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

Sponsor

Arbeitsgemeinschaft medikamentoese Tumortherapie (Other)

Overall Status

Terminated

CT.gov ID

NCT02993094

Collaborator

Takeda (Industry)

Enrollment

Locations

Arm

44.8

Actual Duration (Months)

2.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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.

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

31 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

Actual Study Start Date :

Nov 21, 2016

Actual Primary Completion Date :

Aug 15, 2020

Actual Study Completion Date :

Aug 15, 2020

Arms and Interventions

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 Names: 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.

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 Names:

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.

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose (MTD) [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

Safety profile based on adverse events evaluation [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
Overall response rate [During study treatment every 8 weeks until progression + end of study treatment (approximately 3 years)]
Clinical benefit rate [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
Progression-free survival (PFS) [During study treatment every 8 weeks until progression + end of study treatment (approximately 3 years)]
Quality of Life of MBC patients [Baseline + every 8 weeks until progression + at end of study treatment (approximately 3 years)]
EORTC quality of life questionnaire (QLQ-C30 and QLQ-BR23)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Klinikum Kreuzschwestern Wels GmbH	Wels	Oberösterreich	Austria	A-4600
2	Universitätsklinik für Innere Medizin Graz	Graz	Steiermark	Austria	8036
3	Universitätsklinik für Frauenheilkunde Innsbruck	Innsbruck	Tirol	Austria	6020
4	Landeskrankenhaus Feldkirch, Innere Med. II, Interne E	Feldkirch	Vorarlberg	Austria	6807
5	UK Graz: Universitätsklinik für Frauenheilkunde und Geburtshilfe, Klinische Abteilung für Gynäkologie	Graz		Austria	8036
6	LKH Hochsteiermark: Department für Hämato-Onkologie	Leoben		Austria	8700
7	BHS Linz: Interne I: Internistische Onkologie, Hämatologie und Gastroenterologie	Linz		Austria	A-4020
8	KUK Linz: Klinik für Interne 3 - Schwerpunkt Hämatologie und Onkologie	Linz		Austria	A-4020
9	PMU Salzburg: Universitätsklinik für Innere Medizin III	Salzburg		Austria	A-5020
10	Landeskrankenhaus Steyr, Innere Medizin II Onkologie	Steyr		Austria	A-4400
11	AKH Wien Universitätsklinik für Frauenheilkunde: Klin. Abt. f. Allg. Gynäkologie und gynäkologische Onkologie	Vienna		Austria	A-1090
12	LK Wiener Neustadt: Innere Medizin, Hämatologie und internistische Onkologie	Wiener Neustadt		Austria	2700