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INNO-406, an oral dual Abl/Lyn tyrosine kinase inhibitor (TKI), demonstrates specific Lyn kinase activity with no or limited activity against other Src-family member kinases. Several Bcr-Abl kinase domain mutations are sensitive to INNO-406 in vitro, including the F317L and F317V mutations. In this study, we evaluated INNO-406 in Philadelphia (Ph) chromosome–positive chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) post-imatinib resistance or intolerance.
A dose escalation study was conducted with a starting dose of 30mg administered orally once daily. Cohorts of at least 3 patients were treated at each dose level until the maximum tolerated dose (MTD) was reached. Twice-daily (BID) dosing was also evaluated. Therapy was allowed for a maximum of 24 months.
INNO-406 was administered to 56 patients with imatinib resistance (n=40) or intolerance (n=16). Other previous treatments included nilotinib (n=20), dasatinib (n=26), and dasatinib/nilotinib (n=9). Common mutations upon study entry included Y253H (n=6), G250E (n=4), T315I (n=4) and F317L (n=3). Among 31 patients with CML in chronic phase treated with INNO-406, the major cytogenetic response rate was 19%. In this study, no responses were seen in patients with CML-AP, CML-BP, or Ph-positive ALL. Dose-limiting toxicities (DLTs) at INNO-406 480mg BID were liver function abnormalities and thrombocytopenia.
INNO-406 showed anti-CML efficacy in this heavily pretreated study population. Based on the classical determinations of both DLT and MTD, the recommended phase 2 dose of INNO-406 is 240mg orally BID. Lower doses of INNO-406 may be equally effective and should be explored.
Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder in which ≥95% of patients display a reciprocal translocation between chromosomes 9 and 22. The resulting Philadelphia (Ph) chromosome abnormality yields a fusion gene encoding a constitutively active Bcr-Abl tyrosine kinase that is considered essential for the pathophysiology of CML.1, 2
In the United States, about 5000 people are diagnosed with CML each year.3 Historically, the 5-year survival rate for patients with CML in chronic phase (CML-CP) was approximately 40%.4 Since the introduction in 2001 of the first specific Bcr-Abl tyrosine kinase inhibitor (TKI), imatinib mesylate, the estimated 5 to 7-year survival rates for newly diagnosed patients with CML-CP have increased to over 90%.5-8 As patients with CML live longer, prevalence of the disease is expected to increase over the coming years.
The success of imatinib demonstrates that specific inhibition of Bcr-Abl kinase has clinical benefits in the treatment of CML. However, based on the findings of a 5-year follow up assessment, imatinib resistance occurs at a rate of approximately 4% per year.7, 8 Resistance is believed to be due to 3 main mechanisms: (1) increased expression of Bcr-Abl; (2) Bcr-Abl mutations; and (3) the development of Bcr-Abl-independent resistance pathways, such as Lyn kinase activation.6, 9, 10 In patients with Ph-positive acute lymphocytic leukemia (ALL), or those with CML in accelerated phase (CML-AP) or blastic phase (CML-BP), imatinib treatment often fails to achieve high rates of complete cytogenetic response; these patients frequently develop resistance to therapy and relapse. In 20% to 55% of such patients, treatment resistance can be attributed to the emergence of clones with mutant forms of Bcr-Abl, which exhibit a decreased sensitivity to imatinib. More than 60 mutant forms of Bcr-Abl have been detected,11-14 the most common of which are E255K, T315I, and M351T. Mutants have varying degrees of imatinib resistance,15-17 and thus more potent Bcr-Abl inhibitors or dual Abl/Lyn inhibitors may improve treatment results.
INNO-406, a dual Abl/Lyn tyrosine kinase inhibitor, may be an effective treatment for certain leukemias (Ph-positive CML and ALL). INNO-406, was developed to overcome imatinib resistance.11, 12 Unlike other second-generation TKIs, INNO-406 demonstrates specific Lyn kinase activity with no or limited activity against other Src-family member kinases. Numerous Bcr-Abl kinase domain mutations are sensitive to INNO-406 in vitro, including the F317L and F317V mutations. INNO-406 is 25 to 55 times more potent than imatinib against Bcr-Abl-positive leukemic cell lines K562 and KU812 and against BaF3 cells overexpressing unmutated Bcr-Abl (BaF3/um). Autophosphorylation of unmutated Bcr-Abl is also more potently inhibited by INNO-406 than by imatinib. In vivo, INNO-406 is at least 10 times more potent than imatinib.18, 19 Chemically, INNO-406 is a 2-phenlaminopyrimidine with structural resemblance to both imatinib and nilotinib. The molecular structure of INNO-406 is shown in Figure 1.
