Supplementary appendix

Transcription

1 Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Jain P, Kantarjian H, Jabbour E, et al. Ponatinib as first-line treatment for patients with chronic myeloid leukaemia in chronic phase: a phase 2 study. Lancet Haematol 2015; published online July 31.

2 Supplemental Table-1: Dose intensity and dose modifications with frontline ponatinib. No. (%) or Median [range] Patients with Rx interruptions 43 (85) Patients with >1 interruption 18 (35) Total No. interruptions 70 Median days Rx interrupted [range] 9 [1-48] Patients requiring dose reductions 45 (88)* Median dose [range] 30mg QD [15mg QOD 45mg QD] O ff study (as of June 2014) # All * 33 patients were dose reduced due to adverse events and 12 patients per FDA recommendation; 18 patients required >1 dose reduction All patients dose reduced to 30 mg daily after updated safety information available from PACE trial (Ponatinib in Ph+ ALL and CML Evaluation) # As of June 2014, all patients are taken off study 38 due to FDA concern of increased risk of thromboembolism and 13 due to adverse events.

3 Supplementary Figure Legends Supplementary Figure Transformation free survival (TFS) for all patients treated with ponatinib as initial therapy for chronic phase CML.

4 Supplementary Figure -2 Overall survival (OS) for all patients treated with ponatinib as initial therapy for chronic phase CML.

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6 Page 1 of 32 Ponatinib as Initial Therapy for Patients with Chronic Myeloid Leukemia in Chronic Phase PI: Jorge Cortes Department of Leukemia The University of Texas, MD Anderson Cancer Center

7 Page 2 of 32 TABLE OF CONTENTS 1.0 Objectives Background Purpose Historical Experience Imatinib Mesylate (STI571; Gleevec) in CML Second Generation Tyrosine Kinase Inhibitors as Initial Therapy for CML Proposed Therapy with Ponatinib MDASI Background Drug Information Background Preclinical Pharmacology Studies Preclinical Toxicology Studies Clinical Studies Rationale for Ponatinib in Newly Diagnosed Patients Investigational Product Patient Eligibility Inclusions Exclusions Treatment Plan General Treatment Plan Dose Modifications of Ponatinib Missed Doses...22

8 Page 3 of Duration of Therapy Prohibited and Restricted Therapies During the Study Pretreatment Evaluation Evaluation During Study Criteria for Response Criteria for Removal from the Study Statistical Considerations Reporting Requirements References... 29

9 1.0 Objectives Page 4 of 32 Primary: To estimate the proportion of patients with previously-untreated chronic phase CML attaining complete cytogenetic response (CCyR) at 6 months of treatment with ponatinib. Secondary: To estimate the proportion of patients achieving a CCyR, major molecular response (MMR) and complete molecular response (CMR) at 3, 6, 12, 18 and 24 months of treatment with ponatinib To estimate the time to CCyR, MMR and CMR for patients treated with ponatinib as initial therapy for CML To evaluate the durations of hematologic, cytogenetic and molecular response to ponatinib. To define the time to progression and overall survival for patients with CML in early chronic phase treated with ponatinib. To evaluate the toxicity profile of ponatinib in patients with CML in early chronic phase. To evaluate the probability of developing ABL mutations for patients with CML in early chronic phase treated with ponatinib. To analyze differences in response rates and in prognosis within different risk groups and patient characteristics. To investigate mechanisms of resistance in patients who develop resistance to ponatinib used as initial therapy for CML. To evaluate symptom burden in patients with CML receiving ponatinib Exploratory Objective: To investigate the plasma/serum levels of specific mirnas in CML patients receiving ponatinib as initial therapy for CML in CP. 2.0 Background 2.1 Purpose The basic hypothesis underlying our therapeutic programs in CML is to be able to achieve meaningful and long-lasting suppression of the Philadelphia chromosome and BCR-ABL. Complete cytogenetic responses have been associated with 4

10 Page 5 of 32 improved survival in CML, while major molecular responses are associated with improved event-free survival. 2.2 Historical Experience The prognosis of patients with chronic myelogenous leukemia is improving. 1 Historically, the median survival of untreated patients with CML was 19 months from diagnosis. In our historical experience of 303 patients with a diagnosis of Philadelphia-positive early chronic-phase CML referred to our institution within 3 months of diagnosis with minimal or no prior therapy, the overall median survival was 39 months. 2 Patients were divided into good, intermediate and poor risk groups with different hazard rates and median survivals Imatinib Mesylate (STI571; Gleevec) in CML Imatinib is an inhibitor of the protein-tyrosine kinases associated with Bcr-Abl, the platelet-derived growth factor (PDGF) receptor and c-kit. CML represents an ideal disease target for imatinib, given that the Bcr-Abl kinase plays a dominant role in the deregulated myeloid cell proliferation which is the hallmark of this disease. Imatinib shows selectivity for the Abl protein tyrosine kinase at the in vitro, cellular and in vivo level. 3 The compound specifically inhibits proliferation of Bcr-Abl expressing cells. In colony forming assays using ex vivo peripheral blood and bone marrow samples, imatinib shows selective inhibition of Bcr-Abl positive colonies from CML patients. 3-5 In animal models, the compound shows potent anti-tumor activity against Bcr-Abl and v-abl expressing cells at tolerated doses. In phase I studies, imatinib has demonstrated activity in all CML phases post IFN- failure and in Ph-positive ALL. 6,7 Three large-scale pivotal trials of imatinib in CML chronic, accelerated and blastic phases have been completed In chronic phase CML, 454 evaluable patients who had failed IFN- therapy were treated with imatinib 400 mg orally daily. The CHR rate was above 90%. The complete cytogenetic response rate (Ph-positive less than 35%) was 60%, including a complete response in 41%. Imatinib was well-tolerated. Side effects included nausea, vomiting, diarrhea, skin rashes, muscle cramps, bone and joint aches, and liver dysfunction. Grade 3-4 toxicities requiring discontinuation of therapy occurred in 2% or less of patients. Periorbital and leg edema and fluid retention were frequent at imatinib doses of 600 to 1000 mg orally daily. An open-label, multicenter, randomized phase III study (International Randomized Interferon vs. STI571 [IRIS]) has been conducted in patients with newly diagnosed Ph+ CML. 12 This study compared treatment with either singleagent Imatinib or a combination of IFN plus cytarabine (Ara-C), and allowed for 5

