Treatment cancers using a combination comprising PARP inhibitors
Inventors
Wang, Lai • Tang, Zhiyu • Luo, Lusong • Wei, Min • Li, Kang • Song, Jing • Zhang, Tong • Wang, Hexiang • Ren, Bo • Zhou, Changyou
Assignees
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Publication Number
US-11202782-B2
Publication Date
2021-12-21
Expiration Date
Abstract
Disclosed herein is a method for the prevention, delay of progression or treatment of cancer in a subject, comprising administering to the subject in need thereof a PARP inhibitor, particularly, (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one, a sesqui-hydrate thereof, or a pharmaceutically acceptable salt thereof, in combination with an immune checkpoint inhibitor or a chemotherapeutic agent. Also, disclosed a pharmaceutical combination comprising a PARP inhibitor, particularly, (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one, a sesqui-hydrate thereof, or a pharmaceutically acceptable salt thereof, in combination with an immune checkpoint inhibitor, or a chemotherapeutic agent and the use thereof.
Core Innovation
The document describes methods and pharmaceutical combinations for the delay of progression or treatment of cancer by administering a PARP inhibitor together with an immune checkpoint inhibitor and/or a chemotherapeutic agent. The PARP inhibitor is defined by structural Formula (I), stereoisomers, pharmaceutically acceptable salts, and alternative structural options including Formula (III) and Formula (IV).
The immune checkpoint inhibitor is an antibody or fragment thereof that specifically binds to human PD-1, where the antibody comprises a heavy chain variable region (Vh) and a light chain variable region (Vl). The Vh and Vl sequences include defined CDRs with SEQ ID NO assignments, and the document additionally describes preferred IgG4 constant or effector domain sequence-defined options and antibody formats including F(ab) and F(ab)2.
The disclosed solution is a cancer treatment regimen that combines a PARP inhibitor selected from the defined structural formula sets with an immune checkpoint inhibitor specifically binding human PD-1 and/or with chemotherapeutic agents selected from paclitaxel or etoposide plus carboplatin (E/C). The document further references a representative antibody (Mab-1) binding PD-1 residues.
Claims Coverage
The independent claims are directed to a method of delaying progression or treating cancer using a PARP inhibitor in combination with either an immune checkpoint inhibitor or a chemotherapeutic agent, and to pharmaceutical combinations comprising a PARP inhibitor and a chemotherapeutic agent or a PARP inhibitor and an immune checkpoint inhibitor. Across these independent claims, the inventive features center on the defined PARP inhibitor structural scope, the defined human PD-1 binding antibody scope, and the defined chemotherapeutic agent options.
Cancer progression delay or treatment by PARP inhibitor plus immune checkpoint inhibitor or chemotherapeutic agent
A method for the delay of progression or treatment of cancer in a subject, wherein administering a therapeutically effective amount of a PARP inhibitor in combination with a therapeutically effective amount of an immune checkpoint inhibitor, or a chemotherapeutic agent, and wherein the cancer is selected from the specified group.
PARP inhibitor is a compound of Formula (I), stereoisomer, salts, or Formula (III) or Formula (IV)
A method wherein the PARP inhibitor is a compound of Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salts thereof, or a compound of Formula (III) or a pharmaceutically acceptable salt thereof, or a compound of Formula (IV).
Human PD-1 specific antibody characterized by Vh/Vl CDR SEQ IDs
The method wherein the immune checkpoint inhibitor is an antibody or fragment thereof that specifically binds to human PD-1, comprising a heavy chain variable region (Vh) and a light chain variable region (Vl) with defined SEQ ID NO CDR sequences.
Chemotherapeutic agent selected from paclitaxel or etoposide plus carboplatin (E/C)
The method wherein the chemotherapeutic agent is paclitaxel or etoposide plus carboplatin (E/C).
Pharmaceutical combination of PARP inhibitor plus chemotherapeutic agent
A pharmaceutical combination for use in the delay of progression or treatment of cancer comprising a PARP inhibitor and a chemotherapeutic agent selected from paclitaxel and etoposide/carboplatin (E/C), wherein the PARP inhibitor is a compound of Formula (I), stereoisomer, or pharmaceutically acceptable salts, or a compound of Formula (III) or Formula (IV) with related salt options.
Pharmaceutical combination of PARP inhibitor plus immune checkpoint inhibitor
A pharmaceutical combination for use in the delay of progression or treatment of cancer comprising a PARP inhibitor and an immune checkpoint inhibitor, wherein the PARP inhibitor is a compound of Formula (I), stereoisomer, or pharmaceutically acceptable salts, or a compound of Formula (III) or Formula (IV), and wherein the immune checkpoint inhibitor is an antibody or fragment thereof that specifically binds to human PD-1 and comprises a heavy chain variable region (Vh) and a light chain variable region (Vl) with specified CDR SEQ ID numbers.
Collectively, the independent claims cover a cancer delay/progression or treatment regimen defined by a PARP inhibitor structural scope using Formula (I)/(III)/(IV) and salts, a human PD-1 binding antibody checkpoint inhibitor scope characterized by specified Vh/Vl CDR SEQ ID numbers, and chemotherapeutic agent selection limited to paclitaxel or etoposide/carboplatin (E/C), implemented either as a method of administration or as a pharmaceutical combination.
Stated Advantages
Improved anti-tumor activity versus monotherapy without severe toxicity.
Delays progression or provides treatment of cancer.
The approach addresses the delay of progression or treatment of cancer.
Experimental pharmacology reports synergy and efficacy of the PARP inhibitor with anti-PD-1 mAb, paclitaxel, and etoposide/carboplatin (E/C).
Reported readouts include IFN-γ in primary human tumor co-culture assays and tumor growth inhibition outcomes, including regression and complete/partial regression categories in primary tumor xenograft models.
Clinical trial summary reporting includes Phase Ia safety and mentions observed antitumor responses and durable outcomes across multiple solid tumor types.
Documented Applications
Delay of progression or treatment of cancer in a subject, including cancers selected from the specified group.
Treatment or delay of progression of colorectal, gastric, lung, small cell lung, bladder, breast, ovarian, fallopian tube carcinoma, cervical, peritoneal, prostate, castration-resistant prostate, bile duct, gastric/gastro-esophageal junction, urothelial, pancreatic, peripheral nerve sheath, uterine, and melanoma cancers.
Use of the PARP inhibitor combination framework in non-clinical/assay and xenograft experiment references/figures, including IFN-γ readouts with Compound B + Mab-1 and tumor growth effects reported with Compound A/B combinations.
Use of a pharmaceutical combination comprising a PARP inhibitor and an immune checkpoint inhibitor (anti-human PD-1 antibody) for the delay of progression or treatment of cancer.
Use of a pharmaceutical combination comprising a PARP inhibitor and a chemotherapeutic agent (paclitaxel or etoposide/carboplatin (E/C)) for the delay of progression or treatment of cancer.
Clinical trial summary reporting across multiple solid tumor types.
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