This phase 1, open-label, nonrandomized dose-escalation study was conducted at 6 international sites from July 17, 2006, to November 28, 2007, to determine the safety, tolerability, pharmacokinetic profile, and clinical activity of INNO-406 administered orally daily in adult patients with Ph-positive CML or ALL post-imatinib resistance or intolerance.
Patients with Ph-positive leukemias, including CML-CP, CML-AP, CML-BP, and Ph-positive ALL), and imatinib resistance or intolerance were included in the trial. The definitions of imatinib resistance and intolerance were as previously described.20-23 Imatinib resistance was classified as either hematologic (white cell count greater than or equal to 15,000 cells/mm3, documented on 2 occasions separated by at least 2 week) or cytogenetic (greater than 35% of Ph-positive cells in the bone marrow after at least 1 year of therapy, or an absolute rise in the percentage of Ph-positive cells of 30% over best response). Imatinib intolerance was defined as the presence of any toxicity that prevented patients from receiving therapy (according to the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events version 3.0 [CTCAE v3.0] grade 3 or 4 toxicity or persistent grade 2 toxicity). Patients with resistance or intolerance to other second-line TKIs, such as dasatinib or nilotinib, were also included. Definitions of CML phases were as previously reported.20-23
To be enrolled in the study, patients had to be 18 years of age or older, have an Eastern Cooperative Oncology Group (ECOG) score of 0-2, and have normal cardiac, hepatic, and renal functions. Females enrolled in the study could not be pregnant or lactating. Patients were not allowed to have received chemotherapy within 1 week or imatinib within 3 days before the start of the trial. Exceptions included hydroxyurea administration, as clinically indicated before and during the first 21 days of treatment, and corticosteroids up to 48 hours before the first study dose. Patients with comorbid states, such as opportunistic and/or uncontrolled systemic infections, impaired gastrointestinal function, psychiatric disorders, and/or sustained toxicity from prior therapies, were excluded from the study, as were those with a history of another primary malignancy of clinical significance requiring intervention.
The study protocol was reviewed and approved by institutional review boards at each study site. Patients were required to provide written informed consent.
The primary objective of this phase 1 study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of INNO-406. Secondary objectives included evaluation of response, safety, and pharmacokinetic parameters.
The starting dose of INNO-406 was 30 mg administered orally once daily (QD), equaling 10% of the 30 mg/kg dose level used in a previous 4-week rat toxicity study, at which no deaths occurred (data on file).24 In the absence of a CTCAE v3.0 grade 2 or higher drug-related toxicity, the dose of INNO-406 was escalated by 100% in cohorts of at least 3 patients. If grade 2 drug-related toxicity occurred, INNO-406 dose was increased by 50% until the MTD was reached. The INNO-406 doses evaluated were: 30, 60, 120, 240, and 480 mg QD, and then 120, 240, and 480 mg administered orally twice daily (BID). Because all of the patients in the 480 mg BID cohort experienced toxicities, a BID cohort between the 240 mg and 480 mg BID cohorts was evaluated; this intermediate cohort received 360 mg BID. Once the MTD was determined, up to 20 patients in each of the 3 CML phases and up to 20 patients with Ph-positive ALL were treated at that dose.
Intrapatient dose escalation of INNO-406 was permitted in patients who had a suboptimal response to INNO-406 therapy only after the next dose level had been documented to be safe. A suboptimal response was defined as a failure to achieve either a hematologic response after 1 month or a major cytogenetic response after 6 months of therapy. This is based on observations that failure to achieve early hematologic response or major cytogenetic response after 6-12 months are associated with worse outcome.22,23
At each step, the investigators evaluated the relevant risks and benefits of continued study participation for each patient. No more than 2 dose reductions were allowed before the patient was withdrawn from the study, unless this was considered in the patient’s best interest.