11 Page 6 of 32 crossover for lack of response, loss of response or toxicity. A total of 1106 patients have been randomized from 177 centers in 16 countries, 553 to each arm. The major cytogenetic response rate for patients treated with Imatinib was 83% (68% complete) compared to 20% with IFN and ara-c (7% complete). With the follow-up currently available, the 4-year estimated rate of free of progression was over 90% with imatinib. 13 High-dose imatinib 400 mg orally BID has improved the early incidences of complete cytogenetic and molecular remissions. Its impact on long-term prognosis remains to be determined. 14, Second generation Tyrosine Kinase Inhibitors as Initial Therapy for CML Recently, second generation tyrosine kinase inhibitors have been investigated as initial therapy for CML. Results of two large randomized trials comparing each of these agents to imatinib have been reported. One study, the ENESTnd trial, randomized patients to receive nilotinib in one of two treatment schedules, 300 mg twice daily or 400 mg twice daily, or imatinib at the standard 400 mg daily. 16 The rates of complete cytogenetic response by 12 months (i.e., cumulative rates) were significantly higher for nilotinib (80% and 78% for the two schedules) than for imatinib (65%) (p<0.001). The rates of major molecular response at 12 months were 44% and 43% for the two nilotinib schedules and 22% for imatinib (p<0.001). There was a significant reduction in the rate of transformation to accelerated and blast phase in both nilotinib arms (<1%) compared to the imatinib arm (4%). Toxicity profile was similar or better for the nilotinib arm. However, despite a follow-up of only 14 months, 16% to 18% of patients had been already taken off nilotinib for various reasons, most frequently adverse events or treatment failure. 16 The second study, DASISION, randomized patients to receive dasatinib at a dose of 100mg once daily or imatinib at the standard dose of 400mg once daily. 17 The rate of a complete cytogenetic response by 12 months (i.e., cumulative) was higher with dasatinib than with imatinib (83% vs. 72%, p=0.001) and the rate of confirmed complete cytogenetic response (ie, observed at least twice in a row) was also higher with dasatinib (77% vs. 66%, p=0.007). The rate of major molecular response was higher with dasatinib (46% vs. 28%, p<0.0001). Progression to the accelerated or blastic phase of CML occurred in 1.9% of patients receiving dasatinib and in 3.5% of those who received imatinib. The safety profiles of the two treatments were similar with dasatinib showing higher rates of pleural effusion and thrombocytopenia compared to imatinib. With a median duration of therapy of 14 months, 16% of patients had discontinued therapy with dasatinib, most frequently because of adverse events or failure. 17 A recent analysis of patients treated with dasatinib or nilotinib as initial therapy fro CML demonstrated that early responses are associated with a superior outcome. 18 Patients that achieve a complete cytogenetic response by 6 months of therapy have a 3-year probability of EFS of 97% compared to only 72% for those without a complete cytogenetic response at this time (p<0.001). Similarly, the 6

12 Page 7 of 32 overall survival is significantly better for those with a complete cytogenetic response at 6 months (99%) than those without such response (90%) (p<0.001). 18 These results suggest that improving the rate of complete cytogenetic response as early as 6 months is associated with an improved long-term outcome. Although dasatinib and nilotinib have greatly improved the response rate at 6 months, still only 65% achieve such a response at this early timepoint. 16,17 Options that may improve these results are thus desirable. 2.5 Proposed Therapy with Ponatinib In this study we propose to treat patients with early chronic phase CML with ponatinib. Due to its higher in vitro potency and the lack of induced resistance in induced mutagenesis studies, 19 we hypothesize that ponatinb may be more effective than imatinib in achieving early (i.e., at 6 months) cytogenetic responses in patients with early chronic phase CML. We also hypothesize that responses may be more durable and that development of resistance will be less common. The endpoints of therapy in early chronic phase will be to achieve a CCyR at 6 months of therapy. We will also evaluate the cumulative overall incidence of complete cytogenetic response and the rate of MMR at 12 and 18 months. Recent data suggests that CCyR at 6 months in the era of second generation TKI may be the best predictor of long-term outcome for patients receiving TKI as frontline therapy for their disease. 18 Based on the data from large, randomized trials, the rate of CCyR at 6 months is approximately 65%. The goal of this study would be to determine whether therapy with ponatinib may improve this to at least 80%. We will treat 50 patients in a phase II study. 2.6 MDASI Symptoms are subjective phenomena reported by patients that indicate a change in normal functioning, sensation, or appearance due to disease. Symptom burden is the combined impact of disease- and therapy-related symptoms on the ability of persons to function as they did prior to onset of their disease and/or therapy. The MD Anderson Symptom Inventory (MDASI) is a valid and reliable measure of symptom burden. Recently a CML-specific version of the MDASI, the MDASI- CML, has been validated. Common symptoms of chronic myeloid leukemia (CML) and its treatment can significantly impair the daily functioning of patients. Symptoms such as fatigue, nausea and vomiting, diarrhea, muscle cramps, skin changes, and headache add to the burden of CML. Patients with serious illnesses often report that they would like to return to a normal life. Decreasing the symptom burden of CML and its treatments will allow patients to function as normally as possible. Currently, there is little research on symptoms and their impact on daily functioning experienced by patients with CML to direct interventions that may assist patients in returning to normal. 7

