Objectives: Pazopanib is a multikinase angiogenesis inhibitor. Alisertib is a highly selective inhibitor of mitotic Aurora A kinase. There is preclinical evidence that mitosis-targeting agents exhibit antiangiogenic effects. Thus, the combination of these 2 agents may have a synergistic effect on tumor vasculature. The primary objective of this study is to determine the optimal tolerated dose (OTD) for alisertib and pazopanib. Materials and Methods: This phase 1b study evaluated the OTD of alisertib twice a day, on days 1 to 7 with pazopanib, once a day, continuously in a 21-day cycle, both taken orally. Disease response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1 every 2 cycles. OTD cohort was expanded to assure safety and perform pharmacokinetics analysis. Results: A total of 27 patients received treatment. Seventy-seven percent of the patients had received at least 3 prior chemotherapy regimens. Dose-limiting toxicities occurred in dose level (DL) 2+ (grade 4 thrombocytopenia and grade 3 mucositis) and DL 3 (grade 3 liver transaminases elevation and grade 3 abdominal pain). The OTD was determined to be DL 2: alisertib 20 mg twice daily and pazopanib 600 mg daily. Pharmacokinetic analysis revealed that clearance of alisertib was reduced by ∼40% in the presence of pazopanib compared with clearance in the absence of pazopanib. Fourteen patients had stable disease and 2 patients had a partial response. Conclusions: The combination of alisertib with pazopanib demonstrates manageable safety and early clinical evidence of antitumor activity in patients with advanced malignancies (NCT01639911).
Relapsed or refractory acute myeloid leukemia (R/R AML) has a poor prognosis and is best treated with salvage chemotherapy as a bridge to allogeneic stem cell transplant (alloSCT). However, the optimal salvage therapy remains unknown. Here we compared two salvage regimens; mitoxantrone, etoposide, and cytarabine (MEC) and mitoxantrone and high‐dose Ara‐C (Ara‐C couplets). We analyzed 155 patients treated at three academic institutions between 1998 and 2017; 87 patients received MEC and 68 received Ara‐C couplets. The primary endpoint was overall response (OR). Secondary endpoints included progression‐free survival (PFS), overall survival (OS), duration of hospitalization, hematologic and nonhematologic toxicities, and success in proceeding to alloSCT. Baseline characteristics of the cohorts were well matched, though patients receiving Ara‐C couplets had more co‐morbidities (48.5% vs 33%; P = .07). OR was achieved in 43.7% of MEC and 54.4% of Ara‐C couplets patients (P = .10). Ara‐C couplets patients also trended towards a longer OS and PFS, more frequently proceeded to alloSCT (31% vs 54.4%; P = .003), and experienced less febrile neutropenia (94% vs 72%; P < .001) and grade 3/4 gastrointestinal toxicities (17.2% vs 2.94%; P = .005). No significant differences in other toxicities or median duration of hospitalization were noted. This is the first multi‐institutional study directly comparing these regimens in a racially diverse population of R/R AML patients. Although these regimens have equivalent efficacy in terms of achieving OR, Ara‐C couplets use is associated with significant reductions in toxicities, suggesting it should be used more frequently in these patients.
TPS7566 Background: AML is predominantly a disease of the elderly, yet outcomes remain dismal, especially for relapsed/refractory (R/R) AML patients (pts). Gemtuzumab Ozogamicin (GO) is a monoclonal antibody targeting CD33–commonly expressed on AML blasts, and, critically, AML stem cells (LSC)–that is linked to the cytotoxin calicheamicin. Recognized mechanisms of GO resistance include decreased (or aberrant) blast CD33 expression, upregulation of p-glycoprotein (re-exports calicheamicin), and decreased mitochondrial apoptosis. GO-induced apoptosis depends on pro-apoptotic Bax and Bak and is inhibited by overexpression of anti-apoptotic BCL-2 and BCL-XL. Venetoclax (VEN) is a BH3 mimetic, binding BCL-2, dislodging its binding to Bak/Bax, thus facilitating apoptosis. LSC uniquely overexpress BCL-2, however VEN resistance develops rapidly. Hypothesis: VEN targeting of BCL-2 proteins that protect LSC from GO-induced apoptosis will synergistically increase GO efficacy. Correlative studies include pre-treatment AML blast BH3 profiling and CD33 expression (& sequencing for isoforms), MRD measurement at post-therapy timepoints using digital drop PCR technology, and quality of life assessments (EORTC QLQ-C30, FACT-Fatigue). Methods: Single arm, open-label, multi-center (BTCRC), dose-escalation phase Ib study of combination of VEN and GO in R/R AML pts (18-75y), using a 3+3 design. Major eligibility: ECOG 0-2, adequate organ function, CD33+ in ≥ 20% AML blasts, ≤2 lines of prior therapy, no prior use of GO or VEN, no previous VOD, no BMT within 2 months, no CNS disease, and no history of HIV. Induction: 3-day VEN ramp-up to the target dose of 200 (cohort i), 400 (ii), or 600 (iii) mg daily x 28 d, with GO 3mg/m2 infused d 1, 4, and 7. If CR/CRi achieved, pts proceed to BMT if applicable, otherwise, if in CR/CRi (provided ANC > 1000, plts 100K) or PR (regardless of counts), they are consolidated with VEN at the prescribed dose x 28d and GO 3mg/m2 on days 1 and 4 (Cycle 2). If BMT not applicable, and then in CR/CRi or PR (as above), proceed to VEN alone as Maintenance in cycles 3+ until progression or toxicity. The primary endpoint is MTD of VEN with GO. Secondary endpoints include ORR, anti-leukemic activity, characterization of AEs, and estimates of RFS, EFS, and OS. This study is currently open and has to date enrolled 2 pts. Clinical trial information: NCT04070768 .
