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Msg  5838 of 7381  at  1/19/2021 7:38:21 AM  by

JBWIN


Building IP: Celgene International II Sarl re "Use of marizomib for the treatment of central nervous system (CNS) cancers"

 
United States Patent10,894,036
Trikha , et al.January 19, 2021

Use of marizomib for the treatment of central nervous system (CNS) cancers

Abstract

The present disclosure relates to treatment of central nervous system (CNS) cancers (e.g., malignant glioma, glioblastoma, or CNS-multiple myeloma) using marizomib. The disclosure further relates to uses of synergistic combinations of marizomib with additional therapeutic agents such as bevacizumab, daratumumab, temozolomide, pomalidomide, and radiotherapy.


Inventors:Trikha; Mohit (La Jolla, CA), MacLaren; Ann (La Jolla, CA), Levin; Nancy (La Jolla, CA)
Applicant:
NameCityStateCountryType

Celgene International II Sarl

Couvet

N/A

CH
Assignee:Celgene International II Sarl (Couvet, CH)
Appl. No.:15/611,614
Filed:June 1, 2017

Prior Publication Data

Document IdentifierPublication Date
US 20170348284 A1Dec 7, 2017

Related U.S. Patent Documents

Application NumberFiling DatePatent NumberIssue Date
62344194Jun 1, 2016
62349491Jun 13, 2016
62362845Jul 15, 2016
62374136Aug 12, 2016
62418466Nov 7, 2016
62424178Nov 18, 2016
62471321Mar 14, 2017
62490528Apr 26, 2017
62491943Apr 28, 2017

Current U.S. Class:1/1
Current CPC Class:C07K 16/22 (20130101); C07K 16/2896 (20130101); A61N 5/10 (20130101); A61K 39/39558 (20130101); A61K 31/407 (20130101); A61K 39/3955 (20130101); A61K 31/495 (20130101); A61K 31/407 (20130101); A61K 2300/00 (20130101); A61K 39/3955 (20130101); A61K 2300/00 (20130101); A61K 31/495 (20130101); A61K 2300/00 (20130101); C07K 2317/24 (20130101); A61K 2039/545 (20130101); C07K 2317/73 (20130101); A61N 2005/1098 (20130101); C07K 2317/21 (20130101)
Current International Class:A61K 31/495 (20060101); A61K 31/407 (20060101); A61K 39/395 (20060101); C07K 16/22 (20060101); C07K 16/28 (20060101); A61N 5/10 (20060101); A61K 39/00 (20060101)

References Cited [Referenced By]

U.S. Patent Documents
7144723December 2006Fenical et al.
7179834February 2007Fenical et al.
7276530October 2007Potts et al.
7572606August 2009Lam et al.
7824698November 2010Potts et al.
8003802August 2011Ling et al.
8067616December 2011Ling et al.
8168803May 2012Palladino et al.
8394816March 2013Ghobrial et al.
8722724May 2014Anderson et al.
10011814July 2018Lam et al.
2002/0128228September 2002Hwu
2008/0280968November 2008Palladino et al.
2009/0148445June 2009Bonavida et al.
2020/0085789March 2020Trikha et al.
Foreign Patent Documents
WO 2007/120801Oct 2007WO
WO 2007/130404Nov 2007WO
WO 2008/124699Oct 2008WO
WO 2009/140287Nov 2009WO
WO 2017/210463Dec 2017WO
WO 2018/169740Sep 2018WO