13 Page 8 of 32 We have successfully developed IVR technology for the assessment of multiple symptoms using the MDASI in patients with cancer undergoing chemotherapy, radiation therapy, and surgery. We currently have one active study in a sample of patients with CML, many of whom are receiving kinase inhibitor therapies, using the MDASI-CML. Initial evaluation has shown this to be a feasible option for patient-reported symptom burden assessment in this group of patients and further evaluation is ongoing. The patient chooses the day and the time to receive the IVR system call; the system calls the patient three times if necessary to complete the assessment. 3.0 Background Drug Information 3.1 Background AP24534 (United States Adopted Name [USAN]: ponatinib) is a novel, synthetic, orally-active multi-targeted tyrosine kinase inhibitor (TKI). The primary target for ponatinib is BCR-ABL, an abnormal tyrosine kinase that is the hallmark of chronic myeloid leukemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib was designed using the Sponsor s computational and structure-based drug design platform to inhibit the enzymatic activity of BCR-ABL with very high potency and broad specificity. The agent was intended to target not only native BCR-ABL, but also BCR-ABL isoforms that carry mutations that confer resistance to treatment with existing TKIs, including especially the T315I mutation for which no effective therapy exists. Preclinical data demonstrate that the compound inhibits the activity of all the isoforms tested, as well as the proliferation and survival (in vitro and in vivo) of cell lines expressing known BCR-ABL mutants that confer broad TKI resistance. Clinical data from an ongoing phase 1 trial also suggest clinical activity against resistant BCR-ABL mutants. Thus, ponatinib exhibits broadspectrum inhibition of BCR-ABL mutants; it is a pan-bcr-abl inhibitor. It is proposed to carry out pivotal clinical studies of ponatinib in CML and Ph+ ALL patients resistant or intolerant to therapy with either of the second generation approved TKIs, dasatinib or nilotinib, or who carry the T315I mutation. 3.2 Preclinical Pharmacology Studies A preclinical development program has been completed to support the clinical development of ponatinib. Studies conducted to examine the nonclinical pharmacologic and pharmacodynamic activity of ponatinib (O Hare et al., 2009) are summarized below. In vitro kinase assays demonstrated that ponatinib inhibits native BCR-ABL and all 5 mutants tested, including T315I, with 50% inhibitory concentration (IC50) of 0.37 to 2.0 nm. Ponatinib also inhibited the activity of other TKIs in vitro with IC50 < 10 nm including members of the SRC, vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR) families (Table 0-1). 8

14 Page 9 of 32 Table 0-1 Kinase Inhibition Profile of Ponatinib for Native ABL, ABL T315I, and Selected Kinases Kinase IC 50 (nm) ABL 0.37 ABL T ABL Q252H 0.44 ABL Y253F 0.30 ABL M351T 0.30 ABL H396P 0.34 c-src 5.4 LYN 0.24 c-kit 12.5 VEGFR2 1.5 FGFR1 2.2 PDGFRα 1.1 IR >1000 IGF-1R >1000 Aurora A >1000 CDK2/Cyclin E >1000 In cellular assays, ponatinib inhibited proliferation of Ba/F3 cells expressing native BCR-ABL and all 14 clinically relevant mutants tested, including T315I, with IC50 of 0.5 to 36 nm (Table 0-2). Ponatinib also inhibited the phosphorylation of BCR-ABL, as well as the direct BCR-ABL substrate CrkL. In assays using primary cells derived from CML patients with T315I mutant BCR- ABL, ponatinib inhibited cell growth, colony formation and levels of phosphorylated CrkL. Table 0-2 Ponatinib IC 50 Values for Ba/F3 Cellular Proliferation Assays and CML and Non-CML Cellular Proliferation Assays Ba/F3 Cell Proliferation Assay IC 50 (nm) BCR-ABL Ponatinib Imatinib Nilotinib Dasatinib Native M244V G250E Q252H Y253F Y253H 6.2 > E255K E255V 36 > T315A

15 Page 10 of 32 T315I 11 >6400 >2000 >200 F317L F317V nd 53 M351T F359V H396P Parental 1713 >6400 >2000 >200 O Hare T. et al (2005) Cancer Res. 65: O Hare T. et al (2007) Blood. 110: O Hare T. et al (2009) Cancer Cell. 16: Ba/F3 cells expressing T315I BCR-ABL were used to test the antitumor activity of ponatinib in vivo. In a xenograft model, in which cells were injected SC, significant inhibition of tumor growth occurred with daily oral dosing of ponatinib at doses of > 10 mg/kg. Inhibition of BCR-ABL and CrkL phosphorylation was observed in tumors from mice treated with ponatinib. In a survival model, in which cells were injected intravenously, daily oral administration of ponatinib significantly improved survival at doses as low as 5 mg/kg. Ponatinib also improved survival significantly when Ba/F3 cells expressing native BCR-ABL were injected. To identify mutations that may confer resistance to ponatinib a mutagenesis screen was performed using Ba/F3 cells expressing native BCR-ABL. This screen has successfully identified clinically relevant mutations that confer resistance to other BCR-ABL inhibitors (Bradeen et al., 2006). When the selection was performed in the presence of 40 nm ponatinib, outgrowth of resistant clones was suppressed completely (Figure 0-1). Thus, by this assessment, ponatinib appears to be a pan-bcr-abl inhibitor. Since exposure of cells to 40 nm suppressed the emergence of any resistant mutants, and since this concentration had potent activity against all individual mutants tested in Ba/F3 cells, including T315I, 40 nm can be considered a target efficacious trough concentration. Figure 0-1 Single-Agent Ponatinib (AP24354) Completely Suppresses Resistant Outgrowth in Cell-Based Mutagenesis Screens 10

