Phase I Safety, Pharmacokinetic, and Pharmacodynamic Study of KW-2449 in Acute Leukemias (AML), Myelodysplastic Syndromes (MDS), and Chronic Myelogenous Leukemia (CML)
Overview
- Phase
- Phase 1
- Status
- Terminated
- Sponsor
- Kyowa Kirin, Inc.
- Enrollment
- 37
- Locations
- 4
- Primary Endpoint
- Safety of KW-2449 - Number of Participants With Treatment-related Adverse Events (TEAEs) as Assessed by NCI-CTCAE v3.0
Overview
Brief Summary
Non-randomized, open, dose ranging and dose scheduling study of ascending doses of KW-2449 in subjects with AML, ALL, MDS and CML.
Detailed Description
This is a Phase I open-label dose escalation study of KW-2449 in subjects with acute leukemias, high risk MDS, and CML who are not candidates for approved therapy. Over an 18-month period, the investigative sites collectively will enroll up to a total of 96 subjects. Subjects will be enrolled sequentially into 1 of 7 dose groups to evaluate 2 dosing schedules (Arm A = 14 consecutive days of dosing followed by a 7-28 day rest period as determined by recovery from any acute hematologic and non-hematologic toxicities, or Arm B = 28 consecutive days of dosing followed by a 7-28 day rest period, as determined by recovery from any acute hematologic and non-hematologic toxicities). The safety of a dose level in Arm A (14-day dosing regimen) will be established prior to enrollment of subjects in the same dose level in Arm B (28-day dosing regimen).
In April 2007 the protocol was amended to discontinue Arm B (28 consecutive days of dosing). The protocol will continue as planned for Arm A (14 days of consecutive dosing).
Enrollment will proceed until a maximum tolerated dose (MTD) has been established for each study Arm. Once the MTD has been reached, 12 additional subjects, with 1 or more of the hematologic conditions included in this study, may be enrolled at the MTD as an expanded safety cohort.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Histologically confirmed diagnosis of:
- •AML (including APL refractory to all-trans retinoic acid and arsenic) that has relapsed or was not responsive to prior chemotherapy;
- •Relapsed/refractory ALL;
- •CML that has failed to respond or has lost a response to imatinib; and
- •Advanced MDS (INT-2 and High risk by IPSS) with failure or intolerance to approved therapy.
- •ECOG Performance Status score of 0, 1, or 2;
- •Male or female, at least 18 years of age;
- •Signed written informed consent;
- •Serum creatinine ≤ 2.0 mg/dL;
- •Serum SGOT (AST) and SGPT (ALT) ≤ 5x ULN; serum bilirubin ≤ 2 mg/dL (serum bilirubin may be ≤ 3.0 mg/dL in any subject with Gilbert's Syndrome); and
Exclusion Criteria
- •Candidates for approved therapies;
- •Concomitant treatment with any investigational agent, chemotherapy, radiotherapy, or immunotherapy;
- •Active CNS leukemia;
- •Previous or concurrent malignancy except noninvasive non-melanomatous skin cancer, in situ carcinoma of the cervix, or other solid tumor treated curatively, and without evidence of recurrence for at least 2 years prior to study entry;
- •Uncontrolled systemic infection (viral, bacterial, or fungal);
- •Uncontrollable disseminated intravascular coagulation;
- •Major surgery within the 28 days preceding the first dose KW-2449;
- •Radiotherapy, or lack of recovery of any radiotherapy-related acute toxicity, within the 28 days preceding the first dose KW-2449;
- •Treatment with systemic therapy for the underlying hematologic condition, or lack of recovery of toxicity from such treatment, within 28 days of the first dose of KW-2449, with the following exceptions: hydroxyurea for treatment of hyperleukocytosis (discontinued for at least 48 hours prior to the first dose of KW-2449); imatinib (discontinued for at least 48 hours prior to the first dose of KW-2449); and interferon (discontinued for at least 7 days prior to the first dose of KW-2449);
- •Treatment with any other investigational agent, or lack of recovery of toxicity from such treatment, within the 28 days preceding the first dose of KW-2449;
Arms & Interventions
KW-2449
Treatment with ascending doses of KW-2449
Intervention: KW-2449 (Drug)
Outcomes
Primary Outcomes
Safety of KW-2449 - Number of Participants With Treatment-related Adverse Events (TEAEs) as Assessed by NCI-CTCAE v3.0
Time Frame: Baseline up to Cycle 2, Day 1
In addition to the number of TEAEs, the number of serious TEAEs, the number of related TEAEs, the number of Grade 3-4 TEAEs, and the number of subjects who died or discontinued due to TEAEs were also assessed. The maximally tolerated dose (MTD) was also to be determined, but it was not actually reached in either arm.
Secondary Outcomes
- Terminal Half Life (t 1/2)(Days 1 and 14 (and Day 28 for Arm B) of Cycle 1)
- Time to Peak Plasma Concentration (Tmax)(Days 1 and 14 (and Day 28 for Arm B) of Cycle 1)
- Area Under the Plasma Concentration-time Curve From 0 to Tau (AUC (0-tau, Tau is the Dosing Interval))(Days 1 and 14 (and Day 28 for Arm B) of Cycle 1)
- Accumulation Ratio (AUC 0-tau Day 14 or 28 / AUC 0-tau Day 1)(Day 1 and either Day 14 or Day 28 of Cycle 1)
- Observed Peak Plasma Concentration (Cmax)(Days 1 and 14 (and Day 28 for Arm B) of Cycle 1)
- Disease Response(Day 14 (Arm A) or Day 28 (Arm B) for all cycles)