Method of optimizing the treatment of proliferative diseases mediated by the tyrosine kinase receptor KIT with imatinib

Abstract

The invention relates to a method of treating proliferative diseases mediated by the tyrosine kinase receptor KIT, in particular GIST, in a human patient population.

Claims

1. A method of selectively treating a patient having unresectable/metastatic GIST harboring the Exon 11 KIT mutation, said method comprising: (a) administering a predetermined fixed dose of 400 mg or 600 mg of imatinib mesylate to the patient; (b) obtaining at least one blood sample from the patient within the first 12 months of treatment; (c) detecting a plasma trough level (Cmin) of less than 1100 ng/mL in the blood sample of the patient; and (d) thereafter selectively adjusting the dose of imatinib mesylate in a manner that maintains a Cmin of between 1100 and 2040 ng/mL of imatinib mesylate in the patient.

2. The method according to claim 1 wherein the at least one blood sample is collected within the first 3 months of treatment.

3. The method according to claim 1 wherein the at least one blood sample is collected within the first 30 days of treatment.

Description

SHORT DESCRIPTION OF THE FIGURES

(1) FIG. 1 depicts the Imatinib trough distribution of the study described in Example 1 (400 mg and 600 mg data combined).

EXAMPLE 1

Imatinib Pharmacokinetics (PK) and its Correlation with Clinical Response in Patients with Unresectable/Metastatic Gastrointestinal Stromal Tumor (GIST)

(2) PURPOSE: In the randomized Phase II study (B2222), 147 pts with unresectable/metastatic GIST were randomized 1:1 to receive imatinib (IM) at 400 vs 600 mg daily. Fifty-two (52%) percent of patients are alive for >5 years, regardless of initial dose level. We report the pharmacokinetics (PK) of imatinib (IM) and the relationship between IM levels and clinical response.

(3) METHODS: The IM plasma levels were analyzed in a subset of patients (n=73) for whom PK data on day 1 and at steady state (Day 29) was available (n=34 and 39 for 400 and 600 mg/day, respectively). The effect of patients demographics and blood chemistry parameters on IM PK was evaluated using a population PK approach. A relationship between IM plasma exposure and clinical outcome was explored by grouping patients into quartiles according to IM trough levels (Cmin). The clinical outcome parameters evaluated include overall objective responses (OOR=CR+PR+SD), time to progression (TTP), and KIT mutations.

(4) RESULTS: Population PK analysis showed that patients age, gender, and BW had little effect on imatinib clearance, whereas plasma albumin and WBC counts at baseline were identified as significant covariates. Patients with a higher albumin level or lower WBC counts at baseline appeared to have a higher clearance for IM. Clinical outcomes appeared to be correlated with IM trough exposure. OOR was achieved by 12 of 18 (67%) patients in Q1 (Cmin<1110 ng/mL) compared with 29 of 36 (81%) and 16 of 19 (84%) in Q2-Q3 (1110-<2040 ng/mL), and Q4 (2040 ng/mL), respectively (p=0.177 for Q1 vs Q2-Q4). The median TTP was 11.3 months for patients in Q1 and over 30 months for Q2-Q4 (p=0.0029). In patients with Exon 11 KIT mutations (n=39), the OOR was 67% for Q1 vs 100% for Q2-Q4 (p=0.009). Exon 9 KIT mutation was found in only 12 patients with Cmin data, limiting the power of any correlative analyses in this subset. The IM plasma AUC, peak concentration, and Cmin were highly correlated, with IM Cmin having the best correlation with response.

(5) CONCLUSION: IM demonstrated good oral absorption, but large inter-patient variability in IM exposure. Patients with the lowest IM trough levels (<1100 ng/mL) show lowest OOR rate and shortest TTP.