Patent Application
20250019441
The instant application contains a Sequence Listing which has been submitted electronically in XML format, is part of the specification, and is hereby incorporated by reference herein in its entirety. The electronic copy of the Sequence Listing, created on Jul. 3, 2024, is named 022548.US092.xml and is 29,035 bytes in size.
The glycoprotein receptor immunoglobulin-like transcript-2 (ILT2) is a surface glycoprotein inhibitory receptor expressed on a wide range of immune cells, including monocytes, dendritic cells, natural killer (NK), B cells, and T cells. ILT2 has been shown to bind to classical and nonclassical major histocompatibility complex (MHC) class I molecules, with a higher affinity to the nonclassical MHC-I molecule human leukocyte antigen-G (HLA-G). HLA-G is commonly expressed by solid tumors and plays an important role in immunotolerance by inhibiting cytolytic functions of NK cells and cytotoxic T-lymphocytes, and T-cell allo-proliferative responses. While HLA-G is believed to have an advantageous role in pregnancy, organ transplantation, and combatting autoimmune disease, its immunosuppressive effects may aid cancer growth by allowing cancer cells to evade the innate anti-cancer response.
The interaction between ILT2 and MHC-I (e.g., HLA-G) in the context of an immune reaction can lead to impairment of immune cell proliferation, differentiation, phagocytosis, cytotoxicity, cytokine secretion and chemotaxis, and to induction of regulatory cells and myeloid-derived suppressor cells (MDSC) or M2 type macrophages. These immunosuppressive effects identify the ILT2 signaling axis as a potential target for anti-cancer immunotherapies.
Some of the current cancer immunotherapies combat tumor progression by targeting proteins that aid in tumor immune evasion. However, such therapies are often inadequate due to primary tumor refractoriness and acquired tumor resistance. Thus, there remains a need for new and improved cancer immunotherapies.
The present disclosure provides methods for cancer therapy using anti-human ILT2 antibody SAR444881 (i.e., BND-22) or a related antibody.
In some embodiments, the present disclosure provides a method of treating cancer in a human patient in need thereof, comprising administering to the patient a humanized monoclonal anti-human ILT2 IgG4 antibody whose heavy chain CDR1-3 and light chain CDR1-3 comprise SEQ ID NOs: 1-6, respectively, in two or more treatment cycles, wherein each treatment cycle comprises a single dose of the anti-ILT2 antibody at 0.1-20 mg/kg per dose. In certain embodiments, the dose is 0.1, 0.3, 1, 3, 10, or 20 mg/kg. In certain embodiments, each treatment cycle is about two or three weeks. The antibody may, for example, comprise a heavy chain variable domain and a light chain variable domain comprising SEQ ID NOs: 7 and 8, respectively, or may comprise a heavy chain comprising SEQ ID NO: 9 (or SED ID NO: 9 without the C-terminal lysine) and a light chain comprising SEQ ID NO: 10.
In certain embodiments, the cancer is selected from the group consisting of breast cancer, triple negative breast cancer, biliary tract cancer, cervical cancer, cholangiocarcinoma, colorectal cancer, esophageal cancer, gastric cancer, gastroesophageal junction adenocarcinoma, hepatobiliary cancer, hepatocellular carcinoma, head and neck cancer, non-small cell lung cancer, renal cell carcinoma, skin squamous cell carcinoma, ovarian cancer, pancreatic cancer, renal cell carcinoma, and urothelial cancer.
In some embodiments, the antibody is administered at a first dose and a second dose. The first dose may be higher than the second dose, or the second dose may be higher than the first dose. For example,
In some embodiments, the antibody is administered to the patient by intravenous infusion.
In some embodiments, the method further comprise administration of a single dose of pembrolizumab to the patient in each treatment cycle. For example, the pembrolizumab may be administered intravenously at 200 mg per dose. In certain embodiments, chemotherapy is also administered to the patient, e.g., carboplatin, pemetrexed, or both. In particular embodiments, the carboplatin may be administered intravenously to an AUC of 5 per treatment cycle. In particular embodiments, the pemetrexed may be administered intravenously at a dose of 500 mg/m2 per treatment cycle. Optionally, the patient may be premedicated with folic acid, vitamin B12, dexamethasone, or any combination thereof before each administration of pemetrexed. In some embodiments, each treatment cycle is about three weeks.
In some embodiments, the method further comprises administration of a single dose of cetuximab to the patient in each treatment cycle. For example, the cetuximab may be administered intravenously at 500 mg/m2 per dose. Optionally, the patient may be premedicated with a histamine-1 (H1) receptor antagonist before each administration of cetuximab. In certain embodiments, the Hi receptor antagonist is diphenhydramine, which may be administered, e.g., at a dose of 50 mg. In some embodiments, each treatment cycle is about two weeks.
In some embodiments, the methods described herein are first line therapy, second line or later therapy, or third line or later therapy.
In some embodiments, the present disclosure provides a method of treating breast cancer, biliary tract cancer, cervical cancer, colorectal cancer, esophageal cancer, gastric cancer, hepatocellular carcinoma, head and neck cancer, non-small cell lung cancer, renal cell carcinoma, skin squamous cell carcinoma, or urothelial cancer in a human patient in need thereof, comprising administering to the patient by intravenous infusion a humanized monoclonal anti-human ILT2 antibody that comprises a heavy chain and a light chain having the amino acid sequences of SEQ ID NOs: 9 and 10, respectively, in two or more treatment cycles, wherein each treatment cycle comprises a single dose of the anti-ILT2 antibody at 0.1, 0.3, 1, 3, 10 or 20 mg/kg per dose, wherein each treatment cycle is about two weeks.
In some embodiments, the present disclosure provides a method of treating biliary tract cancer, cervical cancer, colorectal cancer, esophageal cancer, gastric cancer, hepatocellular carcinoma, head and neck cancer, non-small cell lung cancer, pancreatic cancer, renal cell carcinoma, skin squamous cell carcinoma, triple negative breast cancer, or urothelial cancer in a human patient in need thereof, comprising intravenously administering to the patient
In some embodiments, the present disclosure provides a method of treating colorectal cancer, head and neck cancer, non-small cell lung cancer, ovarian cancer, or hepatobiliary cancer in a human patient in need thereof, comprising intravenously administering to the patient
In any of the methods described herein, the humanized monoclonal anti-human ILT2 antibody may be administered at a first dose and a second dose. In some embodiments, the first dose is lower than the second dose.
In some embodiments, the present disclosure provides a method of treating cancer in a human patient in need thereof, comprising administering to the patient by intravenous infusion a humanized monoclonal anti-human ILT2 antibody that comprises a heavy chain and a light chain having the amino acid sequences of SEQ ID NOs: 9 and 10, respectively, in two or more treatment cycles, wherein each treatment cycle comprises a single dose of the anti-ILT2 antibody at 1, 3, 10 or 20 mg/kg per dose, wherein the cancer is advanced stage squamous cell carcinoma of the head and neck, gastric or gastroesophageal junction adenocarcinoma, cholangiocarcinoma, or non-small cell lung cancer (e.g., non-squamous non-small cell lung cancer), wherein each treatment cycle is about two weeks. In some embodiments, the present disclosure provides a method of treating non-squamous non-small cell lung cancer in a human patient in need thereof, comprising administering to the patient by intravenous infusion
In some embodiments, the present disclosure provides a method of treating non-small cell lung cancer in a human patient in need thereof, comprising intravenously administering to the patient
In some embodiments, the present disclosure provides a method of treating gastric cancer or gastroesophageal junction adenocarcinoma in a human patient in need thereof, comprising intravenously administering to the patient
In some embodiments, the present disclosure provides a method of treating colorectal cancer in a human patient in need thereof, comprising intravenously administering to the patient
In some embodiments, the present disclosure provides a method of treating non-small cell lung cancer in a human patient in need thereof, comprising intravenously administering to the patient
In some embodiments, the present disclosure provides a method of treating cholangiocarcinoma in a human patient in need thereof, comprising intravenously administering to the patient a humanized monoclonal anti-human ILT2 antibody that comprises a heavy chain and a light chain having the amino acid sequences of SEQ ID NOS: 9 and 10, respectively, in two or more treatment cycles, wherein each treatment cycle comprises a single dose of the anti-ILT2 antibody at 1, 3, 10 or 20 mg/kg per dose, wherein each treatment cycle is about two weeks, and optionally wherein the treatment is second line or later therapy.
