Methods for treating multiple myeloma and the use of companion biomarkers for 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile

Patent metadata

Field	Value
Publication number	US-10969381-B2
Application number	US-201916420031-A
Country	US
Kind code	B2
Filing date	May 22, 2019
Priority date	May 23, 2018
Publication date	Apr 6, 2021
Grant date	Apr 6, 2021

Abstract

A method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising administering the treatment compound to the subject having the cancer; obtaining a sample from the subject; determining the level of a biomarker in the sample from the subject; and diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample of the subject changes as compared to a reference level of the biomarker; wherein the treatment compound is Compound 1, Compound 2, or Compound 3.

First claim

What is claimed is:

1. A method of identifying a subject having cancer who is likely to be responsive to a treatment compound, predicting responsiveness of a subject having or suspected of having cancer to a treatment compound, or monitoring efficacy of a treatment compound in treating cancer in a subject, the method comprising:
(a) obtaining a sample from the subject;
(b) determining a level of a biomarker in a sample; and
(c) diagnosing the subject as being likely to be responsive to the treatment compound or responsive to the treatment compound if the level of the biomarker in the sample is greater than or equal to a reference level of the biomarker;
wherein the treatment compound is Compound 2:

or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof; and
wherein the biomarker is cereblon (CRBN); and wherein the cancer is multiple myeloma (MM) and wherein the MM is relapsed, refractory, or resistant to conventional therapy.

2. The method of claim 1 , further comprising administering the treatment compound to the subject prior to step (a).

3. The method of claim 1 , further comprising administering a therapeutically effective amount of the treatment compound to the subject diagnosed as being likely to be responsive to the treatment compound.

4. The method of claim 2 , further comprising administering a therapeutically effective amount of the treatment compound to the subject diagnosed as being likely to be responsive to the treatment compound.

5. The method of claim 1 , wherein determining the level of the biomarker comprises obtaining one or more of the following:
(i) a mRNA level of the biomarker;
(ii) a protein level of the biomarker,
(iii) a cDNA level of the biomarker; and
(iv) a RNA-sequence (RNA-seq) profile.

6. The method of claim 5 , wherein obtaining the protein level of the biomarker comprises contacting proteins within the sample with a first antibody that immunospecifically binds to the biomarker protein.

7. The method of claim 1 , wherein the reference level of the biomarker is:
(a) obtained from the subject prior to administering the treatment compound to the subject, and wherein the reference sample is from the same source as the sample; or
(b) a predetermined level.

8. The method of claim 3 , further comprising administering a therapeutically effective amount of a second active agent or a support care therapy.

9. The method of claim 4 , further comprising administering a therapeutically effective amount of a second active agent or a support care therapy.

10. The method of claim 8 , wherein the second active agent is selected from the group consisting of:
(a) large molecules, small molecules, and cell therapies; or
(b) melphalan, vincristine, cyclophosphamide, etoposide, doxorubicin, bendamustine, a proteasome inhibitor, a histone deacetylase inhibitor, a BET inhibitor, a BCL2 inhibitor, an MCL-1 inhibitor, a corticosteroid, dexamethasone, an antibody, a checkpoint inhibitor, and CAR cells.

11. A method of treating cancer, comprising:
(a) obtaining a sample from a subject having the cancer;
(b) determining a level of a biomarker in the sample;
(c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is greater than or equal to a reference level of the biomarker; and
(d) administering a therapeutically effective amount of the treatment compound to the subject diagnosed as being likely to be responsive to the treatment compound;
wherein the treatment compound is Compound 2:

or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof,
wherein the biomarker is cereblon (CRBN); and wherein the cancer is multiple myeloma (MM) and wherein the MM is relapsed, refractory, or resistant to conventional therapy.

12. The method of claim 11 , wherein determining the level of the biomarker comprises obtaining one or more of the following:
(i) a mRNA level of the biomarker;
(ii) a protein level of the biomarker,
(iii) a cDNA level of the biomarker; or
(iv) a RNA-sequence (RNA-seq) profile.

13. The method of claim 12 , wherein obtaining the protein level of the biomarker comprises contacting proteins within the sample with a first antibody that immunospecifically binds to the biomarker protein.

14. The method of claim 11 , wherein the reference level of the biomarker is:
(a) obtained from the subject prior to administering the treatment compound to the subject, and wherein the reference sample is from the same source as the sample; or
(b) a predetermined level.

15. The method of claim 11 , further comprising administering a therapeutically effective amount of a second active agent or a support care therapy.

16. The method of claim 15 , wherein the second active agent is selected from the group consisting of:
(a) large molecules, small molecules, and cell therapies; or
(b) melphalan, vincristine, cyclophosphamide, etoposide, doxorubicin, bendamustine, a proteasome inhibitor, a histone deacetylase inhibitor, a BET inhibitor, a BCL2 inhibitor, an MCL-1 inhibitor, a corticosteroid, dexamethasone, an antibody, a checkpoint inhibitor, and CAR cells.

Assignees

• Celgene Corp

Inventors

• Hansen Joshua
• Havens Courtney G
• Lopez-Girona Antonia
• Lu Gang
• Wong Lilly L

Classifications

• G01N33/5758

  involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites · CPC title

• G01N33/57505 Primary

  of the blood, e.g. leukaemia · CPC title

• A61P35/02

  specific for leukemia · CPC title

• G01N2800/52

  Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis · CPC title

• G01N33/6869

  Interleukin · CPC title