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Ixazomib (MLN9708) in Combination With Carboplatin in Pretreated Women With Advanced Triple Negative Breast Cancer

Primary Purpose

Triple-Negative Breast Cancer

Status
Terminated
Phase
Phase 1
Locations
Austria
Study Type
Interventional
Intervention
Ixazomib
Carboplatin
Sponsored by
Arbeitsgemeinschaft medikamentoese Tumortherapie
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Triple-Negative Breast Cancer focused on measuring breast cancer, advanced triple negative, ixazomib, carboplatin, CARIXA, Study Group of Medical Tumor Therapy (AGMT)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

Inclusion Criteria:

  • Metastatic or locally advanced (without curative loco-regional treatment options with curative intention) adenocarcinoma of the breast, histologically confirmed
  • Triple-negative subtype defined as the absence of staining for estrogen receptor (IHC <1%), progesterone receptor (IHC <1%) and HER2/neu (IHC 1+ or ISH ratio of < 2.0 between Her2 gene copy number and centromere of chromosome 17 or a copy number of 4 or less)
  • Signed informed consent prior to any study-specific procedure, with the understanding that consent may be withdrawn at any time without prejudice to future medical care
  • Female patients, age ≥ 18 years
  • At least one prior line of chemotherapy for metastatic or locally advanced disease or disease progression within 12 months of completion of adjuvant chemotherapy
  • Documented disease progression
  • At least one measurable lesion according to RECIST 1.1 criteria
  • Life expectancy of at least 12 weeks
  • Performance status ECOG 0-2
  • Adequate left ventricular ejection fraction at baseline, defined as LVEF ≥ 50% by either echocardiogram or MUGA
  • Peripheral neuropathy NCI CTCAE grade ≤ 1 or grade 2 if no pain on clinical examination
  • Adequate hematological, liver and renal function:

Exclusion Criteria:

  • Pregnant or lactating women
  • Serious medical or psychiatric disorders that would interfere with the patient's safety or informed consent
  • Clinically significant cardiovascular disease, requiring medication during the study and which might interfere with regularity of the study treatment, or not controlled by medication.
  • Radiation of the target lesion within the last 4 weeks prior to randomization
  • Prior radiation to ≥ 30% of bone marrow
  • Active bacterial, viral or fungal infection
  • Known HCV infection
  • Patients with clinically apparent brain metastases or evidence of a spinal cord compression
  • Major surgery within 14 days before enrollment
  • Systemic treatment, within 14 days before the first dose of ixazomib, with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort.
  • Participation in other clinical trials, including those with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial
  • Patients that have previously been treated with ixazomib, or participated in a study with ixazomib whether treated with ixazomib or not
  • History of other malignancy; patients who have been disease-free for 5 years or patients with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible
  • Prior treatment with a platinum derivative (except in (neo-)adjuvant setting if breast cancer recurrence did not occur within 12 months after (neo-)adjuvant chemotherapy completion) and/or with a proteasome inhibitor
  • Known hypersensitivity to the study drugs

Sites / Locations

  • Klinikum Kreuzschwestern Wels GmbH
  • Universitätsklinik für Innere Medizin Graz
  • Universitätsklinik für Frauenheilkunde Innsbruck
  • Landeskrankenhaus Feldkirch, Innere Med. II, Interne E
  • UK Graz: Universitätsklinik für Frauenheilkunde und Geburtshilfe, Klinische Abteilung für Gynäkologie
  • LKH Hochsteiermark: Department für Hämato-Onkologie
  • BHS Linz: Interne I: Internistische Onkologie, Hämatologie und Gastroenterologie
  • KUK Linz: Klinik für Interne 3 - Schwerpunkt Hämatologie und Onkologie
  • PMU Salzburg: Universitätsklinik für Innere Medizin III
  • Landeskrankenhaus Steyr, Innere Medizin II Onkologie
  • AKH Wien Universitätsklinik für Frauenheilkunde: Klin. Abt. f. Allg. Gynäkologie und gynäkologische Onkologie
  • LK Wiener Neustadt: Innere Medizin, Hämatologie und internistische Onkologie

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Ixazomib/Carboplatin

Arm Description

Accelerated dose-escalation phase with a single-patient cohort per dose level until defined DLT is observed during cycle 1, or until dose level 4 is reached. At this dose level the cohort is expanded to three patients and dose escalation reverts to a conventional 3+3 escalation design. Intervention (experimental): Ixazomib; po; 3mg escalated to 4mg; day 1, 8, 15 Intervention (backbone): AUC 1.5 escalated to AUC 2.5; day 1, 8, 15

Outcomes

Primary Outcome Measures

Maximum tolerated dose (MTD)
Determination of maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs)

Secondary Outcome Measures

Safety profile based on adverse events evaluation
Incidence, type, severity and consequences (e.g. study discontinuation) of an adverse event
Overall response rate
Clinical benefit rate
Complete remission, partial remission or stable disease for at least 24 weeks
Progression-free survival (PFS)
Quality of Life of MBC patients
EORTC quality of life questionnaire (QLQ-C30 and QLQ-BR23)

