ALBERT

Description: Background: Pediatric pts with cHL have better responses to therapy compared with adult pts; however, the combination regimens and radiotherapy used in treatment can result in significant morbidity. Including brentuximab vedotin as a component of multi-agent chemotherapy for pediatric pts with newly diagnosed HL may provide clinical benefit by decreasing the need for radiotherapy following chemotherapy, and reducing the risks of late effects associated with radiotherapy, including secondary malignancies, cardiac toxicity and thyroid dysfunction. The phase 1 portion of the study assessed the safety, tolerability, and RP2D of brentuximab vedotin when combined with doxorubicin, vinblastine, and dacarbazine (AVD) for frontline treatment of advanced stage cHL in pediatric pts. Methods: Eligible pts were aged 5 to

Description: Background Amplification and/or over-expression of the mitotic Aurora A kinase (AAK) have been reported in a variety of tumors. The investigational, selective, AAK inhibitor MLN8237 (alisertib) has shown signs of anti-tumor activity in pts with hematologic malignancies including aggressive non-Hodgkin lymphoma (NHL). Over-expression of AAK leads to resistance to microtubule targeted agents such as vincristine (V) and inhibiting AAK leads to synergy in the presence of these agents (Mahadevan D et al. CCR 2012). The combination of MLN8237 (M) + rituximab (R) ± V has shown synthetic lethality in pre-clinical B-NHL mouse models (ibid) supporting clinical evaluation of this combination; we report the safety and recommended phase 2 dose (RP2D) from the phase 1 clinical data of this MR ± V combination in pts with aggressive B-NHL. Methods Adults with CD20+ B-NHL after 1–4 prior regimens (including ASCT) and ECOG PS 0–2 were eligible. In part 1 (MR), pts received one dose level of M 50 mg BID days 1–7 + R 375 mg/m2 IV day 1 in 21-day cycles (up to 8) in combination, followed by single agent M. In part 2 (MRV), M dose escalation followed a 3+3 design (M starting dose: ∼50% of MR RP2D [30mg BID] days 1–7 + R 375 mg/m2 IV on day 1 + V 1.4 mg/m2 [max, 2 mg] IV on days 1 and 8 of 21-day cycle). The RP2D was determined as the dose level at which

Description: Abstract 3683 Background: Aurora A Kinase (AAK) is a key regulator in the control of mitosis, and amplification/overexpression of AAK has been reported in a wide variety of cancers. MLN8237 (alisertib) is an investigational, oral AAK inhibitor that is being researched in several clinical trials, in a number of different malignancies. Here we report an integrated analysis of the safety profile of single-agent MLN8237. Methods: Single-agent safety data from 8 studies (5 in solid tumors and 3 in hematologic malignancies: C14001–C14007, C14010) were pooled for this analysis, including MLN8237 starting doses above the recommended Phase 3 dose (RP3D) of 50 mg BID × 7 days q 21-days. A data cut-off date of March 29, 2012 was used and includes some ongoing studies. Results: 653 patients were included in this analysis, 490 with solid tumors and 163 with hematologic malignancies. Median age at baseline was 61 years (range 20–88), and 34% and 62%, respectively, had an ECOG performance status of 0 or 1. Patients received a median of 2 cycles of MLN8237 (solid: 2 [range 1–51]; heme: 2 [range 1–34]), and 134 patients (21%) received ≥6 cycles of therapy (solid: n=104 [21%]; heme: n=30 [18%]). In total, 168 patients (26%) had a reduction in MLN8237 dose (solid: n=120 [24%]; heme: n=48 [29%]), including 42 patients (6%) with ≥2 dose reductions (solid: n=32 [7%]; heme: n=10 [6%]). In total, 422 patients received MLN8237 at the RP3D dose of 50 mg BID for 7 days in 21-day cycles. Of these patients, 412 (98%) had an adverse event (AE) of any grade (solid: 295/305 [97%]; heme: 117/117 [100%]), and 328 (78%) had a grade ≥3 