16 Page 11 of 32 (A) Resistant clones recovered from ENU-treated Ba/F3 cells starting from native BCR-ABL cultured with graded concentrations of ponatinib (10, 20, 40 nm). Each bar represents the relative percentage of the indicated BCR-ABL kinase domain mutant among recovered subclones. Since the percentage of surviving resistant subclones and the concentration of ponatinib are inversely related, a different number of sequenced subclones are represented in the graph for each concentration of ponatinib. The percent of wells surveyed that contained outgrowth is indicated to the right of each graph. In summary, these studies demonstrate ponatinib is an orally-active multi-target TKI that inhibits, with high potency, native BCR-ABL and all mutants tested. In vitro and in vivo absorption, distribution, metabolism, and excretion (ADME) studies have been performed to understand the pharmacokinetics (PK) and metabolism of ponatinib. Ponatinib was bioavailable after oral administration to mice, rats and cynomolgus monkeys. The absolute bioavailability after an oral dose was 18.2% and 20.6%, respectively, in rats and monkeys. The blood clearance of ponatinib was low, approximately 17% of the hepatic blood flow in both rats and monkeys. The steady state volume of distribution (Vss) was large, indicating that ponatinib was extensively distributed in extravascular compartments. The terminal half-life (t½) after an intravenous (IV) dose was 10.2 and 5.3 hours, respectively, in rats and monkeys. In vitro, ponatinib was very highly bound to plasma proteins (>99%) of mice, rats, monkeys and humans, and did not show preferential partitioning into red 11

17 Page 12 of 32 blood cells (RBCs) in whole blood. Ponatinib is most likely to be a permeability glycoprotein (P-gp) substrate based on the Caco-2 model. In vitro, ponatinib was metabolized to mainly AP24567 (N-desmethyl metabolite), and to a lesser extent to AP24734 (N-oxide). There were other mono-oxygenated metabolites whose contribution to the overall metabolism was insignificant. CYP3A4 was the major Cytochrome P450 isozyme responsible for the metabolism of ponatinib. In rat and monkey plasma also AP24567 and AP24734 were the principal metabolites. In mouse plasma, AP24567 was found to be a major metabolite. Ponatinib is a substrate of CYP3A4, and is an inhibitor of CYPs 3A4, 2D6 and 2C19. It is likely that ponatinib might cause drug-drug interaction (DDI) with CYP3A4 inhibitors and substrates of CYPs 3A4/5, 2D6 and 2C19. Overall, the metabolism of ponatinib in rats and monkeys (both in vivo and in vitro) was qualitatively similar to the metabolism of ponatinib in human liver microsomes and hepatocytes. All human in vitro metabolites were also present in the toxicological species, rat and monkey. 3.3 Preclinical Toxicology Studies The safety of ponatinib has been investigated in laboratory animals and in in vitro systems. These investigations included single oral dose toxicology studies in mice, rats and cynomolgus monkeys, as well as 28-day and 6-month oral dose toxicology studies in rats and cynomolgus monkeys. In addition, the mutagenic potential of ponatinib was evaluated in an in vitro reverse mutation assay, an in vitro chromosomal aberration assay, and in an in vivo micronucleus test in mice. A safety pharmacology program was also completed to determine the potential effects of ponatinib on the nervous, renal, pulmonary, gastrointestinal, and cardiovascular systems. Cardiovascular evaluations included in vitro effects on the human ether-a-go-go related gene (herg) and an in vivo study in conscious telemetered dogs. The rat was shown to be the most sensitive species to the toxicologic effects of ponatinib based on both single dose and multiple dose regimens. Rats tolerated single oral doses of 10 mg/kg with mortality occurring at single oral doses of 30 mg/kg and greater. Mice tolerated single oral doses of 500 mg/kg and cynomolgus monkeys tolerated single oral doses of 45 mg/kg (the highest dose tested). In the 28-day oral toxicology study rats did not tolerate dose levels of 3 and 6 mg/kg with death/moribundicity occurring in 11 and 24% of the animals, respectively. In addition, 1 death occurred in the low dose group of 1.5 mg/kg/day on the last day of the dosing period for which a drug-related cause of death could not be ruled out. In the 28-day oral toxicity study in cynomolgus monkeys, an oral dose of 5 mg/kg/day was not tolerated, with mortality/moribundicity occurring in 3 of 10 animals during the last 2 weeks of 12

