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Background Outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) remain poor. Novel therapies specifically targeting AML are of high interest. Brentuximab vedotin (BV) is an antibody-drug conjugate that is specific for human CD30. In this phase 1 dose escalation study, the authors evaluated the safety of BV combined with mitoxantrone, etoposide, and cytarabine (MEC) re-induction chemotherapy for patients with CD30-expressing R/R AML. Methods Using a standard dose escalation design, the authors evaluated 3 dose levels of BV (0.9 mg/kg, 1.2 mg/kg, and 1.8 mg/kg) administered once on day 1 followed by MEC on days 3 through 7. Results There were no dose-limiting toxicities noted and the maximum tolerated dose was not reached. The recommended phase 2 dose of BV was determined to be 1.8 mg/kg when combined with MEC. The side effect profile was similar to that expected from MEC chemotherapy alone, with the most common grade ≥3 toxicities being febrile neutropenia, thrombocytopenia, and anemia (toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Among the 22 patients enrolled on the trial, the composite response rate was 36%, with a composite response rate of 42% noted among those who received the highest dose of BV. The median overall survival was 9.5 months, with a median disease-free survival of 6.8 months observed among responders. Approximately 55% of patients were able to proceed with either allogeneic hematopoietic stem cell transplantation or donor lymphocyte infusion. Conclusions The combination of BV with MEC was found to be safe in patients with CD30-expressing R/R AML and warrants further study comparing this combination with the use of MEC alone in this population (ClinicalTrials.gov identifier NCT01830777). Lay summary The outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) are exceptionally poor. New and emerging treatment combinations are actively being studied in an effort to improve outcomes. The authors examined the combination of brentuximab vedotin, an antibody product that recognizes a marker called CD30, with mitoxantrone, etoposide, and cytarabine (MEC), a common chemotherapy regimen, in patients with R/R AML that expressed the CD30 marker. The authors found that the combination was safe and well tolerated. Future studies comparing this new combination with the use of MEC alone can help to inform its effectiveness for this patient population.

11550 Background: RPS often have local recurrence (LR) after surgery. Preoperative radiation (RT) to 50.4 Gy can reduce LR risk but is not uniformly effective, especially after (+) margin resections. Therefore, we conducted a multi-institutional, prospective Phase II study to assess efficacy and tolerability of preop IMPT with selective dose escalation to 63 GyRBE to the posterior RPS margin (clinical target volume [CTV] 2) at high risk for (+) margins to further reduce the risk of LR. This dose was tolerable in a prior phase I study (DeLaney T et al, 2017, PMID:28740917). Methods: Primary RPS patients (pts) >18 years received preop IMPT, 50.4 GyRBE in 28 fractions (fx) of 1.8 GyRBE to CTV1 (tumor plus adjacent tissue at risk of subclinical disease) with SIB to CTV2 to 63.0 GyRBE in 28 fx of 2.25 GyRBE. Pts with high-grade tumors could get chemotherapy(CTX) prior to IMPT. To avoid treatment delay, 11 fx of IMRT x-rays could be substituted for IMPT. Pts had restaging and surgery 4-8 weeks after IMPT. Primary study endpoint was local tumor control. Secondary endpoints included clinical and pathologic response, surgical margin status, and disease-free and overall survival. Results: We accrued 60 pts from January 2016 to February 2021. Histology: 35 liposarcoma(LPS) (19 dediff and 16 well diff), 22 leiomyosarcoma(LMS), and 3 undifferentiated pleomorphic sarcoma. IMPT was delivered per protocol in all pts. 51 pts have had surgery, 5 are awaiting surgery, and 4 had no surgery due to metastases(DM) on preop imaging. 22 pts had (+) margins. 2 pts had > 75% necrosis. With 23-month median (range 1-52 months) follow-up after start of RT, there were two LRs. A dediff LPS pt had a well diff LPS LR 26 months postop, resected, and is disease-free. A renal vein/IVC LMS pt treated with CTX and IMPT had LR and DM 4 months postop and died from disease. Surgical Clavien-Dindo morbidity scores: 0(21), 1(9), 2(8), 3a (4), 3b(4), 4a(2), 4(b)1, 5(2); the periop deaths were from sepsis(pneumonia) and duodenal ulcer. The grade 3-4 periop morbidity included abscess(3), treated by catheter(2) or operative(1) drainage, prolonged hospital stays (2 pts with IVC LMS), small bowel obstruction (1), and late sigmoid colon anastomotic failure (1). Readmissions for lymphopenia(1), pneumoperitoneum (1), and volume overload (1). One late neuropathy was seen in a Type II diabetic pt with transient postop weakness after femoral nerve dissection who later had significant lower extremity weakness 3.75 years postop. Study was amended to reduce IMPT dose in diabetic pts. Conclusions: Preoperative IMPT with selective dose escalation to 63 GyRBE to the high risk posterior RPS margin is feasible. Early local control results with this approach appear promising. Some peri-operative morbidity was noted but appears to be in the expected range for RPS resections. Clinical trial information: NCT01659203.

