Patients with Ph positive leukemias, including CML CP, CML AP,

CML BP, and Phpositive ALL, and imatinib resistance or

intolerance were included in the trial. The definitions of

imatinib resistance and intolerance were as previously

20 23 Imatinib resistance was classified as either

hematologic or cytogenetic. Imatinib intolerance was defined as

the presence of any toxicity that prevented egfr review

patients from receiving therapy. 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 score of 0 2, and have normal cardiac, hepatic,

and renal functions.
Females enrolled in the study could Vismodegib 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. Study Design and Therapy The primary

objective of this phase 1 study was to determine the maximum

tolerated dose and dose limiting toxicity 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, equaling 10% of the 30 mg/kg

dose level used in a previous 4 week rat toxicity study, at

which no deaths occurred.24 In the absence of a CTCAE v3.0 grade

2 or higher drugrelated 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. 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 month