18 Page 13 of 32 the study. Histologic pancreatic changes observed in monkeys at the 5 mg/kg/day dose level included acinar cell necrosis, fibrosis and atrophy with a corresponding elevation in serum lipase level. The low- (1 mg/kg/day) and mid- (2.5 mg/kg/day) dose levels were tolerated by the monkeys with the exception of a mid-dose animal who appeared in poor physical condition toward the end of the dosing period. In the 6-month oral toxicology study in rats, the no observed adverse effect level (NOAEL) was 0.25 mg/kg/day. Higher dose levels of 0.75 and 2 mg/kg/day caused mortality of some animals, and decreased body weight and food consumption relative to control. Histologic examination revealed decreased numbers of chondrocytes along the physis in the femur at the 0.75 and 2 mg/kg/day dose levels, and lymphoid depletion was observed in the thymus at the 2 mg/kg/day dose level. The observation in the femur appears to be species specific since it was not observed in the nonhuman primate studies. Another histologic observation in the 6-month rat study was a higher frequency and severity of chronic progressive nephropathy in the 2 mg/kg/day dose group in comparison with the vehicle control and lower dose group observations. Chronic progressive nephropathy is a normal age-related finding in rats; however, the higher incidence and severity of this observation in the high dose group suggests a drug-related exacerbation of this normal occurrence. Because chronic progressive nephropathy is a rodent specific entity, the observation of a chemically-related exacerbation is routinely regarded as having no relevance for extrapolation in human risk assessment. The administration of ponatinib to cynomolgus monkeys for 6 months at oral dose levels of 0.25, 0.75 and 2 mg/kg/day was well-tolerated with no ponatinib-related microscopic findings being observed at any dose level. Ponatinib was shown to be non-mutagenic in the 3 mutagenicity assays that were performed, and the drug was shown to have a favorable safety pharmacology profile. 3.4 Clinical Studies Overview of Ponatinib Phase 1 A Phase 1 clinical trial of ponatinib is ongoing (Cortes et al., 2009; Talpaz et al., 2010). The objectives of this study are to assess the safety of ponatinib, establish a maximum tolerated dose (MTD) and a schedule for further investigation, and provide preliminary assessments of clinical activity. As of July 22 nd 2011, 81 patients with refractory or advanced CML and other refractory hematologic malignancies were enrolled and treated with a single oral daily dose of ponatinib capsules at doses ranging from 2 mg to 60 mg. These data were presented at the International CML Foundation Meeting in Estoril, Portugal (Cortes et al., 2011). 13

19 Page 14 of Demographics and Safety Data Patient diagnoses include 60 with CML (43 CP, 9 AP, 8 blast phase [BP]) and 5 with Ph+ ALL. The study consists of heavily pretreated patients. Prior therapies in Ph+ patients included imatinib (97%), dasatinib (86%), nilotinib (56%), and other standard and investigational therapies; 94% of the Ph+ patients failed 2 prior TKIs, 63% failed 3 or more TKIs. BCR-ABL mutations were reported in 65% of Ph+ patients entering the study. Dosing began with 2 mg capsules and escalated up to 60 mg. At doses up to and including 30 mg there were no dose-limiting toxicities (DLTs). In the 45 mg cohort, consisting of 12 evaluable patients, a single DLT was identified grade 3 rash. In the 60 mg cohort, DLTs of chemical and clinical pancreatitis were identified in 4 of 12 patients. Thus, employing the capsule formulation of ponatinib 45 mg is the MTD. Over all doses studied, ponatinib was well-tolerated with most treatment-related AEs (TRAEs) reported as either grade 1 or 2. Treatment-related AEs of any grade that occurred in more than 10% of patients were: thrombocytopenia (25%); anemia (12%); lipase increased (12%); nausea (12%); rash (12%); arthralgia (11%); fatigue (11%); and pancreatitis (11%). Treatment-related hematologic AEs included: anemia of any grade experienced by 7 patients (12%; grade 3: n=1 [2%]; grade 4: n=0); platelet count decreased of any grade experienced by 14 patients (25%; grade 3: n=4 [7%]; grade 4: n=5 [9%]); and neutrophil count decreased of any grade experienced by 4 patients (7%; grade 3: n=0, grade 4: n=1 [2%]). Lipase increased (n=4), blood amylase increased (n=2), pancreatitis (n=2), ECG QT prolonged (n=1), hyperglycaemia (n=1), dyspnoea (n=1), hypokalaemia (n=1), migraine (n=1), abdominal distension (n=1), pain (n=1), abdominal pain (n=1), and blast cell crisis (n=1) were the only nonhematologic TRAEs that were either grade 3 or 4. Most of the grade 3 or 4 TRAEs were reversed when managed with temporary drug holds and/or dose reductions Anti-Leukemia Activity Data Evidence of anti-leukemic and pharmacodynamic activity following ponatinib administration has emerged in this trial. Among the 43 CP CML patients evaluable for hematologic response, 42 (98%) achieved a complete hematologic response (CHR). In addition, 31 (72%) attained a major cytogenetic response (MCyR) and 27 (63%) achieved a complete cytogenetic response (CCyR) as their best response. There were 12 patients with CP CML with the T315I mutation evaluable for response: all 12 (100%) experienced a CHR; 11 (92%) attained a MCyR, of which 9 (75%) had a CCyR and 2 had a PCyR. Patients with AP or blast phase 14

20 Page 15 of 32 (BP) CML or Ph+ ALL were grouped together. Twenty-two patients in this group were evaluable for response, 7 of which had the T315I mutation. Of the 22 patients with AP, BP, or Ph+ ALL, 9 (41%) had major hematologic responses (MaHR), 7 (32%) had a MCyR, and 3 (14%) had a CCyR. Of the 7 patients with the T315I mutation in the advanced group, 2 (29%) had MaHR, 2(29%) had a MCyR, 1 (14%) had a CCyR, and 1 (14%) had a PCyR. For patients in CP by 6 months 57% of patients had achieved a major cytogenetic response, and it increased to 69% by 12 months of therapy Phase II Study A multi-center phase II study of ponatinib for patients with CML or Ph+ ALL who have failed prior therapy with nilotinib or dasatinib has recently completed accrual. The primary endpoint of the study was to determine the efficacy of ponatinib in this patient population. A total of 450 patients were included in this trial and the accrual was completed ahead of schedule. The preliminary results of this study are anticipated by December of Rationale for Ponatinib in Newly Diagnosed Patients Despite significant progress in the treatment of patients with CML in chronic phase, there is still need to improve the therapy further to reach the goal of disease eradication for all patients. Achieving a complete cytogenetic response is the most important treatment goal as it is associated with improved survival. With imatinib, approximately 45% of patients achieve a CCyR by 6 months and 65% by 12 months. With the second generation tyrosine kinase inhibitors the responses are higher. But still only 63-65% achieve this response by 6 months and 78-80% by 12 months with nilotinib. Corresponding figures for dasatinib are 73% at 6 months and 83% at 12 months. In addition, approximately 20% of patients have discontinued dasatinib or nilotinib for various reasons in these studies. Improving these rates of early responses is very important to optimize long-term outcomes. In addition, studies in vitro have shown that resistant clones have not emerged in induced mutagenesis assays when exposed to ponatinib at concentrations that are achieved in vivo. In contrast, resistant clones emerge with nilotinib or dasatinib and even more frequently with imatinib in similar assays. We thus hypothesize that ponatinib will lead to higher rates of early response and that, in the long term, the ability to induce early responses and the lack of resistance emerging in vitro, will translate into an improved event-free, transformation-free, and overall survival for patients with CML. 3.6 Investigational Product 15