Patients were removed from therapy or further assessment upon disease progression, physician decision that a change in therapy was in the patient’s best interest, or by patient’s request. Other reasons for removal of patients from the study were continued unacceptable toxicities despite optimal dose reduction, noncompliance, and pregnancy.
Adverse events were graded using CTCAE v3.0 criteria. Disease response was assessed at specified intervals by disease-specific response criteria.
Response criteria were as previously described.21 A complete hematologic response (CHR) was defined as normal white blood cell count (WBC) with normal differential and platelet counts <450×109/L, and no signs or symptoms of leukemia, including no splenomegaly. Cytogenetic response was defined as complete (0% Ph-positive), partial (1-35% Ph-positive), and minor (36-95% Ph-positive). A major cytogenetic response included complete and partial cytogenetic responses (i.e., ≤ 35% Ph-positive).
The incidence, severity, duration, causality, seriousness, and type of adverse events, physical examination changes, vital signs, and clinical laboratory results were recorded and tabulated. Standard pharmacokinetic and pharmacodynamic parameters were determined, together with the coefficient of variation of INNO-406 concentrations, to guide decision-making with regard to dosing level and frequency. Patients were evaluated for both complete and partial hematologic and cytogenetic responses. Mutational analyses were performed as previously detailed.22,23
INNO-406 was administered to 56 patients with Ph-positive CML or ALL and resistance to (n = 40 [71%]) or intolerance of (n = 16 [29%]) imatinib (Table 1). Twenty-seven patients (48%) were females. In addition to imatinib, most of the patients had been treated previously with other TKIs, including dasatinib (n = 26), nilotinib (n = 20), and dasatinib/nilotinib (n = 9). Forty-six patients had failed at least two TKIs (imatinib and dasatinib or nilotinib); nine of the 46 patients had failed all three TKIs (imatinib, dasatinib, and nilotinib); 10 of the 56 patients failed only imatinib. Fourteen patients (25%) were resistant to and 12 (21%) were intolerant of dasatinib. Seventeen (30%) patients were nilotinib resistant and 3 (5%) patients were nilotinib intolerant. The median duration of CML was 84 months (range, 43 to 267 months). Median durations of INNO-406 treatment were 3.7 months (range, 1 to 12 months) for the overall study group and 4.4 months (range, 1 to 12 months) for the subgroup with CML-CP. All 17 patients enrolled at 240 mg BID after determination of the MTD had CML-CP.
INNO-406 was well tolerated, and QD dosing cohorts of 30 to 480 mg QD were treated without the development of DLTs. After pharmacokinetic analyses suggested that BID dosing might be beneficial, BID dosing cohorts were initiated, beginning with 120 mg BID. At a dose level of 480 mg BID, DLTs, including elevations of transaminases and thrombocytopenia, were observed. Transaminase elevations were still noted at an INNO-406 dose of 360 mg BID; these included grade 3 alanine aminotransferase (ALT) elevations in 4 patients and grade 3 aspartate aminotransferase (AST) elevations in 2 patients. Seventeen patients were then enrolled at 240 mg BID as part of a protocol-specified expansion cohort, which was limited to patients with CML-CP.
In the 17 patients treated with 240 mg BID, transaminase elevations were still observed but were less severe. No patients had drug-related grade 3 AST elevations and only 1 patient had a drug-related grade 3 ALT elevation. Drug related grade 2 ALT elevations occurred at the 240 mg BID dose level in 9 patients, and a grade 2 AST elevation developed in 1 patient. The elevated transaminase levels observed at 240 mg BID resolved when INNO-406 dosing was withheld temporarily and then resumed at a lower dose. Based on these results, an INNO-406 dose of 240 mg BID is proposed for phase 2 studies.
In addition to elevated transaminases, the other most common drug-related grade 3/4 adverse event noted was thrombocytopenia (Table 2). When both drug- and non–drug-related thrombocytopenic events were considered, 2 and 3 patients experienced grade 3 and 4 thrombocytopenia, respectively, including 1 patient who initiated INNO-406 treatment with preexisting grade 4 thrombocytopenia. Platelet counts recovered when INNO-406 was withheld and then resumed at a lower dose.