In certain embodiments of the above-described methods, the single dose of the anti-ILT2 antibody is 3 mg/kg per dose.
In certain embodiments of the above-described methods, the single dose of the anti-ILT2 antibody is 10 mg/kg per dose.
In certain embodiments of the above-described methods, the single dose of the anti-ILT2 antibody is 20 mg/kg per dose.
In some embodiments, the methods described herein may be used to treat cancers that are unresectable or metastatic, to treat a patient who is refractory to standard approved therapy or who is not a candidate for standard approved therapy, or any combination thereof.
The present disclosure also provides an anti-human ILT2 antibody recited herein (optionally in combination with other agents described herein), for use in treating a human patient in a therapy recited herein, and use of a monoclonal anti-human ILT2 antibody recited herein (optionally in combination with other agents described herein) for the manufacture of a medicament for treating a human patient in a therapy recited herein. Kits and articles of manufacture comprising the recited anti-human ILT2 antibodies, optionally in combination with other agents described herein (e.g., for use in a therapy recited herein), are also provided.
Other features, objectives, and advantages of the invention are apparent in the detailed description that follows. It should be understood, however, that the detailed description, while indicating embodiments and aspects of the invention, is given by way of illustration only, not limitation. Various changes and modification within the scope of the invention will become apparent to those skilled in the art from the detailed description.
The present disclosure provides safe and efficacious cancer treatment with SAR444881 or a related antibody (such as an antibody described herein, e.g., a humanized antibody having the same heavy and light chain CDRs or the same heavy and light chain variable domains as SAR444881). SAR444881 is a humanized monoclonal IgG4 antibody targeting human ILT2. See also PCT Patent Publications WO 2021/028921 and WO 2022/034524
In some embodiments, a cancer therapy described herein uses an anti-ILT2 antibody that is SAR444881 or a related antibody (e.g., an antibody described herein), or an antigen-binding portion of said anti-ILT2 antibody. The SAR444881 heavy chain sequence (SEQ ID NO: 9) is shown below, with its variable domain sequence in boldface and italics (SEQ ID NO: 7) and its CDR1-3 (SEQ ID NOs: 1-3, respectively) underlined:
DVQLQGSGPG LVKPSETLSL TCSVTGYSIT
SGYYWN
WIRQ
FPGKKLEWMG
YISYDGSNNY NPSLKN
RITI SRDTSKNQFS
LKLNSVTAAD TATYYCAH
GY SYYYAMDA
WG QGTSVTVSS
A
The SAR444881 light chain sequence (SEQ ID NO: 10) is shown below, with its variable domain sequence in boldface and italics (SEQ ID NO: 8) and its CDR1-3 (SEQ ID NOs: 4-6, respectively) underlined:
DIQMTQSPSS LSASVGDRVT IT
CRTSQDIS NYLN
WYQQKP
GKAVKLLIS
Y
TSRLHS
GVPS RFSGSGSGTD YTLTISSLQP
EDFATYYC
QQ GNTLPT
FGQG TKLEIK
RTVA APSVFIFPPS
In some embodiments, the anti-ILT2 antibody is of human IgG4 isotype subtype, optionally comprising mutations S228P and/or L235E (Eu numbering). In certain embodiments, (e.g., any of the embodiments described herein), the anti-ILT2 antibody is of isotype IgG4 and has mutations S228P and L235E (Eu numbering).
In certain embodiments, the anti-ILT2 antibody comprises the six CDR amino acid sequences of SAR444881. The CDRs may be assigned in accordance with any method known in the art, such as IMGT® definitions (Lefranc et al., Dev Comp Immunol. (2003) 27(1): 55-77); or in accordance with the definitions of Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, MD (1987 and 1991)); Chothia & Lesk, J Mol Biol. (1987) 196:901-17; Chothia et al., Nature (1989) 342:878-83; MacCallum et al., J Mol Biol. (1996) 262:732-45; or Honegger and Plückthun, J Mol Biol. (2001) 309 (3): 657-70, or any combination of these definitions (Kabat plus Chothia, for example). Examples of CDR definitions under different methods is shown below for SAR444881 (SEQ: SEQ ID NO):
Thus, for example, the SAR444881 IMGT®-defined HCDR1-3 and LCDR1-3 sequences of
SEQ ID NOs: 1-6, respectively, may be replaced in any embodiment described herein by
SEQ ID NOs: 11, 12, 3, 4, 5, and 6, respectively;
SEQ ID NOs: 13, 14, 15, 19, 20, and 6, respectively; or
SEQ ID NOs: 16, 17, 18, 21, 22, and 23, respectively.
Also contemplated is a set of SAR444881 CDRs wherein each of HCDR1, HCDR2, HCDR3,LCDR1, LCDR2, and LCDR3 may individually be specified according to any of the methods for defining SAR444881 CDRs as shown above (e.g., HCDR1 specified by the Kabat definition, HCDR2 specified by the Chothia definition, etc.).
In certain embodiments, the anti-ILT2 antibody comprises HCDR1-3 and LCDR1-3 amino acid sequences of SEQ ID NOs: 1-6, respectively.
In some embodiments, the anti-ILT2 antibody comprises the heavy and light chain variable domain amino acid sequences of SAR444881. In certain embodiments, the anti-ILT2 antibody may comprise a heavy chain variable domain (VH) that is at least 90% (e.g., at least 95%, 98%, or 99%) identical in sequence to SEQ ID NO: 7, and a light chain variable domain (VL) that is at least 90% (e.g., at least 95%, 98%, or 99%) identical in sequence to SEQ ID NO: 8. Optionally, said antibody may comprise the six CDRs of SAR444881 (e.g., SEQ ID NOs: 1-6). In certain embodiments, the anti-ILT2 antibody comprises a VH comprising SEQ ID NO: 7 and a VI. comprising SEQ ID NO: 8.
In some embodiments, the anti-ILT2 antibody comprises the heavy and light chain amino acid sequences of SAR444881. In certain embodiments, the anti-ILT2 antibody comprises a heavy chain (HC) that is at least 90% (e.g., at least 95%, 98%, or 99%) identical in sequence to SEQ ID NO: 9, and a light chain (LC) that is at least 90% (e.g., at least 95%, 98%, or 99%) identical in sequence to SEQ ID NO: 10. Optionally, said antibody may comprise the six CDRs (e.g., SEQ ID NOs: 1-6) or the VH and VL. (e.g., SEQ ID NOs: 7 and 8, respectively) of SAR444881. In certain embodiments, the anti-ILT2 antibody comprises an HC comprising SEQ ID NO: 9 (optionally without the C-terminal lysine) and an LC comprising SEQ ID NO: 10.
SAR444881 can be provided, for example, in solid form (e.g., lyophilized form) that is reconstituted in a suitable pharmaceutical solution before administration to a patient, or in an aqueous pharmaceutical solution. In certain embodiments, the antibody is provided in a pharmaceutical composition that further comprises a pharmaceutically acceptable excipient.