Other References
<>
Trials.gov NCT02330562, first post Jan. 5, 2015 (Year: 2015). cited by examiner .
Lin et al (Neuro-Oncology practice 4:24-28, 2017, online published Dec. 2016 (Year: 2016). cited by examiner .
Potts et al (Curr Cancer Drug Targets, 11:254-284, 2011. (Year: 2011). cited by examiner .
VAL083 clinical trial, start date, Jan. 2017 (Year: 2017). cited by examiner .
Nota, D. et al., "Investigation of pharmacodynamics and predictive biomarkers to define response to proteasome inhibitor marizornib in glioma," Cancer Research, vol. 76, No. 14 Suppl., 4 pages (2016). cited by applicant .
Di, K. et al., "Marizomib activity as a single agent in malignant gliomas: ability to cross the blood-brain barrier," Neuro-Oncology, vol. 18, No. 6, pp. 840-848 (2015). cited by applicant .
Mattes, M. et al., "The proteasome inhibitor NPI-0052 targets glioma stem cells and radiosensitizes glioblastomas in-vitro and in-vivo," Journal of Investigative Medicine, vol. 57, No. 1, p. 120 (2009). cited by applicant .
Clinical Leader, "Triphase Accelerator Corporation Announces Full Enrollment Results of Its Phase 1 Trial of Marizomib and Bevacizumab in Malignant Glioma," Nov. 18, 2016, 2 pages; https://www.clinicalleader.com/doc/triphase-accelerator-corporation-its-p- hase-marizomib-in-malignant-glioma-0001. cited by applicant .
Harrison, S. J. et al., "Phase I Clinical Trial of Marizomib (NPI-0052) in Patients with Advanced Malignancies Including Multiple Myeloma: Study NPI-0052-102 Final Results," Clin Cancer Res, 22(18):45594566 (2016). cited by applicant .
Inman, S., "Improved Optune System Approved for Glioblastoma Multiforme," Jul. 13, 2016, 2 pages; https://www.curetoday.com/articles/improved-optune-system-approved-for-gl- ioblastoma-multiforme. cited by applicant .
Stupp, R. et al., "Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma," N Engl J Med, 352(10):987-996 (2005). cited by applicant .
Vlashi, E. et al., "Differential Effects of the Proteasome Inhibitor NPI-0052 against Glioma Cells," Translational Oncology, 3(1):50-55 (2010). cited by applicant .
Anonymous: "Study of Marizomib With Temozolomide and Radiotherapy in Patients with Newly Diagnosed Brain Cancer," clinicaltrials.gov, Oct. 11, 2016; https://clinicaltrials.gov/ct2/history/NCT02903069?V_View#StudyPage- Top, 7 pages. cited by applicant .
Desisto, J. Abstracts from the 22nd Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology, Nov. 16-19, 2017, Neuro-Oncology, vol. 19, No. suppl. 6, Nov. 6, 2017, 324 pages. cited by applicant .
Kubicek, G.T. et al., "Phase I trial using proteasome inhibitor bortezomib and concurrent temozolomide and radiotherapy for central nervious system malignances," Int. J. Radiation Oncology Biol. Phys., 74(2):433-439 (2009). cited by applicant .
Manton, C. A. et al., "Induction of cell death by the novel proteasome inhibitor marizomib in glioblastoma in vitro and in vivo," Scientific Reports, 6:18953; doi:10.10.8/srep18953, 13 pages. cited by applicant.

Primary Examiner: Yao; Lei
Attorney, Agent or Firm: Cooley LLP

Parent Case Text



CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62/344,194, filed Jun. 1, 2016; U.S. Provisional Patent Application No. 62/349,491, filed Jun. 13, 2016; U.S. Provisional Patent Application No. 62/362,845, filed Jul. 15, 2016; U.S. Provisional Patent Application No. 62/374,136, filed Aug. 12, 2016; U.S. Provisional Patent Application No. 62/418,466, filed Nov. 7, 2016; U.S. Provisional Patent Application No. 62/424,178, filed Nov. 18, 2016; U.S. Provisional Patent Application No. 62/471,321, filed Mar. 14, 2017; U.S. Provisional Patent Application No. 62/490,528, filed Apr. 26, 2017; and U.S. Provisional Patent Application No. 62/491,943, filed Apr. 28, 2017. The contents of which are hereby incorporated by reference in their entirety.
Claims



The invention claimed is:

1. A method of treating a CNS-cancer comprising administering to a subject in need thereof an effective amount of marizomib and bevacizumab; wherein the subject has a level of 0.sup.6-methylguanine-DNA methyltransferase promoter methylation of 8% or less, and wherein the EGFR status of the patient is normal.

2. The method of claim 1, wherein the method further comprises (a) administering to the patient marizomib at a first dose and bevacizumab at a first dose during a first treatment period, and (b) administering to the patient marizomib at a second dose during a second treatment period.

3. The method of claim 1, wherein the CNS-cancer is glioma.

4. The method of claim 3, wherein the glioma is glioblastoma.

5. The method of claim 1, wherein the patient has not received a prior treatment with an anti-angiogenic agent.

6. The method of claim 5, wherein the anti-angiogenic agent is selected from the group consisting of bevacizumab, sorafenib, sunitinib, axitinib, pazopanib, everolimus and cilengitide.

7. The method of claim 1, wherein the patient has not received a prior treatment with a proteasome inhibitor.

8. The method of claim 7, wherein the proteasome inhibitor is selected from the group consisting of marizomib, bortezomib, and carfilzomib.