AE. Most frequently observed all-cause AEs were fatigue (49%), neutropenia (48%), anemia (45%), and diarrhea (43%). Drug-related AEs were observed in 90% of patients, including at grade ≥3 in 252 (60%; Table). Although the most frequently observed grade ≥3 drug-related AE was neutropenia (37%), only ∼23% of the safety population required G-CSF therapy (cycle 1: n=96), with the greatest use seen in one study of patients with solid tumors (C14007: 38 of 96 patients [40%]). Overall, 24% of patients (solid: 19%; heme: 35%) had drug-related serious AEs, of which the most frequently reported were febrile neutropenia (6%), neutropenia (5%), stomatitis (4%), and anemia (2%). 14% of patients (solid: 10%; heme: 23%) had an AE resulting in treatment discontinuation. In total, 52 (12%) on-study deaths have been recorded (solid: 23 [8%]; heme: 29 [25%]); all were considered as being unrelated to treatment with MLN8237, with the exception of 1 patient with diffuse large B-cell lymphoma who had fatal sepsis. Conclusions: In patients receiving MLN8237 at the RP3D, AEs were most frequently reported in rapidly proliferating tissues, reflecting the proposed role of MLN8237 in dysregulating mitosis. This is the largest reported safety database with an AAK inhibitor and is consistent with preclinical data demonstrating the Aurora A inhibition of MLN8237. Currently enrolling trials include a phase 3 study to evaluate MLN8237 in patients with relapsed/refractory peripheral T-cell lymphoma. Disclosures: Benaim: Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership. Off Label Use: Yes – Investigational agent in clinical development for the treatment of advanced hematologic malignancies and solid tumors. Zhou:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Leonard:Millennium Pharmaceuticals, Inc.: Employment. Freedland:Millennium Pharmaceuticals, Inc.: Employment. Niculescu:Millennium Pharmaceuticals, Inc.: Employment.

Description: Background PTCL is an aggressive subgroup of NHL. Outcomes in R/R PTCL remain poor and alternative therapies are needed. Alisertib is an investigational, oral, selective inhibitor of Aurora A kinase, a key mitotic regulator that is overexpressed/amplified in various cancers, including lymphomas. Phase 2 data with single-agent alisertib in R/R NHL (Friedberg et al JCO 2014) and R/R PTCL (Barr et al JCO 2015) suggested promising antitumor activity. This international phase 3 trial evaluated single-agent alisertib vs investigator's choice in pts with R/R PTCL, and was the first initiated randomized trial in this setting. Methods Adult pts with R/R PTCL (WHO criteria) after ≥1 prior conventional systemic cytotoxic therapy, who had measurable disease by 2007 IWG criteria, tumor biopsy for central hematopathology review, and ECOG PS 0-2, were eligible. Pts were randomized 1:1 (stratified by nodal vs extranodal disease, IPI score [0/1/2 vs 3/4/5], and region [North America + EU vs Rest of World]) to receive alisertib 50 mg twice daily as an enteric coated tablet on d 1-7 in 21-d cycles (alisertib arm), or investigator's choice of: pralatrexate 30 mg/m2 IV once weekly for 6 weeks in 7-week cycles; romidepsin 14 mg/m2 IV on d 1, 8, and 15 in 28-d cycles; or gemcitabine 1000 mg/m2 IV on d 1, 8, and 15 in 28-d cycles (comparator arm), until disease progression, unacceptable toxicity, or 2 yrs (extendable if benefit shown). Selected comparator drug could not have been previously received by the pt, and crossover to another study drug was not permitted. The primary endpoints were ORR (CR+PR) and PFS by IWG criteria per central (IRC) assessment. Secondary endpoints included OS, CR rate, DOR, and safety. The study employed an adaptive sample size reassessment approach, with two interim analyses (IA1, futility analysis; IA2) plus a planned final analysis. Sample size was determined to give 