplatin on days 1, 8, and 15. Cycles were repeated every four weeks until progression, unacceptable toxicity or treatment discontinuation for any other reason.
Dose level 1: ixazomib 3 mg/ carboplatin AUC 1.5
Dose level 2: ixazomib 3 mg/ carboplatin AUC 2.0
Dose level 3: ixazomib 4 mg/ carboplatin AUC 2.0
Dose level 4: ixazomib 4 mg/ carboplatin AUC 2.5
After completion of phase I, all patients treated with a dose below the determined MTD were dose escalated at the discretion of the investigator.
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Arm title
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Phase II | |||||||||||||||||||||
Arm description |
After establishing MTD in phase I, accrual continued to evaluate the efficacy and safety of the combination. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Ixazomib
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Investigational medicinal product code |
MLN9708
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Ixazomib on days 1, 8, and 15 in combination with carboplatin on days 1, 8, and 15. Cycles were repeated every four weeks until progression, unacceptable toxicity or treatment discontinuation for any other reason.
Dose level: ixazomib 4 mg/ carboplatin AUC 2.5
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
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End points reporting groups
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Reporting group title |
Phase I
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Reporting group description |
Accelerated dose-escalation phase: A single-patient cohort per dose level was enrolled, until one dose limiting toxicity (DLT), or 3 moderate toxicities were observed during cycle 1, or until dose level 4 was reached. At this dose level the cohort was expanded to three patients and dose escalation reverted to a conventional 3+3 escalation design. | ||
Reporting group title |
Phase II
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Reporting group description |
After establishing MTD in phase I, accrual continued to evaluate the efficacy and safety of the combination. | ||
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End point title |
Maximum tolerated dose (MTD) [1] [2] | ||||||||||||||||||||||
End point description |
Dose limiting toxicities (DLTs) were defined as inability to deliver the drug combination of ixazomib and carboplatin due to drug related toxicities as outlined below:
• grade 3 or 4 non-hematologic toxicity excluding alopecia, nausea, emesis, diarrhea
• grade 3 or greater nausea and/or emesis despite the use of optimal anti-emetic prophylaxis
• grade 3 or greater diarrhea that occurs despite maximal supportive therapy
• grade 2 peripheral neuropathy with pain or polyneuropathy greater or equal grade 3
• neutropenia grade 4 for more than 7 days
• febrile neutropenia grade 3
• thrombocytopenia grade 4
• thrombocytopenia grade 3 with bleeding
Moderate toxicities were defined as inability to deliver the drug combination of ixazomib and carboplatin due to drug related toxicity as outlined below:
• any grade 2 non-hematologic toxicity excluding alopecia
• any grade 3 hematologic toxicity
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End point type |
Primary
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End point timeframe |
Cycle 1 of subjects in phase I
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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: During dosing level 1 to 3 no patient developed a DLT or had more than 2 moderate toxicities. 6 further patients were enrolled into dosing level 4, no DLT occurred, no patient had more than 2 moderate toxicities during cycle 1. Dosing level 4 (ixazomib 4 mg, carboplatin AUC 2.5) was established as the MTD and was defined as starting dose for study phase II. This non-randomised study was not designed for statistical comparisons by treatment arm. [2] - 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: This endpoint is the primary endpoint of phase I of this study. This non-randomised study was not designed for statistical comparisons by treatment arm. |
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
Overall response rate (ORR) [3] [4] | ||||||||||
End point description |
ORR is estimated as the proportion of responders, defined as a patient whose best overall response is partial response (PR) or better during the treatment period. ORR is given as proportion.
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End point type |
Primary
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End point timeframe |
From inclusion to best response during treatment in phase II
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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: Overall response rate was 20%. This non-randomised study was not designed for statistical comparisons by treatment arm. [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: This endpoint is the primary endpoint of phase II of this study. This non-randomised study was not designed for statistical comparisons by treatment arm. |
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| Notes [5] - 2 patients were not evaluable according to protocol. |
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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 |
All patients having received at least one dose of the study medication were followed for adverse events for 28 days after discontinuing study treatment or completion of study treatment. Additional survival follow up was done until cut-off data point.
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Adverse event reporting additional description |
Progression of disease (including death due to the underlying malignant disease) was not to be regarded as SAE.
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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 |
23.0
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Reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
All enrolled patients | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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? No | |||
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. | |||
| Due to low recruitment study was withdrawn prematurely after inclusion of 31 patients. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/30400780 |
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