In some embodiments, a pharmaceutical composition comprising an anti-ILT2 antibody as recited herein (e.g., SAR444881) is provided in an article of manufacture or kit such as one that comprises one or more containers containing the composition and a label associated with the container(s). The container may be a single use container (e.g., for intravenous delivery), such as a single use boule or vial, or a single use, pre-filled syringe or injector. In some embodiments, the container contains a single dose (e.g., a dose recited herein) of the anti-ILT2 antibody, wherein the container may be a vial or a pre-filled syringe or injector. In some embodiments, the article of manufacture or kit further comprises one or more containers comprising additional agents, e.g., those administered in addition to SAR444881 in the combination therapies described herein. For example, the one or more containers may comprise pembrolizumab, cetuximab, carboplatin, pemetrexed, or any combination thereof, e.g., in single or multiple doses described herein for those agents. In certain embodiments, an article of manufacture or kit of the present disclosure comprises 1) containers comprising SAR444881; 2) containers comprising SAR444881 and pembrolizumab; 3) containers comprising SAR444881, pembrolizumab, pemetrexed, and carboplatin; or 4) containers comprising SAR444881 and cetuximab; optionally wherein the containers are for intravenous delivery.
The present disclosure relates to treatment of cancer in human patients in need thereof with SAR444881 or a related anti-ILT2 antibody, such as an anti-ILT2 antibody described herein. The treatment may further comprise pembrolizumab (e.g., in combination with chemotherapy such as carboplatin and/or pemetrexed) or cetuximab.
In some embodiments, the patient is an adult (≥18 years of age).
In some embodiments, the patient has unresectable or metastatic disease and is refractory to or is not a candidate for standard approved therapy. In some embodiments, the patient has failed all standard of care therapies. In some embodiments, the patient has received and failed prior treatment with pembrolizumab or another anti-PD-1 or anti-PD-L1 therapy. In some embodiments, the patient has received and failed prior treatment with fluoropyrimidine, oxaliplatin, or irinotecan, with bevacizumab and/or cetuximab. In some embodiments, the patient has received and failed prior treatment with fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab and/or cetuximab. In some embodiments (e.g., where the patient has RAS wild-type colorectal cancer), the patient has received and failed, or relapsed on, or is ineligible for treatment with, 5-fluorouracil, irinotecan, oxaliplatin, bevacizumab and anti-EGFR. In some embodiments (e.g., where the patient has RAS-mutant colorectal cancer), the patient has received and failed, or relapsed on, or is ineligible for treatment with, bevacizumab. In some embodiments (e.g., where the patient has BRAF-mutant colorectal cancer), the patient has received and failed, or relapsed on, or is ineligible for treatment with, encorafenib or other BRAF targeted therapies.
In some embodiments, the patient has Eastern Cooperative Oncology Group Performance Status (ECOG) of 0 or 1.
In some embodiments, the patient has been diagnosed with one or more conditions selected from the group consisting of: breast cancer (e.g., triple negative breast cancer), cervical cancer, colorectal cancer (e.g., K-Ras wild-type colorectal cancer or BRAF-mutant colorectal cancer; optionally non-MSI-H disease), adenocarcinoma or squamous cell carcinoma of the esophagus, gastric or gastroesophageal junction adenocarcinoma (e.g., Siewert Types 2 and 3), pancreatic adenocarcinoma, squamous cell carcinoma of the head and neck or the skin, hepatobiliary cancers (e.g., hepatocellular carcinoma, gallbladder cancer, or cholangiocarcinoma, such as advanced cholangiocarcinoma), non-small cell lung cancer (e.g., stage IV squamous or non-squamous NSCLC as per American Joint Committee on Cancer [AJCC] 8th edition), renal cell carcinoma, or urothelial carcinoma.
In some embodiments, the patient does not have active, known, or suspected autoimmune disease (optionally except for one or more of type I diabetes mellitus, hypothyroidism only requiring hormone replacement, a skin disorder not requiring systemic treatment (such as vitiligo, psoriasis, or alopecia), or a condition not expected to recur in the absence of an external trigger).
In some embodiments, the patient does not have known active CNS metastases and/or carcinomatous meningitis.
In some embodiments, the patient does not have coronary artery disease or a history of myocardial infarction, high risk of uncontrolled arrhythmia or uncontrolled cardiac insufficiency, and/or uncontrolled or poorly controlled hypertension (e.g., >180 mmHg systolic or >130 mmHg diastolic).
In some embodiments, the patient demonstrates increased baseline levels of ILT2-positive immune cells (e.g., NKT cells, PD-1-negative CD8 TEMRA cells, and/or dendritic cells), and/or increased levels of soluble HLA-G prior to treatment. Levels of ILT2-positive immune cells and/or soluble HLA-G may be increased from baseline by, e.g., by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, or 500%.
In some embodiments, the patient fulfills one or more of the inclusion criteria listed in Examples 1 and 2 below. In certain embodiments, the patient fulfills all of the inclusion criteria listed in Example 1 for a given indication or dosage regimen. In certain embodiments, the patient fulfills all of the inclusion criteria listed in Example 2 for a given indication or dosage regimen.
In some embodiments, the patient does not fulfill one or more of the exclusion criteria listed in Examples 1 and 2 below. In certain embodiments, the patient does not fulfill any of the exclusion criteria listed in Example 1 for a given indication or dosage regimen. In certain embodiments, the patient does not fulfill any of the exclusion criteria listed in Example 2 for a given indication or dosage regimen.
The present disclosure relates to treating cancer in a patient as described herein, with SAR444881 or a related anti-ILT2 antibody (e.g., an anti-ILT2 antibody described herein). In some embodiments, the treatment further comprises pembrolizumab (e.g., in combination with chemotherapy such as carboplatin and/or pemetrexed) or cetuximab.
The present therapies can be used as a first line therapy to treat treatment-naïve patients, i.e., those who have not been treated with anti-cancer drugs (e.g., drugs against the specific cancer with which the patient presents). The present therapies can also be used to treat patients who have been treated with anti-cancer drugs (e.g., drugs against the specific cancer with which the patient presents), but these patients may have failed to respond to the previous treatment, or may have since experienced worsening of the disease or renewed disease activity. In some embodiments, the present therapies are used as a second line or later therapy. In some embodiments, the present therapies are used as a third line or later therapy.
In some embodiments, the present therapies are used to treat a cancer that is unresectable. In some embodiments, the present therapies are used to treat a cancer that is metastatic. In some embodiments, the patient is refractory to standard approved therapy. In some embodiments, the patient is not a candidate for standard approved therapy. In some embodiments, the patient has failed all standard approved therapies. Any combination of the above is also contemplated.
Administration of the anti-ILT2 antibody may be parenteral, e.g., intravenous. For example, the anti-ILT2 antibody may be administered through an intravenous infusion drip over about 15, 30, 45, 60, 75, or 90 minutes. In some embodiments, the antibody is intravenously administered at a dose of 0.05-50 mg/kg, such as at a dose of 0.1-20 mg/kg, e.g., about 0.1, 0.3, 0.5, 1, 1.5, 3, 5, 10, 15, or 20 mg/kg, per treatment cycle. In certain embodiments, the dose is 0.1, 0.3, 1, 3, 10, or 20 mg/kg per treatment cycle. In particular embodiments, the dose is 1, 3, 10, or 20 mg/kg per treatment cycle. In some embodiments, each treatment cycle is about 1, 2, 3, 4, 5, 6, 7, or 8 weeks. In certain embodiments, each treatment cycle is about two weeks or about three weeks. The therapy may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, or more treatment cycles (optionally consecutive). In particular embodiments, the therapy comprises two or more treatment cycles (optionally consecutive). Where treatment cycles are consecutive, there is no period of delay between cycles; for example, for consecutive two week treatment cycles, the day after day 14 of one treatment cycle would be day 1 of the next treatment cycle.
In certain embodiments, the antibody is administered through an intravenous
infusion drip over about 30 minutes (e.g., at a dose of 0.1 mg/kg). In some embodiments, the antibody is administered through an intravenous infusion drip over about 60 minutes (e.g., at a dose of 0.3, 1, 3, 10, or 20 mg/kg).
