Introduction: Outcomes remain poor for adults with acute lymphoblastic leukemia (ALL). Hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (Hyper-CVAD) is a high intensity chemotherapy regimen that results in high complete remission (CR) rates and long-term survival in 30-40% of adults with ALL. Approximately 50% of patients achieve measurable/minimal residual disease (MRD) negativity after Hyper-CVAD therapy. Bortezomib, the first proteasome inhibitor, showed potentially synergistic activity in relapsed ALL in combination with chemotherapy. Carfilzomib is a next-generation irreversible proteasome inhibitor with increased specificity and potency compared to bortezomib and with significant activity in multiple myeloma. Therefore, we hypothesized that the addition of carfilzomib to Hyper-CVAD would be safe and could improve outcomes for adults with ALL by increasing the rate of MRD negativity.
Methods: The primary objectives of this phase I study (NCT02293109) were to determine safety, tolerability, and recommended phase two dose of carfilzomib added to Hyper-CVAD in patients with newly diagnosed, untreated Philadelphia chromosome negative ALL. The secondary objectives were to determine rate of CR and MRD negativity. Time-to-event analyses were not planned. Patients were aged 18-65 with adequate left ventricular, renal, and liver function and Eastern Cooperative Group Performance Status of 0-2. Patients received four 28-day cycles of standard Hyper-CVAD (i.e. two courses each of Part A and Part B) with the addition of 4 doses of carfilzomib on days 0, 1, 7 and 8 of each of the four cycles. Rituximab was added for patients with CD20 positive disease. After completing study mandated carfilzomib plus Hyper-CVAD, patients continued standard Hyper-CVAD therapy. Dose escalation used a standard 3+3 design with carfilzomib dose levels (DL) of 20mg/m2 (DL1), 27mg/m2 (DL2) and 36mg/m2 (DL3). Dose-limiting toxicities (DTLs) were assessed through completion of one A and one B cycle. Patients not evaluable for DLT were replaced. Adverse events (AEs) were graded using NCI Common Terminology for Adverse Events version 4.03. MRD was tested by multiparameter flow cytometry (MFC) and <0.01% was considered negative. Patients were followed for up to 28 days after completion of therapy.
Results: Ten patients were enrolled into DL1 (n=3), DL2 (n=3), and DL3 (n=4). Median age was 38 [range 23-61]. Fifty percent (n=5) were female, and 60% (n=6) were Hispanic. Eighty percent (n=8) had B-ALL, and 20% (n=2) had T-ALL. Fifty percent (n=5) had CD20 positive disease and received rituximab. Seventy percent (n=7) had abnormal cytogenetics, including complex IgH gene rearrangements (n=4). One patient was found to have CNS involvement during standard cycle one CSF assessments. No DLTs were observed in the dose escalation cohorts. One subject was replaced during cycle one for adverse events not meeting DLT criteria. All patients experienced grade 3-4 treatment-emergent AEs at least possibly related to study therapy, including leukopenia (100%, n=10), neutropenia (100%, n=10), anemia (100%, n=10), thrombocytopenia (100%, n=10), lymphopenia (90%, n=9), and febrile neutropenia (70%, n=7) (Table 1). Serious AEs (SAEs) at least possibly related to study therapy occurred in 70% (n=7) of patients and included febrile neutropenia (60%, n=6), leukopenia (20%, n=2), and thrombocytopenia (20%, n=2). There were no grade 5 events, and no cardiac AEs apart from related grade 1 sinus tachycardia in one patient. The median number of cycles on study was four [range 1-4]. Twenty percent (n=2) of patients had a dose modification (both related to AE), and 30% (n=3) had a dose delay (two related to AE). The complete remission rate (CR) was 90% (9/10) after cycle 2 and 100% (10/10) overall (Table 2). The rate of MFC MRD negativity was 70% (7/10) after cycle 4 and 80% (8/10) overall, including 88% (7/8) for B-ALL and 50% (1/2) for T-ALL (Table 2). There were no study-related deaths.
Conclusions: The addition of carfilzomib to Hyper-CVAD is safe and tolerable in patients with untreated ALL. No DLTs were observed with carfilzomib doses up to 36mg/m2. The combination shows promising preliminary efficacy with high rates of MRD negative CR compared to historical controls receiving standard Hyper-CVAD. The regimen may be more active in B-ALL. These results support further study of Hyper-CVAD plus carfilzomib in ALL.
Disclosures
Jonas: AbbVie, Amgen, GlycoMimetics: Other: Travel expenses; AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding. Tuscano:Abbvie: Research Funding; Takada: Research Funding; Amgen: Honoraria; Seattle Genetics: Honoraria; Genentech: Research Funding; Pharmacyclics: Research Funding; Spectrum: Research Funding; Celgene: Honoraria, Research Funding; Novartis: Research Funding. Rosenberg:Amgen: Consultancy, Research Funding. Abedi:Abbie: Speakers Bureau; Takeda: Speakers Bureau; BMS: Speakers Bureau; Gilead: Speakers Bureau; Celgene: Speakers Bureau.
OffLabel Disclosure:
Carfilzomib was tested for use in a prospective Phase I clinical trial.
Phase
I
study of escalating doses of carfilzomib with
HyperCVAD
in patients with newly diagnosed acute lymphoblastic leukemia