80% power to detect a difference in ORR (assumed 55% alisertib vs 30% comparator) at IA2, and ~85% power to detect a reduction in HR for PFS in favor of alisertib at the final analysis with a maximum of 354 randomized pts and a maximum of 261 PFS events. Conditional power calculation based on PFS at IA2 could determine whether the study would be stopped for futility or if sample size would be expanded for the final analysis. Here we report data from IA2 (17Sep2014 data cut-off). Results 238 pts were randomized across 27 countries (120 alisertib, 118 comparator). Baseline characteristics were balanced between arms (alisertib vs comparator): median age 63 vs 64 yrs; male 68% vs 64%; Ann Arbor stage III/IV 74% vs 72%; bone marrow involvement at study entry 29% vs 35%. Efficacy data are shown in the Table. ORR by IRC with alisertib vs comparator was 33% vs 43% (OR 0.65 [95% CI: 0.34-1.23]), including 16% vs 25% CR. Median duration of follow-up was 9.5 vs 9.2 mos with alisertib vs comparator. Median PFS by IRC was 3.7 vs 3.4 mos (HR 0.939 [95% CI: 0.681-1.293]; Figure) and median OS was 9.9 vs 12.2 mos (HR 0.901 [95% CI: 0.607-1.337]; OS data not mature at current follow-up). Median treatment duration with alisertib vs comparator was 12 vs 10 weeks and 15% vs 5% of pts remained on treatment at data cut-off. With alisertib vs comparator, rates of Gr ≥3 AEs were 85% vs 81%, serious AEs 53% vs 55%, discontinuations due to AEs 9% vs 13%, and on-study treatment-related deaths 2% vs 2%. Gr ≥3 AEs (〉20% all pts) were neutropenia 44% vs 27%, thrombocytopenia 29% vs 27%, and anemia 30% vs 11%. Conclusion While alisertib showed activity in R/R PTCL, there was no significant efficacy benefit vs comparator. Based on IA2, there was a low probability of claiming superiority of alisertib for PFS at the final analysis; therefore, per IDMC recommendation enrollment was stopped at 271 pts and pts deriving benefit continue on treatment. The study was unblinded and final data are pending. Table. Efficacy Alisertib Comparator All Pralatrexate Romidepsin Gemcitabine Response, n (%)*† n=83 n=80 n=40 n=17 n=23 ORR (CR+PR) 27 ( 33) 34 (43) 16 (40) 10 (59) 8 (35) CR 13 (16) 20 (25) 10 (25) 5 (29) 5 (22) PR 14 (17) 14 (18) 6 (15) 5 (29) 3 (13) SD 26 (31) 18 (23) 13 (33) 2 (12) 3 (13) PD 30 (36) 27 (34) 11 (28) 4 (24) 12 (52) Median DOR*† (responders), mos 5.0 5.8 - - - PFS*‡ n=120 n=118 n=67 n=21 n=30 Events, n (%) 78 (65) 73 (62) 45 (67) 7 (33) 21 (70) Median, mos 3.7 3.4 3.4 8.0 1.9 *IRC assessment †Response-evaluable pts (n=163); n=75 not evaluable (not dosed/ no post-baseline IRC assessment/ no central confirmation of PTCL) ‡ITT analysis (n=238) Disclosures O'Connor: Spectrum: Research Funding; Seattle Genetics: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding. Off Label Use: Investigational Aurora A kinase inhibitor, alisertib, for patients with relapsed/refractory peripheral T-cell lymphoma.. Demeter:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Masszi:BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Ramchandren:Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding. d'Amore:Takeda Pharmaceutical Company Limited: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Foss:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kim:Merck: Research Funding; Takeda: Research Funding; Novartis: Research Funding; Kyowa-Kirin: Research Funding; Donga: Research Funding; Roche: Research Funding. Zinzani:J&J: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liu:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Jung:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Zhou:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Leonard:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dansky Ullmann:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Shustov:Seattle Genetics: Research Funding.