In some embodiments, the anti-ILT2 antibody is intravenously administered at a dose of 1 mg/kg every two weeks.
In some embodiments, the anti-ILT2 antibody is intravenously administered at a dose of 3 mg/kg every two weeks.
In some embodiments, the anti-ILT2 antibody is intravenously administered at a dose of 10 mg/kg every two weeks.
In some embodiments, the anti-ILT2 antibody is intravenously administered at a dose of 20 mg/kg every two weeks.
In some embodiments, the anti-ILT2 antibody is intravenously administered at a dose of 1 mg/kg every three weeks.
In some embodiments, the anti-ILT2 antibody is intravenously administered at a dose of 3 mg/kg every three weeks.
In some embodiments, the anti-ILT2 antibody is intravenously administered at a dose of 10 mg/kg every three weeks.
In some embodiments, the anti-ILT2 antibody is intravenously administered at a dose of 20 mg/kg every three weeks.
In some embodiments, the anti-ILT2 antibody may be intravenously administered to the patient at two or more doses (e.g., doses recited above) in different treatment cycles. For example, the first administration of the antibody may be at a first dose and subsequent administration of the antibody may be at a second dose. In certain embodiments, the first dose is lower than the second dose. In certain embodiments, the first dose (“loading dose”) is higher than the second dose. For example, the first and second antibody doses may be:
In certain embodiments, the anti-ILT2 antibody is used to treat a cancer, e.g., a PD-1-related or PD-L1-related cancer. A PD-1-related cancer may be, e.g., a cancer associated with the binding of PD-1 to PD-L1 and/or PD-L2, and may in some embodiments to be associated with elevated expression of PD-1 (e.g., as determined in a tumor sample from a patient). A PD-L1-related cancer may be, e.g., a cancer associated with the binding of PD-L1 to PD-1, and may in some embodiments be associated with elevated expression of PD-L1 (e.g., as determined in a tumor sample from a patient). In particular embodiments, the cancer is selected from breast cancer (e.g., triple negative breast cancer), biliary tract cancer, cervical cancer, cholangiocarcinoma, colorectal cancer, esophageal cancer (e.g., adenocarcinoma or squamous cell carcinoma of the esophagus), gastric cancer, gastroesophageal junction adenocarcinoma, hepatobiliary cancer, hepatocellular carcinoma, head and neck cancer (e.g., squamous cell carcinoma of the head and neck), non-small cell lung cancer (e.g., squamous or non-squamous non-small cell lung cancer), renal cell carcinoma, skin squamous cell carcinoma, ovarian cancer, pancreatic cancer, renal cell carcinoma, and urothelial cancer.
In some embodiments, an anti-ILT2 antibody described herein is administered alone (monotherapy). In certain embodiments, the anti-ILT2 antibody monotherapy is used to treat a cancer selected from breast cancer, biliary tract cancer, cervical cancer, colorectal cancer, esophageal cancer, gastric cancer, hepatocellular carcinoma, head and neck cancer, non-small cell lung cancer, renal cell carcinoma, skin squamous cell carcinoma, and urothelial cancer. In certain embodiments, the anti-ILT2 antibody monotherapy is used to treat a cancer selected from advanced stage squamous cell carcinoma of the head and neck, gastric or gastroesophageal junction adenocarcinoma, cholangiocarcinoma, or non-squamous non-small cell lung cancer. In particular embodiments, the anti-ILT2 antibody monotherapy is used to treat cholangiocarcinoma. In some embodiments, the treatment may comprise SAR444881 at a dose of 1, 3, 10, or 20 mg/kg per treatment cycle. In certain embodiments, each treatment cycle is about two weeks.
In some embodiments, the anti-ILT2 antibody described herein (e.g., SAR444881) is administered in combination with an anti-PD-1 or anti-PD-LI agent, e.g., an anti-PD-1 antibody such as pembrolizumab. In certain embodiments, the pembrolizumab is administered intravenously to the patient (such as through intravenous infusion drip over, for example, about 30 minutes), for example at a dose of 100, 150, 200, 250, or 300 mg per treatment cycle. In particular embodiments, the pembrolizumab is administered intravenously to the patient at a dose of 200 mg per treatment cycle.
In some embodiments, the combination therapy comprising an anti-ILT2 antibody described herein (e.g., SAR444881) and an anti-PD-1 or anti-PD-LI agent (e.g., pembrolizumab) further comprises one or more chemotherapeutic agents (e.g., carboplatin and/or pemetrexed). In certain embodiments, the combination therapy comprises SAR444881, pembrolizumab, carboplatin, and pemetrexed. In particular embodiments, the carboplatin is administered intravenously (such as through intravenous infusion drip) in the combination therapy to an AUC (area under the concentration-time curve) of 2.5, 3.75, or 5 (e.g., to an AUC of 5) per treatment cycle. In some embodiments, carboplatin is administered for no more than 3, 4, or 5 (e.g., 4) treatment cycles. In particular embodiments, the pemetrexed is administered intravenously (such as through intravenous infusion drip, for example, over about 10 minutes) at a dose of 250, 375, or 500 mg/m2 (e.g., 500 mg/m2) per treatment cycle. Optionally, one or more administrations of pemetrexed (e.g., all administrations) may be preceded by premedication with folic acid, vitamin B12, dexamethasone, or any combination thereof. In some embodiments, the folic acid is administered at an oral dose of about 350-1000 μg. For example, in certain embodiments, five daily doses of folic acid may be taken during the seven days preceding the first dose of pemetrexed, and folic acid dosing continues during the full course of therapy and for about 21 days after the last dose of pemetrexed. In some embodiments, the vitamin B12 is administered at a dose of about 1000 μg through intramuscular injection (e.g., in the week preceding the first dose of pemetrexed and once every three cycles thereafter, optionally on the same day as pemetrexed administration). In some embodiments, the dexamethasone is administered at an oral dose of about 4 mg twice per day (or equivalent), e.g., the day before, day of, and day after pemetrexed administration.
In some embodiments, the combination therapy comprising an anti-ILT2 antibody described herein (e.g., SAR444881), an anti-PD-1 or anti-PD-LI agent (e.g., pembrolizumab), and optionally one or more chemotherapeutic agents (e.g., carboplatin and/or pemetrexed) is administered in treatment cycles of about two, three, or four weeks. In certain embodiments, each treatment cycle is about three weeks.
In some embodiments, the combination therapy comprising an anti-ILT2 antibody described herein (e.g., SAR444881) and an anti-PD-1 or anti-PD-L1 agent (e.g., pembrolizumab) is used to treat a cancer selected from biliary tract cancer, cervical cancer, colorectal cancer, esophageal cancer, gastric cancer, hepatocellular carcinoma, head and neck cancer, non-small cell lung cancer, pancreatic cancer, renal cell carcinoma, skin squamous cell carcinoma, triple negative breast cancer, and urothelial cancer. For example, the combination therapy may comprise SAR444881 at a dose of 1, 3, 10, or 20 mg/kg per treatment cycle and pembrolizumab at a dose of 200 mg per treatment cycle. In certain embodiments, each treatment cycle is about three weeks.
In some embodiments, the combination therapy comprising an anti-ILT2 antibody described herein (e.g., SAR444881) and an anti-PD-1 or anti-PD-LI agent (e.g., pembrolizumab) is used to treat lung cancer, e.g., non-small cell lung cancer. For example, the combination therapy may comprise SAR444881 at a dose of 1, 3, 10, or 20 mg/kg per treatment cycle and pembrolizumab at a dose of 200 mg per treatment cycle. In certain embodiments, each treatment cycle is about three weeks. In certain embodiments, the combination therapy is second line or later therapy. In certain embodiments, the combination therapy is third line or later therapy.
