Ixazomib (MLN9708) in Combination with Carboplatin in Pretreated Women with Advanced Triple Negative Breast Cancer (CARIXA)
Short title: AGMT_MBC-10 (CARIXA)
Title: Ixazomib (MLN9708) in Combination with Carboplatin in Pretreated Women with Advanced Triple Negative Breast Cancer
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
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.
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.
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.
- Phase I: Determination of maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs)
- Phase II: Overall response rate (ORR)
- Safety profile
- Overall response rate
- Clinical benefit rate
- Progression-free survival (PFS)
- Quality of Life (EORTC QLQ-C30 and EORTC QLQ-BR23)
Inclusion Criteria (selected):
- 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 or very weak staining for estrogen receptor (IHC <10%), progesterone receptor (IHC <10%) and HER2/neu (IHC 0-1+, or 2+ if FISH-test is negative, 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
- 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 (neo-)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
Exclusion Criteria (selected):
- 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 HIV 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
- Patients that have previously been treated with ixazomib, or participated in a study with ixazomib whether treated with ixazomib or not