This study incorporated a planned central evaluation of electrocardiograms (ECGs) during the first cycle of therapy to assess for QT prolongation. During this period of intense monitoring, the QTcB increased to grade 2 in 4 patients and the QTcF increased to grade 2 in 1 patient. Only 1 patient, who entered the study with a waiver due to a prolonged QTc, developed a QTc >500 msec during this routine monitoring after cycle 1. The patient experienced no further events after discontinuing INNO-406.
The NCI categories of adverse events that were experienced by ≥10% of patients were metabolic/laboratory (73.2%), gastrointestinal (64.3%), pain (58.9%), constitutional symptoms (48.2%), infection (33.9%), dermatology/skin (28.6%), blood/bone marrow (25.0%), lymphatics (25.0%), neurology (23.2%), pulmonary/upper respiratory (17.9%), cardiac general (12.5%), hemorrhage/bleeding (10.7%), and musculoskeletal/soft tissue (10.7%).
Five patients have died since beginning treatment; all deaths were related to leukemia progression. Four deaths were among 16 patients in CML blastic phase or Ph-positive ALL; 1 death was among 8 patients in CML accelerated phase; no deaths so far have been recorded among 31 patients in chronic phase. The 5 deaths did not appear to be correlated to dosing regimen: 1 at 30 mg daily, 2 at 120 mg daily, 1 at 480 mg BID, 1 at 360 mg BID. No cases of pleural or pericardial effusions were noted.
Table 3 provides a detailed summary of cytogenetic responses. All of the patients who achieved a cytogenetic response had CML-CP. No responses were observed in patients with CML-AP, CML-BP, or Ph-positive ALL. Major cytogenetic responses were noted in 6 patients with CML-CP. Three patients had a complete cytogenetic response, one at each of the INNO-406 dose schedules of 120 mg QD, 120 mg BID, and 240 mg BID. The remaining 3 patients had a partial cytogenetic response: 2 patients at 240 mg BID and 1 patient at 480 mg BID. None of the six major cytogenetic responders had baseline cytogenetic clonal evolution. Thus, 4 of the major cytogenetic responses occurred in patients treated with INNO-406 doses of 240 mg BID or greater. This represents a major cytogenetic responses rate of 11% (6 of 56 patients) for all patients enrolled, and a rate of 19% (6 of 31 patients) for patients with CML-CP. For the patients with major cytogenetic responses, the pretreatment regimens and the associated reasons for changes in therapy are listed in Table 4, which also provides the mutation status at baseline (eg, prior to INNO-406 exposure). Two additional patients achieved a minimal cytogenetic response. Complete and partial hematologic responses were observed in 3 patients.
Illustrative of the pharmacokinetic data seen in the full analyses, the pharmacokinetic parameters of INNO-406 in the 240 mg BID cohort are presented here. This cohort was selected based on clinical safety and efficacy evaluations that took events at the higher doses into consideration. As illustrated in Figure 2, accumulation of INNO-406 was observed on day 15 for both the 360 and 480 mg BID cohorts. For the 240 mg BID cohort, the mean time to achieve peak concentration (Cmax = 487 ng/mL) was 1.3 hours (standard deviation [SD] = 0.5).
Pharmacokinetic analyses performed in the entire study population also demonstrated an increase in Cmax with increasing INNO-406 doses for both QD and BID dosing. The half-life was relatively short; mean (SD) half-lives for BID dosing on day 1 and day 15 were 1.99 hours (0.817) and 2.28 hours (0.751), respectively. For BID dosing, the mean (SD) accumulation factor was 2.73 (4.96). The maximum concentration and area under the curve (Cmax and AUC) were dose proportional; however, dose proportionality for AUC was not demonstrable with BID dosing.
Mutational analysis performed at the central laboratories revealed mutations in 22 of 49 patients (45%) analyzed. Common mutations included Y253H in 6 patients, G250E in 4 patients, T315I in 4 patients, and F317L in 3 patients.