In some embodiments, the combination therapy comprising an anti-ILT2 antibody described herein (e.g., SAR444881) and an anti-PD-1 or anti-PD-LI agent (e.g., pembrolizumab) is used to treat gastric cancer or gastroesophageal junction adenocarcinoma. For example, the combination therapy may comprise SAR444881 at a dose of 1, 3, 10, or 20 mg/kg per treatment cycle and pembrolizumab at a dose of 200 mg per treatment cycle. In certain embodiments, each treatment cycle is about three weeks. In certain embodiments, the combination therapy is second line or later therapy. In certain embodiments, the combination therapy is third line or later therapy.
In some embodiments, the combination therapy comprising an anti-ILT2 antibody described herein (e.g., SAR444881), an anti-PD-1 or anti-PD-LI agent (e.g., pembrolizumab), and optionally one or more chemotherapeutic agents (e.g., carboplatin and/or pemetrexed) is used to treat lung cancer, e.g., non-squamous non-small cell lung cancer. For example, the combination therapy may comprise SAR444881 at a dose of 1, 3, 10, or 20 mg/kg per treatment cycle, pembrolizumab at a dose of 200 mg per treatment cycle, carboplatin to a dose to AUC of 5 per treatment cycle, and pemetrexed at a dose of mg/m2 per treatment cycle. In certain embodiments, each treatment cycle is about three weeks. In certain embodiments, the combination therapy is first line therapy. In certain embodiments, the combination therapy is second line or later therapy. In certain embodiments, the combination therapy is third line or later therapy. In particular embodiments, the patient is pretreated with folic acid, vitamin B12, and/or dexamethasone (e.g., all three) before each administration of pemetrexed. In some embodiments, carboplatin is administered for no more than 3, 4, or 5 (e.g., 4) treatment cycles.
In some embodiments, the anti-ILT2 antibody described herein (e.g., SAR444881) is administered in combination with an anti-EGFR agent, e.g., an anti-EGFR antibody such as cetuximab. In certain embodiments, the cetuximab is administered intravenously (such as through intravenous infusion drip, for example, over about 120 minutes) to the patient, e.g., at a dose of 400, 450, 500, 550, or 600 mg/m2 per treatment cycle. In particular embodiments, the cetuximab is administered intravenously to the patient at a dose of 500 mg/m2 per treatment cycle. Optionally, one or more administrations of cetuximab (e.g., all administrations) may be preceded by premedication with a histamine-1 (H1) receptor antagonist (and additionally or alternatively with acetaminophen/paracetamol and/or corticosteroids). Administration of the H1 receptor antagonist may be intravenous (such as through intravenous infusion drip, for example over about 30-60 minutes). In certain embodiments, the H1 receptor antagonist is diphenhydramine. The diphenhydramine may be administered at a dose of, e.g., 30, 40, or 50 mg per treatment cycle, and in particular embodiments is administered at a dose of 50 mg per treatment cycle.
In some embodiments, the combination therapy comprising an anti-ILT2 antibody described herein (e.g., SAR444881) and an anti-EGFR agent (e.g., cetuximab) is administered in treatment cycles of about one, two, or three, weeks. In certain embodiments, each treatment cycle is about two weeks.
In some embodiments, the combination therapy comprising an anti-ILT2 antibody described herein (e.g., SAR444881) and an anti-EGFR agent (e.g., cetuximab) is used to treat a cancer selected from colorectal cancer, head and neck cancer, non-small cell lung cancer, ovarian cancer, and hepatobiliary cancer. In some embodiments, the hepatobiliary cancer is hepatocellular carcinoma, gallbladder cancer, or cholangiocarcinoma.
In some embodiments, the combination therapy comprising an anti-ILT2 antibody described herein (e.g., SAR444881) and an anti-EGFR agent (e.g., cetuximab) is used to treat colorectal cancer. For example, the combination therapy may comprise SAR444881 at a dose of 1, 3, 10, or 20 mg/kg per treatment cycle and cetuximab at a dose of 500 mg/m2 per treatment cycle. In certain embodiments, each treatment cycle is about two weeks. In certain embodiments, the combination therapy is second line or later therapy. In certain embodiments, the combination therapy is third line or later therapy. Optionally, each administration of cetuximab may be preceded by premedication with diphenhydramine, e.g., at a dose of 50 mg per treatment cycle.
In some embodiments, the combination therapy comprising an anti-ILT2 antibody described herein (e.g., SAR444881) and an anti-EGFR agent (e.g., cetuximab) is used to treat non-small cell lung cancer. For example, the combination therapy may comprise SAR444881 at a dose of 1, 3, 10, or 20 mg/kg per treatment cycle and cetuximab at a dose of 500 mg/m2 per treatment cycle. In certain embodiments, each treatment cycle is about two weeks. In certain embodiments, the combination therapy is second line or later therapy. In certain embodiments, the combination therapy is third line or later therapy. Optionally, each administration of cetuximab may be preceded by premedication with diphenhydramine, e.g., at a dose of 50 mg per treatment cycle.
As used herein, the term “treatment cycle” refers to a period during which agents that comprise a therapeutic regimen are administered on proscribed days; the treatment cycle may be repeated on a regular schedule. For example, in a two-week treatment cycle of SAR444881 monotherapy, SAR444881 may be administered on day 1 of each cycle (e.g., every two weeks). For combination therapies described herein, the recited doses of the agents may be administered on the same day of the treatment cycle, on different days of the treatment cycle, or any combination thereof for more than two agents. For example, SAR444881 may be administered on the same or different days of the treatment cycle from pembrolizumab or cetuximab. In embodiments where the combination therapy comprises SAR444881, pembrolizumab, and chemotherapy (e.g., carboplatin and/or pemetrexed), SAR444881 may be administered on the same day of the treatment cycle as pembrolizumab, but on a different day from the chemotherapy; on different days from pembrolizumab and the chemotherapy (which may be administered on the same or different days); or on the same day as the chemotherapy but on a different day from pembrolizumab. In certain embodiments, the recited doses of the agents are all administered on the same day of the treatment cycle. In some embodiments, pembrolizumab or cetuximab will be administered first, followed by SAR444881. In certain embodiments, SAR444881 administration starts at least about 30 minutes after completion of pembrolizumab administration. In certain embodiments, SAR444881 administration starts at least about 60 minutes after completion of cetuximab administration. For treatments including pembrolizumab and chemotherapy, in some embodiments, the treatment follows the following dosing sequence: pembrolizumab, chemotherapy, and SAR444881 (e.g., wherein the SAR444881 administration is at least about 30 minutes after completion of pembrolizumab administration). For example, where the chemotherapy comprises pemetrexed and carboplatin, the dosing sequence may be, e.g.: pembrolizumab, pemetrexed premedication, pemetrexed, carboplatin, and SAR444881.
In certain embodiments, doses recited herein for any or all agents in the described therapies are single doses per treatment cycle.
In some embodiments (e.g., in the event of a noted or expected infusion reaction), intravenous infusion(s) in a treatment recited herein may be preceded by a prophylactic premedication. In certain embodiments, the premedication may be diphenhydramine (e.g., at a dose of about 50 mg) and/or acetaminophen/paracetamol (e.g., at a dose of about 325-1000 mg). In some embodiments, the premedication is administered at least about 15, 30, or 45 (e.g., at least about 30) minutes before subsequent treatment infusions. In some embodiments, infusion reactions may also be treated or prevented using corticosteroids (e.g., up to about 25 mg of hydrocortisone sodium succinate or equivalent).
The present therapies are contemplated to be efficacious in cancer patients. The therapies may, e.g., result in inhibition of tumor growth, tumor regression, slowing or reversal of metastasis, prolonged survival, prolonged progression-free survival, prevention of cancer recurrence or residual disease, alleviation of cancer symptoms, or any combination thereof. In some embodiments, the therapies increase immune activity in the patient. The increased immune activity may be demonstrated, e.g., by increased levels of CD62L on the surface of classical monocytes. CD62L, also known as L-selectin, is a cell adhesion molecule that plays a role in regulating the recruitment of monocytes to tissues from the blood during inflammation. Additionally or alternatively, the increased immune activity may be demonstrated by increased levels of immune activation markers such as CD69 (e.g., on ILT2-expressing natural killer T cells) and CD107a (e.g., on ILT2-expressing CD8 TEMRA and natural killer cells).