21 3.6.1 Formulation, Packaging, and Labeling Page 16 of 32 Ponatinib drug product is manufactured as tablets. Each tablet contains either 15 mg or 45 mg of ponatinib active ingredient. Other ingredients are typical pharmaceutical excipients (lactose monohydrate, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, polyethylene glycol, talc, polyvinyl alcohol, and titanium dioxide). Tablets will be supplied as follows: 45 mg tablets: 30 count in 30 cc white high density polyethylene (HDPE) bottles with induction-sealed child resistant caps. 15 mg tablets: 60 count in 30 cc white HDPE bottles with inductionsealed child resistant caps. Note: 15 mg tablets will be used for patients reducing dose. Bottle labels will bear the appropriate label text as required by governing regulatory agencies. At a minimum, such text will include product name, product strength, number of tablets, and lot number Storage and Stability The recommended storage condition for ponatinib is room temperature. Drug Disposal: Unused/expired drug will be disposed of onsite following institutional guidelines. 4.0 Patient Eligibility 4.1 Inclusions: Diagnosis of Ph-positive (by cytogenetics or FISH) or Bcr-ABL-positive (by PCR) CML in early chronic phase CML (i.e., time from diagnosis 6 months) Patients must have received no or minimal prior therapy, defined as 1 month of prior IFN-α (with or without ara-c) and/or an FDA-approved tyrosine kinase inhibitor (e.g, dasatinib, nilotinib). Prior use of hydroxyurea or anagrelide is allowed with no limitations Age >18 years ECOG performance of Adequate end organ function, defined as the following: total bilirubin <1.5x ULN, SGPT <2.5x ULN, creatinine clearance (CrCl) >/= 30 16

22 Page 17 of 32 ml/min at screening (calculation according to Cockroft & Gault formula) Patients must sign an informed consent indicating they are aware of the investigational nature of this study, in keeping with the policies of the hospital Women of pregnancy potential must practice an effective method of birth control during the course of the study, in a manner such that risk of failure is minimized. Prior to study enrollment, women of childbearing potential (WOCBP) must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. In addition, men enrolled on this study should understand the risks to any sexual partner of childbearing potential and should practice an effective method of birth control. Adequate forms of contraception are barrier methods (e.g., condoms, diaphragm), oral, depo provera, or injectable contraceptives, intrauterine devices, spermicidal jelly or foam, abstinence, and tubal ligation. Women and men must continue birth control for the duration of the trial and at least 3 months after the last dose of study drug. All WOCBP MUST have a negative serum or urine pregnancy test within 7 days prior to first receiving investigational product. If the pregnancy test is positive, the patient must not receive investigational product and must not be enrolled in the study. 4.2 Exclusions: NYHA cardiac class 3-4 heart disease Cardiac Symptoms: Patients meeting the following criteria are not eligible: Unstable angina or myocardial infarction within 3 months Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes). Prolonged QTc interval on pre-entry electrocardiogram (> 470 msec) on both the Fridericia and Bazett s correction. Symptomatic congestive heart failure within 3 months prior to first dose of ponatinib (NYHA class III or IV) Patients with active, uncontrolled psychiatric disorders including: psychosis, major depression, and bipolar disorders Pregnant or breast-feeding women are excluded. 17

23 4.2.5 Patients with history of pancreatitis Page 18 of Treatment Plan Patients in late chronic phase (i.e., time from diagnosis to treatment >6 months), or blast phase are excluded. The definitions of CML phases are as follows: a. Early chronic phase: time from diagnosis to therapy 6 months b. Late chronic phase: time from diagnosis to therapy > 6 months c. Blastic phase: presence of 30% blasts or more in the peripheral blood or bone marrow. d. Accelerated phase CML: presence of any of the following features: Peripheral or marrow blasts 15% or more Peripheral or marrow basophils 20% or more Thrombocytopenia < 100 x 10 9 /L unrelated to therapy Documented extramedullary blastic disease outside liver or spleen e. Clonal evolution defined as the presence of additional chromosomal abnormalities other than the Ph chromosome has been historically been included as a criterion for accelerated phase. However, patients with clonal evolution as the only criterion of accelerated phase have a significantly better prognosis, and when present at diagnosis may not impact the prognosis at all. Thus, patients with clonal evolution and no other criteria for accelerated phase will be eligible for this study. 5.1 General All patients should be registered with the Data Management Office PDMS system. 5.2 Treatment Plan Patients will receive ponatinib therapy according to the suggested guidelines below. Individual minor variations in the initiation of therapy, WBC count at start of therapy, are acceptable as indicated by patient condition and physician judgment CML Debulking: patients may receive hydroxyurea for debulking before and during the first 6 weeks of therapy. Patients who cannot take hydroxyurea may receive other agents such as 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) for up to 6 weeks Therapy: Patients will receive ponatinib at a dose of 45 mg orally, once 18