This phase 1 study of INNO-406, a novel, potent dual BCR-AbL/Lyn TKI, evaluated dose levels ranging from once-daily doses of 30 to 480 mg and from BID doses of 120 to 480 mg. The DLTs observed included liver dysfunction and myelosuppression. The proposed INNO 406 dose scheduled for phase 2 study is 240 mg orally BID, and this value is based on the classical determinations of DLT and MTD from phase I studies. Lower dose schedules of INNO-406 may be as effective and should be explored.
In this heavily pretreated study group of 56 patients, INNO-406 therapy resulted in 6 major cytogenetic responses (3 complete and 3 partial), all in 31 patients treated for CML-CP, for a major cytogenetic response rate of 19%.
Of the 56 patients treated in this study, 71% were resistant to and 29% were intolerant of imatinib. In addition, 26 patients experienced resistance to or intolerance of dasatinib, and 20 patients, resistance to or intolerance of nilotinib. In the majority of patients, therefore, prior treatment with multiple Bcr-Abl TKIs had failed. As many of the patients in this study were being treated in the third-line setting, a lower response rate would be expected than seen in the second-line setting represented by the dasatinib and nilotinib studies.
In this study, no responses were seen in patients with CML-AP, CML-BP, or Ph-positive ALL. Major cytogenetic responses were noted in 6 patients with CML-CP. Four of the responses occurred in patients in the cohort that received a starting INNO-406 dose of 240 mg BID or greater. This represents a major cytogenetic responses rate of 11% (6 of 56 patients) for all patients enrolled and a rate of 19% (6 of 31 patients) for patients with CML-CP. Major cytogenetic responses have been reported in 40% to 45% of patients with CML-CP treated in the second-line setting with dasatinib or nilotinib.21-23 It is unclear what response would be expected with dasatinib or nilotinib in a study population that included both second- and third-line setting patients.
Myelosuppression and pleural effusions are serious adverse events that have been seen with dasatinib, and myelosuppression and liver dysfunction, with nilotinib.21, 24, 25 These events were observed infrequently with INNO-406. The safety profile of INNO-406 is therefore unique, offering a potential advantage in the treatment of patients who have developed toxicities during treatment with other Bcr-Abl TKIs. Of note, a planned central evaluation of ECGs during the first cycle of INNO-406 therapy revealed only 1 patient with a QTc >500 msec; this patient, who had an elevated QTc at baseline, entered the study with a waiver.
Mutational analysis revealed mutations prior to the start of INNO-406 in 22 of the 49 patients analyzed (45%). Among these were 4 patients who had T315I mutations, which are known to confer resistance to imatinib, dasatinib, and nilotinib. None of the 4 patients with T315I mutations responded to INNO-406.
Outcomes of CML treatment have improved dramatically since the introduction of imatinib mesylate. The rising incidence of imatinib resistance and intolerance has resulted in the need for alternative agents. Nilotinib, dasatinib, and bosutinib are second-generation TKIs that have been developed to overcome imatinib resistance.11, 12 All 3 agents have similar efficacy with slightly different adverse effect profiles. There is a need for additional agents that are more potent than both imatinib and the existing second-generation TKIs. As patients are being treated longer, they are more commonly cycling through different treatment regimens.
This study demonstrates that INNO-406 is tolerated at a dose of 240 mg BID. Lower dose schedules may also be equally effective and deserve further evaluation. Further studies are needed to better evaluate the efficacy of INNO-406 in patients who have developed resistance to or intolerance of imatinib and/or other TKIs.
INNO-406, an oral dual Abl/Lyn kinase inhibitor, is tolerated at a dose of 240 mg BID in patients with Philadelphia chromosome–positive leukemias resistant to or intolerant of imatinib. INNO-406 showed anti-CML efficacy in this heavily pretreated study population and warrants further evaluation.
Research support: Supported by the “Betty Foster Leukemia Grant” and by P01CA049639.
Financial disclosures: All authors received research grant support to conduct the study; Dr. Pinilla-Ibarz served as an expert reviewer for Innovive.
Informed consent: The rationale of the study, procedural details, and investigational goals were explained to each patient, along with potential risks and benefits. Each patient was assured of his/her right to withdraw from the study at any time. Prior to the initiation of any study procedures, each patient signed and dated an approved informed consent form