Background: Brentuximab vedotin (BV) is an antibody-drug conjugate (ADC) consisting of an antibody specific for human CD30, an anti-microtubule agent monomethyl auristatin E (MMAE), and a protease-cleavable linker attaching MMAE to the antibody. BV is efficacious therapy against certain CD30-expressing malignancies, including classical Hodgkin lymphoma and anaplastic large cell lymphoma, and is currently approved for use in these diseases. We and others previously demonstrated CD30 expression on a sizeable proportion of primary AML samples as well as cell lines. Given this data, we conducted a phase I dose-escalation trial of BV in combination with re-induction chemotherapy (MEC) for patients with relapsed or refractory AML. Methods: In this phase I, 3+3 cohort dose-escalation study, BV was administered 3 days prior to initiation of MEC re-induction for relapsed or refractory AML. Eligibility for enrollment included adults over age 18, adequate organ function, an ECOG performance status of ≤ 2, and a diagnosis of relapsed or refractory AML with > 20% CD30 expression (as assessed by immunohistochemistry or flow cytometric analysis). On day 1 of the trial, all enrolled participants were initiated on therapy with BV intravenously using three sequential dosing levels (0.9 mg/kg, 1.2 mg/kg, 1.8mg/kg). On day 3, patients were initiated on MEC re-induction chemotherapy (Mitoxantrone 10mg/m2 IV administration for five days [D3-8], etoposide 100mg/m2 IV D3-8, cytarabine 1000mg/m2 IV D3-8). The period of dose limiting toxicity (DLT) assessment occurred during the period of re-induction (approximately D1-35). Once dose escalation for BV reached a dose of 1.8 mg/kg IV, no further escalation would occur. An additional cohort of ten patients were to be treated at this maximum dose, or if a maximum tolerated dose (MTD) was reached, an additional 10 patients were to be treated at this dose. Thereafter, maintenance therapy with BV could be initiated, and administered IV every 21 days, as per dose level during prior re-induction, and continued for up to 12 months. Those eligible for stem cell transplant (SCT) were removed from study for this purpose. Results: 22 eligible patients were enrolled on study. The median age was 58 (range 23-72); 15 (68%) were male, and 20 (91%) were Caucasian. 7 patients (32%) had secondary AML (6 with antecedent MDS and 1 with therapy related AML). 6 (27%) exhibited adverse risk karyotype. FLT3 mutations were seen in 7 (32%), NPM1 in 4 (18%), and CEBPA in 2 (9%). The median degree of blast CD30 expression in those assessed by flow cytometry was 92% (range 30-98%). 6 patients had refractory disease, while the remaining had relapsed AML at time of enrollment. 10 patients (46%) had undergone prior allogeneic stem cell transplantation (SCT), one of whom had undergone two prior stem cell transplants. Three patients were treated at dose level 1, 5 at dose level 2, and 4 at dose level 3. Two of the patients treated at dose level 2 were removed prior to end of DLT period due to lack of response and were replaced, and 1 patient treated at dose level 3 died due to infectious complications prior to end of DLT monitoring period and was replaced. No new attributable toxicities apart from that expected from MEC re-induction alone were seen with the combination therapy. No DLTs were detected, and the recommended phase 2 dose (RP2D) was deemed to be dose level 3 (1.8 mg/kg). An additional 10 patients were treated at the RP2D. Overall, 4 patients achieved a complete remission (CR) and 4 achieved a complete remission with incomplete hematologic recovery (CRi), for a composite remission rate (CCR) of 36% (8/22). Among the 14 patients treated at the RP2D of 1.8mg/kg, 6 achieved a CR or CRi (CCR 43%). Of the remaining cases, one was replaced prior to response assessment and the others experienced progressive disease. The degree of baseline CD30 expression by flow cytometry did not appear to predict for response in this phase 1 dose escalation study, although study of correlative samples is ongoing. Conclusions: BV is well tolerated when administered in conjunction with conventional re-induction chemotherapy in patients with relapsed-refractory AML, in whom CD30 is an intriguing target. Adverse events on this study were predominantly expected and related to marrow suppression from MEC re-induction. No DLT was identified. Additional and larger studies are needed to more comprehensively assess the efficacy of CD30-targeted therapy in AML. Disclosures Fathi: Jazz: Honoraria; Boston Biomedical: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astellas: Honoraria; Agios: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Emadi:NewLink Genetics: Research Funding. Brunner:Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. Amrein:Takeda: Research Funding.