24 Page 19 of 32 daily. If a dose is missed or vomited, the next dose should not be increased to account for missing a dose Dose Adjustments: Dose adjustments will be done as described below using the following dose-levels: Dose Level* Dose of ponatinib in mg/day mg 0 45 mg mg mg mg every other day * Dose reductions will be done based on the closest possible strength of the pill. Dose escalations/reductions above or below those described in this table should be discussed with PI or Co-PI. 5.3 Dose Modifications of Ponatinib General guidelines include the following: a) Non-Hematologic Toxicity Grade 2: Patients with persistent ponatinib-related grade 2 toxicity that is considered clinically significant, unresponsive to appropriate therapy, may have treatment held until the toxicity has resolved to grade <1. Ponatinib may then be resumed at the same dose the patient was receiving at the time treatment was interrupted. If the grade 2 toxicity recurs, ponatinib may be held until the toxicity has resolved to grade 1. Treatment may then be resumed with a one dose level reduction. Grade 3-4: If a patient experiences Grade 3-4 toxicity that is considered clinically significant and related to ponatinib, therapy must be withheld until the toxicity has resolved to Grade < 1. Ponatinib may then be resumed with a one dose level reduction. If grade 3-4 toxicity recurs, the same process can be implemented with subsequent dose reductions. b) Pancreatitis Grade 2 (elevated amylase or lipase only): see amylase/lipase section below. Grade 2 (mild symptoms or radiologic findings): Hold ponatinib and consider performing (if clinically indicated) ultrasound or abdominal CT scan with contrast if the patient is not allergic to or intolerant to contrast or has contraindications 19

25 Page 20 of 32 for contrast. When resolved to grade </=1, resume at the dose the patient was receiving at the time treatment was interrupted. If recurrent at this dose level repeat above, except resume at one dose level reduction after recovery to grade 1. If recurrent at the reduced dose repeat above, except resume at a second dose level reduction after recovery to grade 1. If recurrent at the second dose reduction consider discontinuing ponatinib. Grade 3: Hold ponatinib and consider performing (if clinically indicated) ultrasound or abdominal CT scan with contrast if the patient is not allergic to or intolerant of contrast or has contraindications for contrast. After recovery to grade </= 1, resume at one dose level reduction the patient was receiving at the time treatment was interrupted. If negative, or after resolution by imaging, resume at a one dose level reduction after recovery to grade 1. If recurrent at the one dose level reduction repeat above, except resume at a second dose level reduction after recovery to grade 1. If recurrent at that dose consider discontinuing ponatinib. Grade 4: Hold ponatinib. Consult with PI and sponsor to decide on resumption of therapy. c) Amylase/lipase Grade 2: No intervention. Grade 3 or 4: Hold ponatinib. Consider performing ultrasound or abdominal CT scan with contrast if the patient is not allergic to or intolerant to contrast or has contraindications for contrast. If imaging positive, continue holding ponatinib and repeat according to clinical care. If negative, or after resolution by imaging and/or after recovery to grade </= 1, resume at the same dose the patient was receiving at the time treatment was interrupted. If recurrent at this dose level repeat above, except resume at one dose level reduction after recovery to grade 1. If recurrent at the reduced dose repeat above, except resume at a second dose level reduction after recovery to grade 1. If recurrent at the 2 nd dose reduction consider discontinuing ponatinib. d) Hematologic Toxicity If granulocytes are < 0.5 x 10 9 /L or platelets are < 40 x 10 9 /L, hold therapy until granulocytes are above 10 9 /L and platelets are above 60 x 10 9 /l, then resume therapy. 20

26 Page 21 of 32 If recovery takes more than 2 weeks, resume ponatinib at 1 dose level reduction from the dose the patient was receiving at the time therapy was interrupted. If recovery takes less than 2 weeks, resume ponatinib at the same dose the patient was receiving at the time treatment was interrupted. If myelosuppression recurs, resume ponatinib at one dose level reduction from the dose the patient was receiving at the time the treatment was interrupted. If a similar degree of toxicity returns, a further dose reduction by one dose level can be performed, using the above procedures. e) Modifications of dose schedules other than the above will be allowed within the following guidelines: Further dose reductions can be made to keep clinically significant ponatinib-related toxicity grade < 2. However, the lowest acceptable dose is 15 mg/every other day. Dose adjustments by more than 1 dose level at a time (e.g., from 45 mg daily to 15 mg) can be considered when judged in the best interest of the patient (e.g., neutropenia with sepsis, bleeding requiring platelet transfusions) when toxicity has resolved. The reason for this reduction will be discussed with the PI or Co PI and documented in the medical record. A patient who has had a dose reduction because of any of the reasons mentioned above may have their dose escalated provided the patient has remained free of toxicity requiring dose adjustments as defined above for at least 1 month. Escalation will be made by 1 dose-level increments only, and not more frequent than every month. The maximum allowable daily dose of ponatinib is 60 mg, to be possibly used in patients resistant to lower levels Dose Escalations Patients who do not achieve a complete cytogenetic response after 6 months or a major molecular response after 12 months of therapy and have experienced no grade 3 ponatinib-related toxicity may have their doses escalated to dose level +1 (i.e., 60 mg daily). Patients who have had a prior dose reduction of ponatinib and who have no toxicity for at least 1 month of therapy may increase the dose of ponatinib following the 21