Description: Abstract 95 Background: Aurora kinases are a family of oncogenic serine-threonine kinases that regulate multiple phases of the mitotic signaling cascade. Inhibition of aurora A kinase (AAK) leads to mitotic errors, followed by aneuploidy, apoptosis, and senescence. Investigational drug alisertib is an ATP-competitive, orally available inhibitor of AAK, that has been evaluated for safety and efficacy in Phase I hematological malignancies. We conducted the first phase II multicenter trial of alisertib in adult patients with aggressive B- and T- cell NHL. Methods: Eligible patients had normal organ function, ANC ≥1250/mm3, platelets ≥ 75,000/mm3 and no prior allogeneic transplant. Patients were treated with alisertib at a dose of 50mg twice daily for 7 days on 21 day cycles until either documented progression or unacceptable treatment-related toxicity. Using fluorescent in situ hybridization (FISH), gene amplification was assessed in archived tumors by a dual assay measuring AAK copy number on chromosome 20q13 as well as the ratio to a control probe located on chromosome 20q11. Immunohistochemistry (IHC) was performed on archived paraffin embedded diagnostic tissue using a dual assay measuring the protein levels of total AAK and that of phospho histone H3. PK sampling was performed with inclusion of steady-state trough plasma PK samples on the morning of Cycle 1 Day 8. Results: 48 pts were enrolled, including 41 response-evaluable. Histologies included DLBCL (n=21, 44%), mantle cell (MCL; n=13, 27%), peripheral T- cell (n=8, 17%), transformed follicular (n=5, 10%) and Burkitt (n=1, 2%). Median age was 68 y (range 32–85). Pts received median 3 prior regimens (range 1–11); 11 pts received prior ASCT. Most common Grade 3/4 adverse events were neutropenia (63%), thrombocytopenia (31%), stomatitis (15%), febrile neutropenia (13%) and fatigue (6%). Four deaths on study were attributed to progressive NHL (2), treatment-related sepsis (1), and unknown cause (1). 11 pts discontinued and 24 reduced dose due to adverse events (AEs). Evaluation of steady state trough concentration of alisertib (N=25) revealed that PK variability was consistent with that observed in other trials with alisertib, and there was a trend toward higher levels in patients who required AE-related dose reductions compared to those who did not (geometric mean 2375 nM [n=10, CV: 54%] vs. 1504 nM [n=15, CV: 35%]). FISH analysis for AAK gene amplification did not reveal differences between histologies (N=31). When total AAK protein was evaluated by immunohistochemistry (N=32), marked variability in both proportion of expression as well as intensity was observed both between and within histologies; there was no correlation of AAK protein expression and clinical response. The overall response rate (ORR) was 32% (95% CI 0.181–0.481); response by histology: DLBCL 20%; MCL 23% and T- cell NHL 57%. Conclusion: Current data suggests that alisertib is generally well-tolerated, with responses observed in heavily pretreated patients with aggressive NHL, including patients after ASCT. Emerging data supports single agent activity in several histologies, with proportionally more responses observed in relapsed/refractory T-cell NHL. Some patients have now been treated for up to two years with this agent, and the generally manageable toxicity profile suggests an opportunity to combine this drug with other agents. IHC of aggressive lymphoma histologies suggests heterogeneity in AAK protein expression and intensity. The geometric mean of alisertib steady-state trough concentration was 1.8 μM (CV= 47%, N = 25), which was above the 1 μM steady-state plasma concentrations associated with saturating levels of pharmacodynamics and antitumor activity in preclinical xenograft models. The observed trend for association between trough concentration of alisertib and AEs supports the dose modification scheme implemented in this trial. Based upon these results, planned future trials include a single-agent study in T-cell NHL, and a combination study exploring alisertib with rituximab and vincristine in aggressive B-cell NHL. Disclosures: Friedberg: Genentech: Consultancy; astellas:; Lilly:; Abbott/Trubion:; Seattle Genetics: Honoraria; Cephalon: Consultancy. Off Label Use: novel agents for relapsed DLBCL. Jung:Millennium: Employment. Danaee:Millennium Pharmaceuticals Inc.: Employment. Zhou:millennium: Employment. Leonard:millennium: Employment.

