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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02993094
Recruitment Status : Recruiting
First Posted : December 15, 2016
Last Update Posted : January 7, 2020
Sponsor:
Collaborator:
Takeda
Information provided by (Responsible Party):
Arbeitsgemeinschaft medikamentoese Tumortherapie

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.

Condition or disease Intervention/treatment Phase
Triple-Negative Breast Cancer Drug: Ixazomib Drug: Carboplatin Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 53 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Ixazomib (MLN9708) in Combination With Carboplatin in Pretreated Women With Advanced Triple Negative Breast Cancer
Study Start Date : November 2016
Estimated Primary Completion Date : September 2020
Estimated Study Completion Date : September 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Ixazomib/Carboplatin

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

Drug: Ixazomib
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.
Other Name: MLN9708

Drug: Carboplatin
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 Measures :
  1. Maximum tolerated dose (MTD) [ Time Frame: From treatment start until MTD (12 months --> start Phase II Q3 2017) ]
    Determination of maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs)


Secondary Outcome Measures :
  1. Safety profile based on adverse events evaluation [ Time Frame: During study treatment + 28 day after last study drug (approximately 3 years) ]
    Incidence, type, severity and consequences (e.g. study discontinuation) of an adverse event

  2. Overall response rate [ Time Frame: During study treatment every 8 weeks until progression + end of study treatment (approximately 3 years) ]
  3. Clinical benefit rate [ Time Frame: During study treatment every 8 weeks until progression + end of study treatment (approximately 3 years) ]
    Complete remission, partial remission or stable disease for at least 24 weeks

  4. Progression-free survival (PFS) [ Time Frame: During study treatment every 8 weeks until progression + end of study treatment (approximately 3 years) ]
  5. Quality of Life of MBC patients [ Time Frame: Baseline + every 8 weeks until progression + at end of study treatment (approximately 3 years) ]
    EORTC quality of life questionnaire (QLQ-C30 and QLQ-BR23)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02993094


Contacts
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Contact: Richard Greil, MD 004357255 ext 25801 r.greil@salk.at
Contact: Daniela Wolkersdorfer, PhD 0043662640 ext 4412 d.wolkersdorfer@agmt.at

Locations
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Austria
Klinikum Kreuzschwestern Wels GmbH Recruiting
Wels, Oberösterreich, Austria, A-4600
Contact: Renate Pusch, MD         
Contact: Teresa Bogensperger         
Principal Investigator: Renate Pusch, MD         
Universitätsklinik für Innere Medizin Graz Not yet recruiting
Graz, Steiermark, Austria, 8036
Contact: Herbert Stöger, MD         
Principal Investigator: Herbert Stöger, MD         
Universitätsklinik für Frauenheilkunde Innsbruck Not yet recruiting
Innsbruck, Tirol, Austria, 6020
Contact: Daniel Egle, MD         
Principal Investigator: Daniel Egle, MD         
Landeskrankenhaus Rankweil Recruiting
Rankweil, Vorarlberg, Austria, 6830
Contact: Holger Rumpold, MD         
Principal Investigator: Holger Rumpold, MD         
BHS Linz: Interne I: Internistische Onkologie, Hämatologie und Gastroenterologie Recruiting
Linz, Austria, A-4020
Contact: Andreas Petzer, MD         
Contact: Martina Lang         
Principal Investigator: Andreas Petzer, MD         
KUK Linz: Klinik für Interne 3 - Schwerpunkt Hämatologie und Onkologie Recruiting
Linz, Austria, A-4020
Contact: Michael Fridrik, MD         
Contact: Bettina Pfleger         
Principal Investigator: Michael Fridrik, MD         
PMU Salzburg: Universitätsklinik für Innere Medizin III Recruiting
Salzburg, Austria, A-5020
Contact: Richard Greil, MD         
Contact: Michaela Schachner         
Principal Investigator: Richard Greil, MD         
Landeskrankenhaus Steyr, Innere Medizin II Onkologie Recruiting
Steyr, Austria, A-4400
Contact: Dieter Rossmann, MD         
Contact: Regina Neuhauser         
Principal Investigator: Dieter Rossmann, MD         
AKH Wien Universitätsklinik für Frauenheilkunde: Klin. Abt. f. Allg. Gynäkologie und gynäkologische Onkologie Recruiting
Vienna, Austria, A-1090
Contact: Christian Singer, MD         
Contact: Philipp Pappenscheller         
Principal Investigator: Christian Singer, MD         
Sponsors and Collaborators
Arbeitsgemeinschaft medikamentoese Tumortherapie
Takeda
Investigators
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Study Director: Richard Greil, MD PMU Salzburg: Universitätsklinik für Innere Medizin III
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Arbeitsgemeinschaft medikamentoese Tumortherapie
ClinicalTrials.gov Identifier: NCT02993094    
Other Study ID Numbers: AGMT_MBC-10 (X16087)
2016-001421-13 ( EudraCT Number )
First Posted: December 15, 2016    Key Record Dates
Last Update Posted: January 7, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Arbeitsgemeinschaft medikamentoese Tumortherapie:
breast cancer
advanced triple negative
ixazomib
carboplatin
CARIXA
Study Group of Medical Tumor Therapy (AGMT)
Additional relevant MeSH terms:
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Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Carboplatin
Ixazomib
Antineoplastic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action