Breast Cancer

Short title: AGMT_MBC-10 (CARIXA)

Title: Ixazomib (MLN9708) in Combination with Carboplatin in Pretreated Women with Advanced Triple Negative Breast Cancer

Status: closed

Start: February 2017

Coordinating Investigator: Univ. Prof. Dr. Richard Greil

Protocol Contact: OA Dr. Gabriel Rinnerthaler, OA Dr. Simon Gampenrieder

EudraCT Number: 2016-001421-13

ClinicalTrialsID: NCT02993094

Number of patients: 53 (Phase I: 9 to 24 patients, Phase II: 41 evaluable patients)

Sponsor: AGMT gemeinnützige GmbH

Subjects meeting all inclusion criteria will be enrolled 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.

Phase I:
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 3 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:

• 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 (definition see section 9)
• grade 3 or greater diarrhea that occurs despite maximal supportive therapy (definition see section 9)
• 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 are defined as:

• any grade 2 non-hematologic toxicity excluding alopecia
• any grade 3 hematologic toxicity

The maximum-administered dose (MAD) is defined as the dose at which DLT or 3 moderate toxicities 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 or 3 moderate toxicities are 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 or 3 moderate toxicities observed during the first treatment cycle.

Beginning with the 2nd cycle an intrapatient dose escalation is allowed to reduce the number of patients treated at sub-effective doses within the phase I part of the trial. If the nadir ANC was ≥ 500/mL, the nadir platelet count ≥ 50,000/mL, and non-hematologic toxicities in the previous cycle were grade ≤ 1. If all of these criteria are fulfilled, then the current dose level can be escalated by one dose level by each cycle.

This is separate from the alternate dose escalation design of the phase I part. After completion of phase I, all patients, that are treated with a dose below the determined MTD, can be dose escalated at the discretion of the investigator.

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.