Description: Abstract 3273 Background: AAK is essential for mitotic progression and is amplified or overexpressed in AML and other hematologic malignancies. The investigational agent MLN8237 is an orally available, potent, and selective AAK inhibitor with preclinical activity against leukemias, lymphomas, and myeloma. Phase 1–2 and pharmacodynamic results show a mechanism of selective AAK inhibition, and some durable clinical activity in patients with treatment-resistant malignancies. Methods: Open-label, multicenter, phase 2 trial (NCT00830518) of MLN8237 in patients aged ≥18 years with advanced AML or intermediate-2/high-risk MDS. Eligibility criteria included ECOG performance status 0–2, adequate organ function, and 〉10% blasts in bone marrow. Patients were not excluded based on number of prior therapies, treatment with hydroxyurea or steroids, prior transplant, or ongoing cytopenias. Patients received 21-day cycles of MLN8237 50 mg BID for 7 days followed by 14 days' rest until disease progression or unacceptable toxicity. The primary endpoint was response rate, defined as complete (CR) plus partial (PR) response, which included CR (CRi) or PR (PRi) with incomplete blood count recovery in AML patients and marrow CR or PRi in MDS patients. Response was evaluated by modified AML/MDS international working group (IWG) criteria; stable disease was defined as failure to achieve PRi but no evidence of progression in AML patients, and as failure to achieve PR but no evidence of progression for 〉8 weeks in MDS patients. Adverse events (AEs) were graded by National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) version 3.0. Results: 57 patients were enrolled; median age was 72 years (range 46–85), 56% were male, and 81% white. Forty-six (81%) patients had AML, of whom 21 (37%) had secondary leukemia. Of 11 (19%) patients with MDS, 8 had an IPSS score of intermediate-2 (1.5 or 2.0), and 3 had a high (≥2.5) score. Forty-nine (86%) patients had received prior therapies, and 9 (16%) received ≥3 prior therapies. Patients received a median of 2 cycles (range 1–16) of MLN8237. Treatment-related grade 3/4 AEs were seen in 24 (42%) patients and included febrile neutropenia (11%), thrombocytopenia (9%), anemia (9%), fatigue (7%), and neutropenia (7%). Treatment-emergent somnolence was identified in 14 (25%) patients, and grade 3/4 treatment-related somnolence was reported in 2 (4%) patients. Fourteen (25%) patients discontinued due to AEs. Twenty-two on-study deaths were reported, caused by events unrelated to MLN8237, including progressive disease (46%), and sepsis (14%); of these, 9 deaths from AML occurred within 2 months of study entry. Overall, 6 (13%) responses were observed (all AML patients; response-evaluable population n=45); 5 patients had PR. One CR was documented in a 79-year old female with AML and no prior therapy, who presented with 23% bone marrow blasts at the time of progression from MDS/RAEB-2, and remains in CR through 16 cycles (1 year). Seventeen (49%) AML and 2 MDS (20%) patients achieved stable disease. Ongoing analyses suggest that co-morbidities influenced clinical outcomes. Conclusions: Data suggest that single-agent MLN8237 has anti-leukemia activity with a 13% response rate (all AML) in this clinical study of patients with advanced, mainly pre-treated disease. In patients with rapidly progressive disease, these results indicate that improved outcomes require strategies to enhance both disease control and risk management in early cycles, allowing time needed to achieve clinical benefit from AAK inhibition. These results support further clinical studies of MLN8237 in heme-lymphatic malignancies and solid tumors. Disclosures: Goldberg: Millennium Pharmaceuticals, Inc.: Research Funding. Off Label Use: Investigational agent in clinical development for the treatment of AML/MDS. Fenaux:Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding; GSK Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Craig:Genentech: Membership on an entity's Board of Directors or advisory committees. Gyan:Amgen: Research Funding; Janssen-Cilag: Research Funding; Celegene: Honoraria, Research Funding; Roche: Honoraria. Schiller:Millennium Pharmaceuticals, Inc.: Research Funding. Jung: Millennium Pharmaceuticals, Inc.: Employment. Leonard:Millennium Pharmaceuticals, Inc.: Employment. Fingert:Millennium Pharmaceuticals, Inc.: Employment, Equity Ownership. Westervelt:Novartis: Honoraria; Celgene: Honoraria, Speakers Bureau.

