Cerdulatinib For The Treatment Of B-Cell Malignancies

A sedutinib, refractory technology, applied in the field of sedutinib for the treatment of B-cell malignant tumors, can solve the problem of not being curable

Pending Publication Date: 2018-02-09
PORTOLA PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these compounds inhibit disease and are usually not curative

Method used

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  • Cerdulatinib For The Treatment Of B-Cell Malignancies
  • Cerdulatinib For The Treatment Of B-Cell Malignancies
  • Cerdulatinib For The Treatment Of B-Cell Malignancies

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0116] Example 1: Preclinical Models, Clinical PK / PD and Tumor Response

[0117] Materials and methods

[0118] Purified Kinase Assay: Performed at Millipore at a fixed concentration of 30OnM ATP. IC (Inhibitory Concentration) was determined using a 10-point concentration curve.

[0119] Human whole blood assay: Inhibition of SYK and JAK dependent and independent signaling was determined by stimulating human whole blood with various agonists against BCR and cytokine receptors. Use an 8-point concentration curve to determine the IC 50 , 100 μL aliquots of heparinized healthy human whole blood were stimulated as previously described (Coffey et al., J. of Pharm. and Experimental Therapeutics, 351:538-548, 2014). Signaling and activation responses were determined by fluorescence activated cell sorting ("FACS"). For clinical trials, whole blood samples were collected before and after dosing. Percent inhibition was calculated by normalizing to pre-dose stimulus response.

[01...

Embodiment 2

[0149] Example 2: Effect of Sadutinib on Primary Human CLL Cells

[0150] Sadutinib in 24 primary CLL samples

[0151]CLL cell isolation and culture: CLL cells (available from ATCC) were purified using the Human B Cell Enrichment Mixture Kit (Stemcell Technologies, Vancouver, BC, Canada), and stained with anti-CD5 / CD19 for verification of purity, which was present in all More than 95% of the cases. 1x10 in the presence or absence of 2.5 mg / mL CpG, 100 ng / mL CD40L, 10 ng / mL IL-4 7 Isolated CLL cells were cultured in RPMI-1640 with 15% fetal bovine serum (Gibco, Grand Island, NY, USA), penicillin (100 IU), and streptomycin ( 100 μg / mL). Anti-IgM stimulation was performed with plate-bound anti-IgM (10 μg / mL). CLL cells were stimulated with 10 ng / mL IL-6 (R&D Systems, Minneapolis, MN) to detect phosphorylation of JAK1 / JAK2 (Cell Signaling Technology, Danvers, MA) and STAT3 (Cell Signaling Technology, Danvers, MA, USA).

[0152] Cell viability assay and IC 50 Determined: CD5 ...

Embodiment 3

[0166] Example 3: Clinical and Relevant Results of a Phase I Study of Sarutinib

[0167] A first-in-human study of cerdutinib in patients with relapsed / refractory CLL / SLL or B-cell non-Hodgkin's lymphoma (NHL). A 3+3 dose-escalation study with a 28-day cycle was conducted; the doses studied ranged from 15 mg to 65 mg once daily and up to 45 mg twice daily. Patients received a single dose on Day 1 for a 72-hour PK assessment. Continuous dosing was initiated on day 4. Dosed in 43 patients with CLL / SLL or B-cell NHL. The median age was 67 years (range 23-85), and the median prior therapy (tx) was 3 (range 1-8).

[0168] Pharmacokinetics ("PK"), pharmacodynamics ("PD"), and safety were monitored. Responses were assessed by standard norms. Inhibition levels of SYK and JAK were determined using various whole blood assays measuring signaling through receptors for B cell antigens, IL2, IL4, IL6, and GM-CSF. Serum markers of tumor burden including CCL3, CCL4, and other inflammato...

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Abstract

Provided herein are compositions and methods for treating a relapsed or refractory hematologic cancer in a human patient in need thereof. The methods entail administering to the patient a daily dose of about 10 mg to about 75 mg of cerdulatinib or a pharmaceutically acceptable salt thereof, wherein the patients suffer one or more of a B-cell malignancy, chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL) or other transformed FL and / or have relapsed or not responded to a prior chemotherapy.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application 62 / 168,530, filed May 29, 2015, and U.S. Provisional Application 62 / 263,582, filed December 4, 2015, both of which are incorporated by reference in their entirety Incorporated into this article. technical field [0003] The present disclosure generally relates to methods of using saijutinib to treat hematological cancers, including B cell malignancies and relapsed or refractory hematological cancers. Background technique [0004] Neoplasms of hematopoietic and lymphoid tissues or hematopoietic and lymphoid malignancies are neoplasms that affect the blood, bone marrow, lymph, and lymphatic system. Since those elements are closely related through both the circulatory and immune systems, diseases affecting one will often also affect the other, making myeloproliferation and lymphoproliferation (and thus leukemia and lymphoma) close...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/519A61K31/4745
CPCA61K31/506A61P35/02A61P35/00A61K45/06A61K31/497
Inventor 安加利·潘迪格雷戈里·科菲珍妮特·利兹
Owner PORTOLA PHARMA INC
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