Full Information

First Posted
December 4, 2016
Last Updated
November 26, 2020
Sponsor
Arbeitsgemeinschaft medikamentoese Tumortherapie
Collaborators
Takeda
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1. Study Identification

Unique Protocol Identification Number
NCT02993094
Brief Title
Ixazomib (MLN9708) in Combination With Carboplatin in Pretreated Women With Advanced Triple Negative Breast Cancer
Official Title
Ixazomib (MLN9708) in Combination With Carboplatin in Pretreated Women With Advanced Triple Negative Breast Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
November 2020
Overall Recruitment Status
Terminated
Why Stopped
Due to slow recruitment, the study had to be terminated prematurely.
Study Start Date
November 21, 2016 (Actual)
Primary Completion Date
August 15, 2020 (Actual)
Study Completion Date
August 15, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Arbeitsgemeinschaft medikamentoese Tumortherapie
Collaborators
Takeda

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This is an open-label phase I/II study for patients with advanced (locally advanced inoperable or metastatic) triple-negative breast cancer progressing after first-line therapy receiving ixazomib on days 1, 8, and 15 in combination with carboplatin on days 1, 8, and 15. Cycles will be repeated every four weeks.
Detailed Description
The phase I part of this study uses an alternate dose escalation accelerated titration design. In the accelerated dose-escalation phase a single-patient cohort per dose level will be enrolled, until one dose limiting toxicity (DLT) or 2 moderate toxicities are observed during cycle 1, or until dose level 4 is reached. At this dose level the cohort is expanded to three patients and dose escalation reverts to a conventional 3+3 escalation design. DLTs are defined as inability to deliver the drug combination of ixazomib and carboplatin due to drug related toxicity. The maximum-administered dose (MAD) is defined as the dose at which DLT occur in at least two of six patients treated at that dose level. The dose just below the MAD is considered the maximum-tolerated dose (MTD), providing that DLT is observed in fewer than two of six treated patients (or fewer than one third if more than six patients will be treated) at that dose level. Determination of MAD and MTD is based on DLT observed during the first treatment cycle. Phase II: After establishing MTD in phase I, accrual continues to evaluate the efficacy and safety of the combination. A total of 41 patients will be included (patients enrolled in the phase I part within the conventional dose escalation phase at the dose level considered as the MTD may be included). All subjects will continue on study drugs until disease progression, unacceptable toxicity or treatment discontinuation for any other reason.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Triple-Negative Breast Cancer
Keywords
breast cancer, advanced triple negative, ixazomib, carboplatin, CARIXA, Study Group of Medical Tumor Therapy (AGMT)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
31 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Ixazomib/Carboplatin
Arm Type
Experimental
Arm Description
Accelerated dose-escalation phase with a single-patient cohort per dose level until defined DLT is observed during cycle 1, or until dose level 4 is reached. At this dose level the cohort is expanded to three patients and dose escalation reverts to a conventional 3+3 escalation design. Intervention (experimental): Ixazomib; po; 3mg escalated to 4mg; day 1, 8, 15 Intervention (backbone): AUC 1.5 escalated to AUC 2.5; day 1, 8, 15
Intervention Type
Drug
Intervention Name(s)
Ixazomib
Other Intervention Name(s)
MLN9708
Intervention Description
Cycles will be repeated every four weeks. All subjects will continue on study drug until disease progression, unacceptable toxicity or treatment discontinuation for any other reason.
Intervention Type
Drug
Intervention Name(s)
Carboplatin
Intervention Description
Cycles will be repeated every four weeks. Cycles will be repeated every four weeks. All subjects will continue on study drug until disease progression, unacceptable toxicity or treatment discontinuation for any other reason.
Primary Outcome Measure Information:
Title
Maximum tolerated dose (MTD)
Description
Determination of maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs)
Time Frame
From treatment start until MTD (12 months --> start Phase II Q3 2017)
Secondary Outcome Measure Information:
Title
Safety profile based on adverse events evaluation
Description
Incidence, type, severity and consequences (e.g. study discontinuation) of an adverse event
Time Frame
During study treatment + 28 day after last study drug (approximately 3 years)
Title
Overall response rate
Time Frame
During study treatment every 8 weeks until progression + end of study treatment (approximately 3 years)
Title
Clinical benefit rate
Description
Complete remission, partial remission or stable disease for at least 24 weeks
Time Frame
During study treatment every 8 weeks until progression + end of study treatment (approximately 3 years)
Title
Progression-free survival (PFS)
Time Frame
During study treatment every 8 weeks until progression + end of study treatment (approximately 3 years)
Title
Quality of Life of MBC patients
Description
EORTC quality of life questionnaire (QLQ-C30 and QLQ-BR23)
Time Frame
Baseline + every 8 weeks until progression + at end of study treatment (approximately 3 years)