Description: Introduction: Ph+ ALL accounts for 3-5% of pediatric ALL and is associated with improved outcomes when tyrosine kinase inhibitors (TKIs) are added to chemotherapy, with 5-year event-free survival (EFS) and overall survival (OS) of 58-60% and 70-86%, respectively. Ponatinib is a potent third-generation TKI pan-BCR-ABL1 inhibitor that is active against BCR-ABL1 and all identified single resistance mutations, including the gatekeeper alteration, T315I, which confers resistance to other TKIs. Ponatinib has marketing approval in more than 50 countries, which includes the United States and European Union, for adults with chronic-/accelerated-/blast-phase chronic myeloid leukemia or Ph+ ALL that are resistant/intolerant to other TKIs or are T315I+. Ponatinib may also overcome drug resistance in pediatric patients with relapsed or resistant Ph+ ALL. This study will assess the pharmacokinetics, safety, and efficacy of ponatinib in pediatric patients. Methods: This Phase 1/2, single-arm, open-label, multicenter study (NCT04501614) will enroll approximately 18 patients in Phase 1 and 68 patients in Phase 2, including those enrolled in Phase 1 at the recommended Phase 2 dose (RP2D). Patients (aged ≥1 year to ≤21 years) with Ph+ ALL, Ph+ mixed phenotype acute leukemia, or Ph-like ALL (US only) with ABL class lesions will be enrolled. Enrolled patients must have either relapsed or are resistant or intolerant to ≥1 prior therapy with a BCR-ABL1-targeted TKI or have a BCR-ABL1 T315I mutation. Patients 〉16 years must have a Karnofsky performance status ≥50%; patients ≤16 years must have a Lansky Play Scale ≥50%. During Phase 1, prior to availability of an age-appropriate formulation (AAF), patients must weigh ≥30 kg and be able to swallow tablets. The Phase 1 study will establish the RP2D of ponatinib in combination with the chemotherapy backbone using the adult tablet formulation in patients able to swallow tablets. Patients will receive fixed doses of ponatinib based on body weight ranges. The initially selected doses are expected to achieve systemic exposures that approximately match adult exposures after a 30-mg dose. Dose selection for the AAF will be in a separate cohort and informed by the results of a relative bioavailability study in healthy adult volunteers. A rolling 6 design will be used for both cohorts; additional cohorts may be enrolled at lower or higher doses based on the emerging data. In both Phase 1 and Phase 2, patients will receive two 35-day blocks of therapy (reinduction and consolidation). Each block includes 29 days of study treatment consisting of daily ponatinib and a modified United Kingdom ALL R3 chemotherapy backbone regimen, followed by a rest period of at least 6 days with daily ponatinib only. Disease assessment will occur at the end of each block. Patients will undergo an end-of-treatment visit 25 to 30 days after the last dose of study treatment in the consolidation block, or earlier if the patient is proceeding to alternate therapy or optional ponatinib continuation therapy. For the Phase 1 study, the primary endpoint is the RP2D of ponatinib (tablet and AAF) in combination with chemotherapy. Secondary endpoints are complete response (CR) rate at the end of the reinduction block and characterization of BCR-ABL1 domain mutations prior to and following ponatinib treatment. For the Phase 2 study, the primary endpoint is the CR rate at the end of the reinduction block. Secondary endpoints will be summarized descriptively, and include the proportion of patients in continued CR or who achieve CR at the end of consolidation, the proportion with minimal residual disease-negative status