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Method for Determining the Response of Acute Myeloid Leukemia to Farnesyltransferase Inhibitor Therapy

A technology for acute myeloid cells and leukemia, applied in the direction of extracellular fluid disease, microbial measurement/test, blood disease, etc., can solve the problem of low response rate

Active Publication Date: 2016-09-28
JANSSEN PHARMA NV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Furthermore, no clinical studies have yet demonstrated an association between RAS mutations and FTI efficacy, as noted in U.S. Patent Publication No. 20070048782, which is incorporated herein by reference
In fact, although early clinical studies of FTI focused on cancers exhibiting high rates of RAS mutations, response rates in these trials were very low

Method used

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  • Method for Determining the Response of Acute Myeloid Leukemia to Farnesyltransferase Inhibitor Therapy
  • Method for Determining the Response of Acute Myeloid Leukemia to Farnesyltransferase Inhibitor Therapy
  • Method for Determining the Response of Acute Myeloid Leukemia to Farnesyltransferase Inhibitor Therapy

Examples

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example 1

[0103] Materials and methods

[0104] clinical assessment

[0105] In one example, bone marrow samples were collected from an open-label, multicenter, uncontrolled phase 2 study of tipifarnib in elderly patients with previously untreated high-risk AML To study the efficacy and safety of farnesyltransferase inhibitory therapy.

[0106] Sample collection and processing

[0107] With patient consent, bone marrow samples were collected prior to tipifarnib treatment, and monocytes were subsequently processed on-site. The bone marrow aspirate was diluted with phosphate buffered saline (PBS), and centrifuged with ficoll-diatrizoate (1.077 g / ml). Oxygen-enriched leukemic blood cells were washed twice with PBS, resuspended in PBS containing 10% DMSO, and immediately frozen at -70°C to -80°C. Total RNA was extracted from cell samples using the Trizol kit (Qiagen, Santa Clarita, CA). RNA quality was determined by assessing the presence of ribosomes on an Agilent Bioanalyzer. ...

example 2

[0154] This example describes a modified RT-PCR assay suitable for the application of two gene assays to FTI combination therapy. Taqman assays were designed for the following 3 markers in the analytical assay: RASGRP1 (guanylate exchange factor that activates RAS), APTX (Aprataxin involved in DNA excision repair) and HMBS (for internal reference). HMBS is used as an internal reference in one embodiment, but omitted in other embodiments. The Taqman primer probe sets and their amplicons are listed in the abstract and sequence sections of this application. That is, for APTX-SEQ#3-4 and 2, RASGRP1 primer-probe set SEQ#56 and 1; and HMBS-SEQ#7-9.

[0155] Quantitative RT-PCR assays were developed and optimized using the ABI-7500 platform in a single-tube multiplex format to assess 2-gene ratio performance using FAM-tagged RASGRP1, Gold 540-APTX and Cy5-HMBS. JY Cell RNA and Universal RNA (Stratagene) were used as external normalization.

[0156] RASGRP1:APTX ratio = 2^-"A-B)-(C...

example 3

[0190] This example shows that two-gene testing is effective in newly diagnosed AML patients. The 2-gene response prediction assay test was first performed on leukemic cells from a cohort of 84 newly diagnosed AML patients enrolled in a phase 1 dosing study of tipifarnib and etoposide as used in Blood 2008, 111:2589 Describe the RT-PCR protocol. The clinical plan for the phase 1 trial is described in Blood 2009, 113:4841.

[0191] Briefly, 51 unpublished assessed patient samples from the study were analyzed for a preliminary assessment of the performance of the 2-gene assay. Table 11 summarizes the threshold value of 5, RR represents the response rate of CR or PR responders, PPV is the positive predictive value, and NPV is the negative predictive value. Thirteen of 51 patients responded with an RR value of approximately 0.25. Of those above the threshold of 5 on the two-gene assay, half (9 of 18) responded with a PPV of approximately 0.5. Among patients who did not cross t...

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Abstract

The method of the present invention can rapidly identify with expected accuracy those that are likely to respond to farnesyl transferase inhibitors and etoposide, teniposide, tamoxifen, sorafenib, paclitaxel, temozolomide, topotecan AML patients, including elderly AML patients, who respond to a combination of one or more of , trastuzumab, and cisplatin. In one embodiment, the improvement includes using whole blood instead of the usual bone marrow sample, making the test more accurate, faster, less intrusive, less expensive and less painful. The method includes evaluating the expression ratio of the two genes (RASGRP1:APTX) in combination with corresponding thresholds, which provides sufficient precision for the prediction of response to combination therapy. A preferred embodiment is the combination therapy of tipifarnib (R1 15777,) combined with etoposide. Further, elderly AML patients identified as likely to respond to the combination of tipifarnib and etoposide had full recovery rates comparable to younger patients under optimal treatment conditions.

Description

Background technique [0001] The prevalence of acute myelogenous leukemia (AML) in the United States is low at about 50,000 patients, which is considered to be well below the 200,000 prevalence requirement for the definition of an orphan disease in the United States. Acute myeloid leukemia is more prevalent in older adults and tends to be more difficult to treat. Elderly patients, usually defined as patients at least 60 years old (although some classifications require patients to be at least 65 or even 70 years old) die from the disease at high rates. The average response rate and survival rate of elderly acute myelogenous leukemia patients are 30% to 50%, and the median recurrence-free survival (RFS) of complete remission is only 9 to 12 months. Few elderly patients live past two years. [0002] Therapeutic management of elderly patients with acute myeloid leukemia faces many challenges. Although about seventy percent (70%) of patients achieve remission with conventional in...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): G01N33/48
CPCC12Q1/6886C12Q2600/106C12Q2600/16C12Q2600/158C12Q2600/156C12Q1/6809A61P35/00A61P35/02A61P43/00A61P7/00
Inventor T.I.维纳C.C.德雷乔J.F.帕尔马M.拉波尼
Owner JANSSEN PHARMA NV
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