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Metastatic or locally advanced (without curative loco-regional treatment options with curative intention) adenocarcinoma of the breast, histologically confirmed Triple-negative subtype defined as the absence of staining for estrogen receptor (IHC <1%), progesterone receptor (IHC <1%) and HER2/neu (IHC 1+ or ISH ratio of < 2.0 between Her2 gene copy number and centromere of chromosome 17 or a copy number of 4 or less) Signed informed consent prior to any study-specific procedure, with the understanding that consent may be withdrawn at any time without prejudice to future medical care Female patients, age ≥ 18 years At least one prior line of chemotherapy for metastatic or locally advanced disease or disease progression within 12 months of completion of adjuvant chemotherapy Documented disease progression At least one measurable lesion according to RECIST 1.1 criteria Life expectancy of at least 12 weeks Performance status ECOG 0-2 Adequate left ventricular ejection fraction at baseline, defined as LVEF ≥ 50% by either echocardiogram or MUGA Peripheral neuropathy NCI CTCAE grade ≤ 1 or grade 2 if no pain on clinical examination Adequate hematological, liver and renal function: Exclusion Criteria: Pregnant or lactating women Serious medical or psychiatric disorders that would interfere with the patient's safety or informed consent Clinically significant cardiovascular disease, requiring medication during the study and which might interfere with regularity of the study treatment, or not controlled by medication. Radiation of the target lesion within the last 4 weeks prior to randomization Prior radiation to ≥ 30% of bone marrow Active bacterial, viral or fungal infection Known HCV infection Patients with clinically apparent brain metastases or evidence of a spinal cord compression Major surgery within 14 days before enrollment Systemic treatment, within 14 days before the first dose of ixazomib, with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort. Participation in other clinical trials, including those with other investigational agents not included in this trial, within 30 days of the start of this trial and throughout the duration of this trial Patients that have previously been treated with ixazomib, or participated in a study with ixazomib whether treated with ixazomib or not History of other malignancy; patients who have been disease-free for 5 years or patients with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible Prior treatment with a platinum derivative (except in (neo-)adjuvant setting if breast cancer recurrence did not occur within 12 months after (neo-)adjuvant chemotherapy completion) and/or with a proteasome inhibitor Known hypersensitivity to the study drugs
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Richard Greil, MD
Organizational Affiliation
PMU Salzburg: Universitätsklinik für Innere Medizin III
Official's Role
Study Director
Facility Information:
Facility Name
Klinikum Kreuzschwestern Wels GmbH
City
Wels
State/Province
Oberösterreich
ZIP/Postal Code
A-4600
Country
Austria
Facility Name
Universitätsklinik für Innere Medizin Graz
City
Graz
State/Province
Steiermark
ZIP/Postal Code
8036
Country
Austria
Facility Name
Universitätsklinik für Frauenheilkunde Innsbruck
City
Innsbruck
State/Province
Tirol
ZIP/Postal Code
6020
Country
Austria
Facility Name
Landeskrankenhaus Feldkirch, Innere Med. II, Interne E
City
Feldkirch
State/Province
Vorarlberg
ZIP/Postal Code
6807
Country
Austria
Facility Name
UK Graz: Universitätsklinik für Frauenheilkunde und Geburtshilfe, Klinische Abteilung für Gynäkologie
City
Graz
ZIP/Postal Code
8036
Country
Austria
Facility Name
LKH Hochsteiermark: Department für Hämato-Onkologie
City
Leoben
ZIP/Postal Code
8700
Country
Austria
Facility Name
BHS Linz: Interne I: Internistische Onkologie, Hämatologie und Gastroenterologie
City
Linz
ZIP/Postal Code
A-4020
Country
Austria
Facility Name
KUK Linz: Klinik für Interne 3 - Schwerpunkt Hämatologie und Onkologie
City
Linz
ZIP/Postal Code
A-4020
Country
Austria
Facility Name
PMU Salzburg: Universitätsklinik für Innere Medizin III
City
Salzburg
ZIP/Postal Code
A-5020
Country
Austria
Facility Name
Landeskrankenhaus Steyr, Innere Medizin II Onkologie
City
Steyr
ZIP/Postal Code
A-4400
Country
Austria
Facility Name
AKH Wien Universitätsklinik für Frauenheilkunde: Klin. Abt. f. Allg. Gynäkologie und gynäkologische Onkologie
City
Vienna
ZIP/Postal Code
A-1090
Country
Austria
Facility Name
LK Wiener Neustadt: Innere Medizin, Hämatologie und internistische Onkologie
City
Wiener Neustadt
ZIP/Postal Code
2700
Country
Austria

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
30400780
Citation
Rinnerthaler G, Gampenrieder SP, Petzer A, Burgstaller S, Fuchs D, Rossmann D, Balic M, Egle D, Rumpold H, Singer CF, Bartsch R, Petru E, Melchardt T, Ulmer H, Mlineritsch B, Greil R. Ixazomib in combination with carboplatin in pretreated women with advanced triple-negative breast cancer, a phase I/II trial of the AGMT (AGMT MBC-10 trial). BMC Cancer. 2018 Nov 6;18(1):1074. doi: 10.1186/s12885-018-4979-0.
Results Reference
derived

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Ixazomib (MLN9708) in Combination With Carboplatin in Pretreated Women With Advanced Triple Negative Breast Cancer

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