9. The method of claim 1, wherein the patient has a pathophysiological marker selected from the group consisting of a solitary cerebral plasmacytoma, a CNS myelomatosis, a solitary or multiple intraparenchymal lesions and a leptomeningeal disease with the presence of monoclonal plasma cells in the cerebrospinal fluid in the patient.
Description



FIELD OF THE INVENTION

The present invention relates to treatment of central nervous system (CNS) cancers (e.g., malignant glioma, glioblastoma, primary CNS lymphoma, or CNS-multiple myeloma) using marizomib alone or in combination with additional therapeutic agents.

BACKGROUND OF THE INVENTION

Marizomib is an irreversible proteasome inhibitor.

Gliomas account for about 80% of primary malignant tumors in the central nervous system (CNS), with WHO Grade IV malignant glioma (G4 MG; including glioblastoma and gliosarcoma) constituting the majority of gliomas, and are essentially incurable. Currently only surgical resection and radiotherapy (RT) with concomitant and adjuvant temozolomide (TMZ) are standard-of-care treatment strategies for newly diagnosed G4 MG. However, resistance to chemotherapy and radiotherapy results in a high recurrence rate, with median survival of .about.15-16 months. Since no survival advantage has been demonstrated for the addition of bevacizumab (BEV) to temozolomide and radiotherapy in newly diagnosed G4 MG, alternative promising investigational agents need to be tested.

Targeting the proteasome has been used for the treatment of multiple myeloma (MM), and preclinical evidence suggests that targeting the proteasome in glioma cells shows significant anti-tumor activity. Importantly, preclinical evidence demonstrates that proteasome inhibition sensitizes GBM cell lines to irradiation and to temozolomide. Further, the combination of bortezomib (BTZ, one of three proteasome inhibitors [PI] currently approved for the treatment of MM) with temozolomide resulted in synergistic glioblastoma cell death in vitro, and bortezomib reduces glioma cell survival in vitro in cell lines sensitive and resistant to temozolomide. Despite the activity against GBM cells in vitro, bortezomib does not cross the blood brain barrier, and thus has proven ineffective in treatment of GBM in animal models and in the clinic.

Central nervous system-multiple myeloma (CNS-MM) is a rare manifestation of extra-medullary disease with few therapeutic options. Its prevalence is increasing as anti-myeloma therapies become more effective at treating systemic disease, highlighting the urgent unmet clinical need in this patient population.

Accordingly, there is an unmet need for proteasome inhibitors capable of crossing the blood-brain barrier for the treatment of brain cancers (e.g., malignant glioma, glioblastoma, or CNS-multiple myeloma).

SUMMARY OF THE INVENTION

The present disclosure teaches marizomib, alone or in combination with additional therapeutic agents for the treatment of CNS cancers. As set forth herein, marizomib is capable of inhibiting all three domains of the proteasome (i.e., the chymotrypsin-like (CT-L); trypsin-like (T-L); and caspase-like (C-L) domains). Without wishing to be bound by theory, the present disclosure teaches that repeated dosage with marizomib can also overcome compensatory hyperactivation of the C-L and T-L domains of the proteasome.

In one aspect, the present disclosure provides a method of treating a CNS-cancer comprising administering to a subject in need thereof an effective amount of marizomib and bevacizumab.

In some embodiments, the CNS-cancer is a glioma. In some embodiments, the glioma is grade IV malignant glioma. In some embodiments, the glioma is glioblastoma. In some embodiments, the glioma is newly diagnosed. In some embodiments, the glioma is relapsed or refractory. In some embodiments, the promoter of the subject's gene encoding O.sup.6-methylguanine-DNA methyltransferase is unmethylated. In some embodiments, the promoter of the subject's gene encoding O.sup.6-methylguanine-DNA methyltransferase is less than 8% methylated. In some embodiments, subject's EGFR is normal. In some embodiments, the subject's EGFR is altered. In some embodiments, the subject's EGFR alteration is amplified EGFR, mutated EGFR, EGFRVII positive, or a combination thereof.

In another aspect, the present disclosure provides a method of treating a CNS-cancer comprising administering to a subject in need thereof an effective amount of marizomib and temozolomide.

In some embodiments, the CNS-cancer is a glioma. In some embodiments, the glioma is grade IV malignant glioma. In some embodiments, the glioma is glioblastoma. In some embodiments, the glioma is newly diagnosed. In some embodiments, the glioma is relapsed or refractory. In some embodiments, the method further comprises administering to the subject radiotherapy. In some embodiments, the combination of marizomib and temozolomide is synergistic.

In another aspect, the present disclosure provides a method of treating a CNS-cancer comprising administering to a subject in need thereof an effective amount of marizomib, temozolomide and radiotherapy.