In some embodiments, the present therapies increase expression of CD62L on classical monocytes in patients. In some embodiments, the present therapies increase the levels of cytokines such as CCL4, CXCL11, CCL23, granzyme B, TNFα, IFNγ, GM-CSF, or any combination thereof, in patients. In some embodiments, the present therapies downregulate CCL7 in patients. In some embodiments, the present therapies activate monocytes. In some embodiments, the present therapies activate ILT2-expressing T and/or NK cell subsets. In some embodiments, the present therapies increase intratumoral necrosis. In some embodiments, the present therapies increase tumor infiltration of CD8 T cells. Any combination of the above effects is also contemplated.
Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure. In case of conflict, the present specification, including definitions, will control. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Throughout this specification and embodiments, the words “have” and “comprise,” or variations such as “has,” “having,” “comprises,” or “comprising,” will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. All publications and other references mentioned herein are incorporated by reference in their entirety. Although a number of documents are cited herein, this citation does not constitute an admission that any of these documents forms part of the common general knowledge in the art. As used herein, the term “approximately” or “about” as applied to one or more values of interest refers to a value that is similar to a stated reference value. In certain embodiments, the term refers to a range of values that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context.
According to the present disclosure, back-references in the dependent claims are meant as short-hand writing for a direct and unambiguous disclosure of each and every combination of claims that is indicated by the back-reference. Any treatment method disclosed herein may be used to treat any individual as defined herein. Further, headers herein are created for case of organization and are not intended to limit the scope of the claimed invention in any manner.
In order that this invention may be better understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention in any manner.
This Example outlines the protocol and preliminary results for an open-label, multicenter, Phase 1/2, first-in-human study of the safety, tolerability, and anti-tumor activity of intravenous SAR444881, a humanized monoclonal IgG4 antibody targeting ILT2. The study will evaluate SAR444881, as a single agent and when combined with pembrolizumab or with cetuximab, for treatment of cancer patients with advanced solid tumors where no other standard of care treatment option is available. Given the known mechanism of action of ILT2 and its potential role in cancer, the study focuses on tumor types known to express HLA-G. Tumor types included in SAR444881-cetuximab combination cohorts are tumors known to over-express the EGFR protein.
The proposed study is comprised of two parts-a dose escalation phase (Part 1) and a dose optimization/expansion phase (Part 2). Part 1 is comprised of three sub-parts: SAR444881 administered as a monotherapy (Sub-Part 1A), SAR444881 administered in combination with pembrolizumab (Sub-Part 1B), and SAR444881 administered in combination with cetuximab (Sub-Part 1C). Part 2 is composed of two sub-parts: a dose optimization part where up to two doses of SAR444881 per indication are administered in combination with pembrolizumab, pembrolizumab and chemotherapy, or cetuximab (Sub-Part 2A); and a dose expansion part where SAR444881 is administered alone (Sub-Part 2B).
The objectives for the dose escalation phase (Part 1) are to assess the safety and tolerability, and to determine the MTD (or MAAD, if no MTD is reached) and the recommended dose(s) of SAR444881 when administered alone and in combination with pembrolizumab or with cetuximab. Dose escalation in all three sub-parts will follow a standard “3+3” design enrolling at least 3 participants per dose level cohort. The dose escalation phase of the study will enroll cancer patients with advanced disease who are refractory to or are not candidates for standard approved therapy.
Part 2, which includes five cohorts, is designed to assess preliminary anti-tumor activity and optimal dose of SAR444881 as a single agent and in combination in cancer patients with select advanced solid tumors known to express HLA-G and a likelihood of sensitivity to immunotherapies as observed with other checkpoint inhibitors. It will enroll participants with unresectable or metastatic disease. The proposed study aims to establish proof-of-concept for SAR444881 as a monotherapy or in combination with: 1) the anti-PD1 monoclonal antibody pembrolizumab; 2) the anti-EGFR monoclonal antibody cetuximab; or 3) pembrolizumab and chemotherapy. Part 2 is divided into two sub-parts: in Sub-Part 2A (Dose Optimization), the preliminary anti-tumor activity and optimal dose of SAR444881 is assessed in combination with the aforementioned anti-tumor agents; and in Sub-Part 2B (Dose Expansion), the preliminary anti-tumor activity of SAR444881 is assessed as a monotherapy. An overview of the study cohorts is provided below:
The primary objectives of the dose escalation phase of this study (Part 1) are to assess the safety and tolerability of SAR444881, the MTD or MAAD, and the recommended doses of SAR444881 for expansion/optimization when administered alone or in combination with pembrolizumab or with cetuximab.
The secondary objectives of the dose escalation phase of this study are:
The exploratory objectives of the dose escalation phase of this study are:
The primary objectives of the dose expansion/optimization phase of this study (Part 2) are to assess the preliminary antitumor activity of SAR444881 (alone or in combination with pembrolizumab, cetuximab, or pembrolizumab and chemotherapy), and to define the optimal dose of SAR444881 in combination with pembrolizumab, cetuximab, or pembrolizumab and chemotherapy.
The secondary objectives of the dose expansion/optimization phase of this study are:
The exploratory objectives of the dose expansion/optimization phase of this study are:
The primary endpoints for the dose escalation phase of this study (Sub-Parts 1A/1B/1C) are to assess:
The secondary endpoints for the dose escalation phase are to assess:
The exploratory endpoints for the dose escalation phase are to assess:
The primary endpoint for the dose optimization/expansion phase is to assess ORR per RECIST v1.1 (other datapoints may be utilized to supplement assessment of optimal SAR444881 dose).
The secondary endpoints for the dose optimization/expansion phase are to assess:
The exploratory endpoints for the dose optimization/expansion phase are to assess:
Study participants are selected based on the following inclusion and exclusion criteria:
Exclusionary criteria for participants include the following:
SAR444881 Monotherapy Dose Escalation (Sub-Part 1A): SAR444881 will be administered to participants in escalating doses. Each participant will be administered SAR444881 in two-week intervals at one of the following planned dose levels: 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg, or 20 mg/kg.
SAR444881 Combination with Pembrolizumab Dose Escalation (Sub-Part 1B): SAR444881 will be administered in escalating doses in combination with pembrolizumab. The starting dose of SAR444881 in Sub-Part 1B will be 1 mg/kg or one dose level below the established SAR444881 monotherapy MTD, the lower of the two. The dose of SAR444881 will be escalated up to SAR444881 monotherapy MTD (or MAAD, if no MTD is reached) following the same escalation scheme of Sub-Part 1A. All participants will receive pembrolizumab at a dose of 200 mg. Treatment will be administered in three-week intervals.
SAR444881 Combination with Cetuximab Dose Escalation (Sub-Part 1C): SAR444881 will be administered in escalating doses in combination with cetuximab. The starting dose of SAR444881 in Sub-Part 1C will be 1 mg/kg or one dose level below the established SAR444881 monotherapy MTD, the lower of the two. The dose of SAR444881 will be escalated up to SAR444881 monotherapy MTD (or MAAD, if no MTD is reached) following the same escalation scheme of Sub-Part 1A. All participants will receive cetuximab at a dose of 500 mg/m2. Treatment will be administered in two-week intervals. Premedication with a histamine-1 (H1) receptor antagonist will be given prior to each cetuximab dosing.