27 guidelines mentioned above Page 22 of Missed Doses Occasional missed doses will not be considered a deviation. Missed doses of 2 weeks with no proper justification will be considered a protocol deviation. 5.5 Duration of Therapy Total duration of therapy will be 3 to 5 years. Subsequent changes of duration of treatment will depend on the earlier analyses of data from this study and other earlier studies with ponatinib in CML (eg, after TKI failure) Consider holding therapy if BCR-ABL is undetectable continuously over 2 years. 5.6 Prohibited and Restricted Therapies During the Study Prohibited Therapies No other therapy for the treatment of CML, with the exception of anagrelide hydrochloride and/or hydroxyurea (or 6-MP or 6-TG in patients that cannot take hydroxyurea), will be permitted while the patient is on study. Hydroxyurea and/or anagrelide use should be limited to approximately the first 6 weeks duration whenever possible. Use of anagrelide and hydroxyurea, as well as colony-stimulating factors (e.g., G- CSF, GM-CSF, etc) and erythropoietin, is permitted at the discretion of the investigator Restricted Therapies 6.0 Pretreatment Evaluation Ideally, subjects enrolled in this study should not be taking and not begin taking medications known to prolong the QT interval. However, should the investigator believe that beginning therapy with a potentially QT prolonging medication (other than the ones explicitly prohibited) is vital to an individual subject s care, additional ECG(s) will be done as clinically indicated. Caution is warranted when administering ponatinib in combination with drugs that are potent substrates, inhibitors or inducers of CYP3A4, but these drugs are not prohibited. The following should be done within 1 week (+/- 3 days) of start of study drug unless otherwise specified. 6.1 A complete history and physical examination including performance status. 22

28 Page 23 of CBC, platelet count and differential (differential not required if WBC <0.5 x 10 9 /L), total bilirubin, SGPT, and creatinine within 1 week. 6.3 Bone marrow aspirate for morphology and cytogenetics or FISH (if not done within 3 months). 6.4 EKG within 2 weeks. 6.5 Pregnancy test (blood or urine) for female patients of childbearing potential within 7 days before initiation of study drug dosing. 6.6 Peripheral blood or bone marrow for quantitative PCR (QPCR) (if not done within 2 weeks). 6.7 mirna analysis (optional*): one single blood sample (5cc) will be collected only by EDTA or citrate (Dr. Calin's lab at MD Anderson Cancer Center). 6.8 MDASI-CML and single item quality of life (QOL) rating completed by patient (optional*). * Missed collection of any of the optional procedures will not be considered a protocol deviation or violation. 7.0 Evaluation During Study 7.1 Physical exam and evaluation of toxicity every 3 months (±1 month) for the first year then every 6 to 12 months (±1 month). 7.2 CBC, platelet, differential every 1-2 weeks for 4 weeks, every 4-6 weeks until 1 year from the start of therapy, then every 3-4 months until 2 years (±1 month), then every 4 to 6 months thereafter (1 month). Differential not required if WBC 0.5 x 10 9 /L. 7.3 Bone marrow aspirate with cytogenetics or FISH every 3-4 months in year 1 (±1 month), then every 6-12 months until 3 years, then every 2-3 years ( 1 month). 7.4 Total bilirubin, SGPT or SGOT, amylase, lipase and creatinine every 1-2 weeks for 1 month then every 4-6 weeks until 1 year from the start of therapy, then every 3-4 months until 2 years (±1 month), then every 4 to 6 months thereafter ( 1 month). 7.5 EKGs to be done approximately every 3 months until month 12 from the start of therapy. 7.6 Adherence to the prescribed therapy will be verified by diary returned at each 23

29 Page 24 of 32 clinic visit or verbally by patient interview at each clinic visit (Appendix C). Returned study drug will be destroyed in accordance with institutional policies. 7.7 Peripheral blood or bone marrow for quantitative PCR (QPCR) every 3-4 months for 1 year (±1 month) then every 6-12 months ( 1 month). 7.8 mirna analysis (optional*): one single blood sample (5cc) (only by EDTA or citrate) will be collected at the time of any or all scheduled blood collections when PCR is scheduled (Dr. Calin's lab at MD Anderson Cancer Center). 7.9 MDASI CML weekly during the first three months of treatment, then every other week for the remainder of the study. MDASI-CML will be collected by paper, computer, or IVR system. Patients will be instructed during the first visit on the use of the Interactive Voice Response (IVR) system (optional*). Reliable telephone access to receive calls from an interactive voice response system (IVR) (only applicable to patients who will participate in optional symptom burden assessment) Single item QOL at each clinic visit during study (optional*) CBC, blood chemistries, EKG s may be done at outside facilities. Under exceptional circumstances other tests might be done at outside facilities after discussion with PI Patients that come off therapy will continue follow-up for toxicity (clinic visit or telephone interview) for 30 days (+/- 5 days) after end of therapy. * Every effort will be made to collect optional procedures at all time points for all patients; however, missing collection in one or more of these time points in occasional patients will not be considered a protocol deviation/violation. 8.0 Criteria for Response 8.1 Complete Hematologic Remission (CHR) - normalization for at least 4 weeks of the bone marrow (less than 5% blasts) and peripheral blood with WBC < 10 x 10 9 /L and no peripheral blasts, promyelocytes or myelocytes. This is in addition to disappearance of all signs and symptoms of the disease. 8.2 Partial Hematologic Response (PHR) - CHR except for persistence of immature cells (myelocytes, metamyelocytes), or splenomegaly < 50% of pretreatment, or thrombocytosis >450x10 9 /L but <50% of pretreatment. 8.3 Complete hematologic remission will further be classified according to suppression of the Philadelphia chromosome (Ph) by cytogenetics (FISH if cytogenetic analysis not informative, e.g., insufficient metaphases) 24