In another aspect, the present disclosure provides a method of treating a central nervous system hematological cancer in a subject in need thereof, comprising administering to the subject an effective amount of marizomib.

In some embodiments, the central nervous system cancer is newly diagnosed. In some embodiments, the central nervous system hematologic cancer is central nervous system multiple myeloma, central nervous system leukemia, central nervous system myelodysplastic syndrome or central nervous system lymphoma. In some embodiments, the central nervous system-hematologic cancer originates from the central nervous system. In some embodiments, the central nervous system-hematologic cancer originates in the blood and metastasizes to the central nervous system. In some embodiments, the subject suffers from relapsed or refractory central nervous system-hematologic cancer. In some embodiments, the central nervous system-hematologic cancer affects the meninges. In some embodiments, the method further comprises administering to the subject an additional therapeutic agent. In some embodiments, the additional therapeutic agent can cross the blood-brain barrier. In some embodiments, the additional therapeutic agent is an anti-CD38 antibody, pomalidomide, or any combination thereof. In some embodiments, the anti-CD38 antibody is daratumumab. In some embodiments, the combination therapy with the additional therapeutic agent is synergistic.

In another aspect, the present disclosure provides a method of treating central nervous system multiple myeloma comprising administering to a subject in need thereof an effective amount of marizomib.

In another aspect, the present disclosure provides a method of treating a central nervous system multiple myeloma comprising administering to a subject in need thereof an effective amount of marizomib and daratumumab.

In another aspect, the present disclosure provides a method of treating a central nervous system multiple myeloma comprising administering to a subject in need thereof an effective amount of marizomib and pomalidomide.

In one aspect, the present disclosure teaches a method of treating a central nervous system cancer in a subject in need thereof, comprising administering to the subject an effective amount of marizomib.

In one aspect, the present disclosure teaches a method of treating a central nervous system hematological cancer in a subject in need thereof, comprising administering to the subject an effective amount of marizomib.

In one aspect, the present disclosure teaches a method of treating a glioma in a subject in need thereof, comprising administering to the subject an effective amount of marizomib.

In one aspect, the present disclosure teaches a method of treating glioma comprising administering to a subject in need thereof an effective amount of marizomib, temozolomide, and radiotherapy.

In one aspect, the present disclosure teaches a method of treating glioma comprising administering to a subject in need thereof an effective amount of marizomib and radiotherapy.

In one aspect, the present disclosure teaches a method of treating glioma comprising administering to a subject in need thereof an effective amount of marizomib and bevacizumab.

In one aspect, the present disclosure teaches a method of treating central nervous system multiple myeloma comprising administering to a subject in need thereof an effective amount of marizomib and an anti-CD38 antibody.

In one aspect, the present disclosure teaches a method of treating central nervous system multiple myeloma comprising administering to a subject in need thereof an effective amount of marizomib and daratumumab.

In one aspect, the present disclosure teaches a method of treating central nervous system multiple myeloma comprising administering to a subject in need thereof an effective amount of marizomib and pomalidomide.

In one aspect, the present disclosure teaches a pharmaceutical composition comprising marizomib for the treatment of central nervous system cancer.

In one aspect, the present disclosure teaches the use of marizomib in the manufacture of a medicament for the treatment of central nervous system cancer.

In one aspect, the present disclosure teaches the use of marizomib for the treatment of central nervous system cancer.

In one aspect, the present disclosure teaches a method of treating a central nervous system-hematologic cancer in a subject in need thereof, comprising administering to the subject an effective amount of daratumumab.

In one aspect, the present disclosure teaches a method of treating central nervous system multiple myeloma in a subject in need thereof, comprising administering to the subject an effective amount of daratumumab.

In another aspect, the present disclosure provides a pharmaceutical composition comprising marizomib for the treatment of central nervous system cancer. Another aspect of the disclosure is directed to pharmaceutical compositions comprising marizomib, a further therapeutic agent and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant. The additional therapeutic agent can be an anti-CD38 antibody (e.g., daratumumab), pomalidomide, bevacizumab, temozolomide, or any combination thereof.

Another aspect of the disclosure provides the use of marizomib and an additional therapeutic agent for use in treating a CNS cancer. The additional therapeutic agent can be an anti-CD38 antibody (e.g., daratumumab), pomalidomide, bevacizumab, temozolomide, or any combination thereof.

Another aspect of the disclosure provides the use of marizomib and an additional therapeutic agent in the manufacture of a medicament for use in treating a CNS cancer. The additional therapeutic agent can be an anti-CD38 antibody (e.g., daratumumab), pomalidomide, bevacizumab, temozolomide, or any combination thereof.


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