Background: Omacetaxine mepesuccinate (OM) is a semi-synthetic form of Homoharringtonine (HH), a cephalotaxine alkaloid. OM induces cell apoptosis by inhibiting peptide bond formation during mRNA translation, with rapid loss of short-lived proteins, such as MCL-1, c-MYC, and Cyclin D1 (Lu, J Hematol Oncol. 2014, 7: 2). Notably, cytarabine synergizes with HH in causing apoptosis of leukemia cells in vitro. A phase III RCT in China of 620 patients with de novo AML demonstrated superior CR and 3-yr survival rates upon addition of HH to a standard 2-drug AML induction therapy ('7 + 3'; Jin, Lancet Oncol. 2013, 14:599). Thus, we hypothesized that OM, at an appropriate dose, would similarly enhance the efficacy of a 7 + 3 regimen. OM is FDA-approved for the treatment of TKI-resistant CML. The MTD of 1.25 mg/m2/d SQ for 14 days every 28 days, as determined in a phase I/II CML trial of OM (Quintás-Cardama, Cancer 2007, 109: 248), served as a basis for the dose escalation used in this study. Methods: The primary endpoint of this phase I safety trial was to determine the optimally safe and active dose (OD) of OM when added to a standard 7 + 3 induction regimen, cytarabine and idarubicin. OM was administered SQ q12h d1-7 with cytarabine (100mg/m2 CIV) d1-7 and idarubicin (12mg/m2 IV) d1-3. Four dose levels were tested, starting with OM 0.625 mg/m2 q12h (further dose levels: 1.25, 2.0, 3.0, and 4.2 mg/m2 q12h). All newly diagnosed, untreated de novo or secondary AML patients, aged 18-70y with ECOG PS of 0-3 were eligible for this study. Secondary endpoints included overall response rate (ORR) and overall and event free survival (OS, EFS). Hematologic toxicity (HT) was defined as incomplete hematologic recovery; ANC < 1.0 x 109/L or platelet count < 100 x 109/L present at d49, with the bone marrow documented to be free of leukemic infiltration. Dose escalation was based on the EffTox design (Biometrics 2004, 60:684), a Bayesian adaptive design which considers the trade-off between efficacy and toxicity in determining the OD for Phase II trials. Results: Twenty-two patients, median age 58 (range 25-69) years were enrolled from June 2015 to June 2018. 12 patients (54.5%) had adverse cytogenetics, 6 (27%) intermediate risk, 3 (13.7%) favorable risk and 1 patient's cytogenetic risk was unknown (fibrotic BM). Eight patients demonstrated disease evolution from myelodysplastic syndrome (MDS). Altogether 16 of the 22 patients (73%) were deemed high risk based on cytogenetics or MDS-AML evolution. The EffTox design was implemented until cohort 4 (3 mg/m2 q12h), where 2 of 3 patients experienced a grade 5 non-hematologic toxicity (NHT), resulting in a dose-limiting toxicity (DLT). Since no DLTs were observed in cohort 3, an additional 5 patients were thus enrolled at this dose level to ensure safety. The OD was determined to be the dose level used in cohort 3: OM 2 mg/m2. No HTs were observed in 21 of 22 patients, (one patient not evaluable). The most common non-hematologic treatment emergent adverse events (TEAEs) of any grade were fever (68%), nausea (64%), vomiting (55%), hyperglycemia (41%), diarrhea (41%), mucositis (36%), headache (36%), sinus tachycardia (32%), rash/dermatitis (32%), and abdominal pain (32%). The most prevalent non-hematologic grade 3/4 TEAEs were febrile neutropenia (23%), hypoxia (18%), hyperglycemia (18%), and dyspnea (18%). ORR (CR and CRi) was 45.5%. Median OS was 605 days and EFS was 100 days. Conclusion: In this population with predominantly high-risk AML, the combination of OM with a standard 7 + 3 regimen demonstrates a manageable safety profile with acceptable efficacy. As ~ 25% of patients achieving CR with '7 + 3' do so after a second induction (based on meta-analysis of 6 trials, n = 1980, see Cancer 2010, 116: 5012), the ORR here is comparable to those receiving a single standard of care induction. The results in this high-risk group are therefore promising and warrant further investigation in a phase II trial. At present, we are assessing leukemic blast MCL protein expression in stored pre-treatment samples to determine if this predicts OM efficacy. NCT02440568. Teva has performed a Medical Accuracy Review of this abstract. Figure. Figure. Disclosures Khan: Teva: Speakers Bureau. Patel:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.