SAR444881 Combination Dose Optimization (Sub-Part 2A): SAR444881 will be administered in combination with one or more of the following: 1) the anti-PDI monoclonal antibody pembrolizumab at a dose of 200 mg; 2) the anti-EGFR monoclonal antibody cetuximab at a dose of 500 mg/m2; and 3) chemotherapy. The chemotherapy administered will include carboplatin at a dose of 10 mg/mL and pemetrexed at a dose of 500 mg/m2. The dose level of SAR444881 in Sub-Part 2A will be determined based on data from each sub-part of the dose escalation phase. Sub-Part 2A is divided into four cohorts:
SAR444881 Monotherapy Dose Expansion (Sub-Part 2B): SAR444881 will be administered as a monotherapy (Cohort D1). The dose level of SAR444881 in Sub-Part 2B will be determined based on data from the dose escalation phase. SAR444881 will be administered in two-week intervals. The anti-tumor activity of SAR444881 monotherapy will be evaluated in one of the following indications: advanced stage squamous cell carcinoma of the head and neck, gastric or gastroesophageal junction adenocarcinoma, cholangiocarcinoma, and non-squamous non-small cell lung cancer.
Study treatments and modes of administration are summarized in Table 1 below:
SAR444881 will be infused over 60 minutes at all dosage levels, except for the 0.1 mg/kg dosage, which will be infused over 30 minutes. Pembrolizumab, cetuximab, carboplatin, and pemetrexed will be administered according to their recommended dosage and administration including use of premedication. No dose reduction for pembrolizumab is allowed. Cetuximab dosage may be modified for adverse reactions management in accordance with the drug's Prescribing Information.
For combination cohorts, pembrolizumab or cetuximab will be infused first, followed by SAR444881. The SAR444881 infusion will start at least 30 minutes after completion of the pembrolizumab infusion and at least 60 minutes after the cetuximab infusion.
All participants administered cetuximab will be premedicated with a histamine-1 (H1) receptor antagonist intravenously (e.g., diphenhydramine 50 mg) 30-60 minutes prior to each cetuximab dosing. Premedication for patients in cohort A1 receiving pemetrexed include folic acid, vitamin B12, and dexamethasone.
For all study participants, SAR444881 infusions will require a 60-minute observation period following the completion of the infusion for the first 2 doses and a 30-minute observation period for all subsequent doses.
Cohort A1 dosing sequence: pembrolizumab, pemetrexed premedication, pemetrexed, carboplatin, and SAR444881 (start of SAR444881 infusion should be at least 30minutes after completion of pembrolizumab infusion).
This Example outlines the protocol and preliminary results for an open-label, multicenter, Phase 1/2, first-in-human study of the safety, tolerability, and anti-tumor activity of intravenous SAR444881, a humanized monoclonal IgG4 antibody targeting ILT2. The study will evaluate SAR444881, as a single agent and when combined with pembrolizumab or with cetuximab, for treatment of cancer patients with advanced solid tumors where no other standard of care treatment option is available. Given the known mechanism of action of ILT2 and its potential role in cancer, the study focuses on tumor types known to express HLA-G. Tumor types included in SAR444881-cetuximab combination cohorts are tumors known to over-express the EGFR protein.
The proposed study design is as described in Example 1.
The primary, secondary, and exploratory objectives of the dose escalation phase of this study (Part 1) are as described in Example 1.
The primary objectives of the dose expansion/optimization phase of this study (Part 2) are to assess the preliminary antitumor activity of SAR444881 (alone or in combination with pembrolizumab, cetuximab, or pembrolizumab and chemotherapy), and to define the optimal dose of SAR444881 in combination with pembrolizumab, cetuximab, or pembrolizumab and chemotherapy.
The secondary objectives of the dose expansion/optimization phase of this study are:
The exploratory objectives of the dose expansion/optimization phase of this study are:
The primary endpoints for the dose escalation phase of this study (Sub-Parts 1A/1B/1C) are to assess:
The secondary endpoints for the dose escalation phase are to assess:
The exploratory endpoints for the dose escalation phase are to assess:
The primary endpoint for the dose optimization/expansion phase is to assess ORR per RECIST v1.1 (other datapoints may be utilized to supplement assessment of optimal SAR444881 dose).
The secondary endpoints for the dose optimization/expansion phase are to assess:
The exploratory endpoints for the dose optimization/expansion phase are to assess:
Study participants are selected based on the following inclusion and exclusion criteria:
Exclusionary criteria for participants include the following:
The study interventions administered are as described for the Dose Escalation Phase (Part 1) in Example 1.
A two-stage design will be implemented in Part 2 to conduct dose optimization for each indication with combination therapy:
Stage 1 (Preliminary Assessment): Enroll 20 participants and treat the participants at one potential recommended dose identified from dose escalation in each indication to get preliminary efficacy/safety, PK, and PD data.
Stage 2 (Randomization): Randomize 40 participants 1:1 into the two recommended doses with each indication that showed activity in Stage 1 to support selection of optimal dose for the indication. In addition, it is possible that emerging data from Stage 1 may indicate the need to deviate from this randomization scenario. Based on the totality of data across the study as a whole and with agreement of the SRC, the Sponsor will retain flexibility on the design of the Stage 2, which may include, among other possibilities, a single dose level rather than randomization, or termination of the cohort prior to entry to Stage 2.
SAR444881 Combination Dose Optimization (Sub-Part 2A): SAR444881 will be administered in combination with one or more of the following: 1) the anti-PDI monoclonal antibody pembrolizumab at a dose of 200 mg; 2) the anti-EGFR monoclonal antibody cetuximab at a dose of 500 mg/m2; and 3) chemotherapy. The chemotherapy administered will include carboplatin at a dose of 10 mg/mL and pemetrexed at a dose of 500 mg/m2. The dose level of SAR444881 in Sub-Part 2A will be determined based on data from each sub-part of the dose escalation phase.
Sub-Part 2A is divided into four cohorts:
The study includes a safety run-in and core phase for Cohort A1 (SAR444881+pembrolizumab+carboplatin+pemetrexed for non-squamous NSCLC). The initial SAR444881 dose tested in the safety run-in for Cohort A1 will be 10 mg/kg. If unacceptable toxicity is observed at the 10 mg/kg dose level, then the safety run-in dose will be de-escalated to 3 mg/kg SAR444881.
SAR444881 Monotherapy Dose Expansion (Sub-Part 2B): SAR444881 will be administered as a monotherapy (Cohort D1), as a second line and later therapy. The dose level of SAR444881 in Sub-Part 2B will be determined based on data from the dose escalation phase. SAR444881 will be administered in two-week intervals. The anti-tumor activity of SAR444881 monotherapy will be evaluated in cholangiocarcinoma. Study treatments and modes of administration are summarized in Table 2 below:
SAR444881 will be infused over 60 minutes at all dosage levels, except for the 0.1 mg/kg dosage, which will be infused over 30 minutes. Pembrolizumab, cetuximab, carboplatin, and pemetrexed will be administered according to their recommended dosage and administration including use of premedication. No dose reduction for pembrolizumab is allowed. Cetuximab dosage may be modified for adverse reactions management in accordance with the drug's Prescribing Information.
For combination cohorts, pembrolizumab or cetuximab will be infused first, followed by SAR444881. The SAR444881 infusion will start at least 30 minutes after completion of the pembrolizumab infusion and at least 60 minutes after the cetuximab infusion.
All participants administered cetuximab will be premedicated with a histamine-1 (H1) receptor antagonist intravenously (e.g., diphenhydramine 50 mg) 30-60 minutes prior to each cetuximab dosing. Premedication for participants in cohort A1 receiving pemetrexed include folic acid, vitamin B12, and dexamethasone.
For all study participants, SAR444881 infusions will require a 60-minute observation period following the completion of the infusion for the first 2 doses and a 30-minute observation period for all subsequent doses.
Cohort A1 dosing sequence: pembrolizumab, pemetrexed premedication, pemetrexed, carboplatin, and SAR444881 (start of SAR444881 infusion should be at least 30minutes after completion of pembrolizumab infusion).