Background: Relapsed or refractory acute myeloid leukemia (R/R AML) portends a poor prognosis, thus salvage chemotherapy is commonly used as a bridge to HSCT, however the optimal salvage regimen remains unknown. For decades cytarabine (Ara-C) has served as the backbone of regimens frequently used in the R/R setting. MEC is among the most studied regimens for R/R AML; up to 66% of patients achieve complete remission (CR), with a median survival of 36 weeks (Arcese et al., J Clin Oncol. 1991). The Ara-C couplets regimen was shown to have a similar overall response rate (ORR) of 55%, in a single study (Larson et al., Leukemia & Lymphoma. 2012). Currently, there are no studies directly comparing these regimens. Here, in a multi-institution retrospective analysis we assessed the efficacy and toxicity of MEC and Ara-C couplets therapy. Methods: We analyzed the records of 136 patients treated between 1998 and 2017. There were 87 patients (15 from University of Illinois and 72 from Indiana University) treated with MEC (mitoxantrone 8 mg/m2 IV, etoposide 80 mg/m2 IV and Ara-C 1 g/m2 x 5 days) and 49 patients (36 from University of Illinois and 13 from University of Chicago) treated with Ara-C couplets (mitoxantrone 30 mg/m2 daily and Ara-C dosed at 2 g/m2 twice daily or 3 g/m2 daily; both drugs given on days 1 and 5). The primary endpoint was comparison of response rates. Secondary endpoints included progression free survival (PFS), overall survival (OS), duration of hospitalization, hematologic and non-hematologic toxicities, and success in proceeding to HCT. Results: The median age of the MEC group was 52 years (yr) (range: 20-75 yr) vs 55 yr (22-75 yr) in the Ara-C couplets group. There were significantly more white patients in the MEC group (72% vs 41%; p = 0.004). The incidence of unfavorable cytogenetics was similar between groups; 32 in the MEC group (36.8%) and 19 in the Ara-C couplets group (38.7%). High-risk patients, as defined by Charlson Comorbidity Index (CCI) ≥4, comprised 29 of 87 (33.3%) of MEC, and 26 of 49 (53.1%) of Ara-C couplets patients (p = 0.03). Time from initial diagnosis to diagnosis of R/R AML was similar between groups, 303 days (MEC) and 306 days, respectively (p = 0.10). CR or CRi (ORR) was achieved in 44% of MEC, and 55% of the Ara-C couplets patients. OS was 159 days and 186 days, respectively (p = 0.055). PFS was 66 days in the MEC group and 113 days in the Ara-C couplets group (p = 0.56). In total, 27 (31%) of the MEC patients and 24 (49%) Ara-C couplets patients underwent HCT (p = 0.04). Within the MEC group, the median number of days to ANC and platelet recovery was 34 days and 35 days, respectively. ANC and platelet recovery was slightly longer within the Ara-C couplets group, at 41 days and 55 days, respectively (p = 0.02 for platelet recovery). The median duration of hospitalization was similar, 29 days for MEC and 30 days for Ara-C couplets. The most common adverse event was febrile neutropenia (FN), occurring in 93% of the MEC and 78% of the Ara-C couplets patients (p = 0.01). Notably, grade 3/4 GI toxicity occurred in 15 MEC (17.2%) and one (2.0%) of the Ara-C couplets patients (p = 0.01). There were no significant differences between groups in terms of pulmonary, liver, renal, cardiac or neurologic toxicities. Conclusions: This is the first large multi-institutional retrospective study directly comparing salvage regimens in a racially diverse population of R/R AML patients. While matched for a number of variables (including the incidence of unfavorable cytogenetics), patients receiving Ara-C couplets did have a significantly higher CCI. Despite this, use of the Ara-C couplets regimen resulted in improved ORR, significantly improved efficacy as a bridge to HCT, and led to a significant comparative decrease in the incidence of FN and grade 3/4 GI toxicities. Our retrospective analysis suggests that this regimen should be considered as an effective, safe salvage regimen in this population. Disclosures Patel: Janssen: Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Khan:Teva: Speakers Bureau. Stock:Jazz Pharmaceuticals: Consultancy. Odenike:ABBVIE: Honoraria, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI/Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncotherapy Science: Research Funding; Agios: Research Funding; Celgene: Research Funding; NS Pharma: Research Funding; Janssen: Research Funding; Astex: Research Funding; Gilead Sciences: Research Funding.
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