This Example describes preliminary safety, pharmacokinetic, and efficacy data for the first five dose level cohorts (0.1, 0.3, 1, 3, and 10 mg/kg) of Part 1-Sub-Part 1A of the clinical study as described in Example 1.
The primary objectives of the study were to assess the safety and tolerability of SAR444881 when administered alone, and to determine the maximum tolerated dose (MTD) or maximum administered dose (MAAD) and the recommended Phase 2 dose (RP2D) of SAR444881 when administered alone. The secondary objectives of the study were to assess the preliminary anti-tumor activity of SAR444881 and to characterize the PK and immunogenicity of SAR444881. The exploratory objectives were to explore potential associations between SAR444881 anti-tumor activity and select biomarker measures in the tumor and peripheral blood, and to explore the associations between SAR444881 serum PK, safety, efficacy, and clinical biomarkers.
In Sub-Part 1A, each patient was assigned to receive a single dose level of SAR444881 alone, with dose escalation between cohorts run with a standard 3+3 design for the five tested doses (0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg and 10 mg/kg). A sentinel patient was recruited at each dose level and followed for toxicities for 72 hours before two additional patients were enrolled to the same cohort, for a total of at least three patients per dose level. Enrollment into the next cohort did not begin until the completion of a 28-day observation period for the last patient of the previous cohort. At any dose level, if 1 patient has a dose-limiting toxicity (DLT), a total of 6 patients were to be treated with that dose. If only 1 of the 6 subjects had a DLT, then the next cohort was to be treated at the next dose level. If 2 or more DLTs occurred within a cohort, then that dose level was be considered above the MTD (the highest dose where no more than 1 of 6 subjects has experienced a DLT), and additional subjects were to be enrolled at the previous lower (tolerated) dose level until that cohort had 6 subjects. This lower dose level was considered the MTD if ≤1 of the 6 subjects had a DLT.
This study enrolled 20 advanced cancer patients with unresectable or metastatic disease who are refractory to or are not candidates for standard approved therapy. Mean patient age was 59.4+13.9 years and the majority of patients were male (75%) and White (95%) and non-or former smokers (90%). The most common concomitant morbidity was hypertension, which affected 8/20 patients. Most (80%) patients presented with metastatic tumors, with colorectal cancer and non-small cell lung cancer being the most common cancer types (35% and 20%, respectively), while the remaining had unresectable tumors. All patients had undergone at least two lines of prior treatment; the median number of prior treatment lines was 3.5. Median time from cancer diagnosis for the entire patient population was 42.4 months and was lower in the 0.01 mg/kg and 1 mg/kg treatment groups (28.7 months and 12.7 months, respectively) as compared to the other cohorts. See, e.g., Table 3.
The mean number of doses administered in all cohorts ranged between 3.6 (0.1mg/kg) and 8.5 (3 mg/kg), with one patient in the 3 mg/kg cohort receiving 18 doses of the study drug as of the cutoff date. Accordingly, mean duration of treatment to date ranged between 7.3 and 17.5 weeks, with the minimum duration being 2 weeks and the maximum duration being 39 weeks.
Preliminary data indicate that the study treatments were generally well-tolerated. Of the 130 reported AEs, 21 were considered possibly related to the study treatment. Most events were mild to moderate and unrelated to study treatment. Only one Grade 3 event of hepatic enzyme increased (1 mg/kg), measured at the start of Cycle 6, was considered possibly related to the administered drug. Due to hospitalization, the event was considered a serious adverse event (SAE). The patient recovered within 3 days without requiring drug or non-drug therapy. No DLT or grade 4 or 5 events were documented. Apart from the above-mentioned SAE, no other drug-related SAEs were reported. No AEs were the direct cause of patient death.
AEs considered possibly related to SAR444881 treatment included anemia, abdominal distension, constipation, diarrhea, flatulence, nausea, amylase increased, blood creatine phosphokinase increased, hepatic enzyme increased, hyponatremia and oropharyngeal pain, each reported for 1 patient and abdominal pain, fatigue and pruritis, each reported for 2 patients. No events were considered possibly related to the highest tested dose level (10 mg/kg SAR444881). No events were considered possibly related to the highest tested dose level (10 mg/kg SAR444881).
Clinically significant hematological abnormalities were measured in 3 patients, clinically significant blood biochemistry abnormalities were measured in 6 patients and clinically significant coagulation abnormalities were identified in one patient. All were considered non-treatment-related, except for amylase increased (0.1 mg/kg patient), blood creatine phosphokinase increased (0.3 mg/kg patient) and hepatic enzyme increased (1 mg/kg patient).
SAR444881 PK proved to be consistent within cohorts but dose-dependent, with Cmax and AUC increasing and elimination rate declining with increasing doses. No SAR444881 accumulation was apparent between doses. These dose-dependent differences in the pharmacokinetics of SAR444881 strongly suggest target-mediated drug disposition (TMDD) of SAR444881, i.e., increasing extent of saturation of the endogenous pool of ILT2 protein with increases in the drug dose. See FIG. 1 and Table 4 below:
ILT2 receptor occupancy (RO) by SAR444881 was examined in fresh whole blood samples of patients enrolled to 3, 10 and 20 mg/kg dose level cohorts. RO was measured using the “free” indirect method for assessing the proportion of unoccupied (unbound) sites utilizing a phycoerythrin (PE)-labeled antibody that competes with the drug molecule. The analysis was performed on peripheral monocytes collected from patients, which represent the immune population which has the highest ILT2 expression among all peripheral immune cells. The results depicted in
Further, measurement of RO levels in patients that received monotherapy of SAR444881 at dose levels above 3 mg/kg demonstrated target saturation and sustained occupancies for SAR444881 at dose level of 3 mg/kg and up at a Q2W based regimen. In support of this, results observed for patients receiving administration of 1, 3, 10 and 20 mg/kg of SAR444881 in combination with cetuximab (Q2W regimen) or pembrolizumab (Q3W regimen) demonstrated sustained saturation at SAR444881 doses that were equal to or higher than 3 mg/kg (
Evidence for the immunomodulatory activity of SAR444881 was observed in both myeloid and lymphocyte compartments. Patients treated with saturating doses of SAR444881 (≥3 mg/kg) showed elevated levels of the CD62L marker on the surface of classic monocytes (
Analysis also demonstrated that patients with a clinical benefit (PR or SD, vs. PD) had statistically significantly higher baseline levels of ILT2-positive NKT cells (
Serum samples from patients enrolled in the study were analyzed for the presence of 16 different chemokines and cytokines. An elevation compared to baseline levels was observed for CXCL11 and CCL4 during the first cycle of SAR444881 treatment (
One patient, treated with 3 mg/kg SAR444881, showed a partial response. The patient was still on treatment (Cycle 9) at the interim cutoff date, with a duration of response of 13.3 weeks. Stable disease (SD) was documented in 1 (33.3%) patient receiving 1 mg/kg SAR444881, 3 (50%) patients receiving 3 mg/kg SAR444881 and 1 (33.3%) patient receiving 10 mg/kg SAR444881. A best overall response of progressive disease (PD) was documented for 11 (55%) patients. Taken together, the ORR for the 3 mg/kg dose level was 16.7% and for the entire Sub-Part 1A population was 5%. The disease control rate, defined as best overall response of CR, PR, or SD, for the 1 mg/kg, 3 mg/kg, and 10 mg/kg cohorts, was 33.3%, 66.7% and 33.3%, respectively and was 30% for the entire Sub-Part 1A population. Median progression-free survival (PFS) time, defined as the time from the date of first dose of study drug to the date of first documented disease progression or death due to any cause, was 1.8 months across all dose levels and ranged between 1.6 months (0.1 and 0.3 mg/kg cohorts) and 5.8 months (3 mg/kg cohort) (
The results of this analysis of first-in-human testing of SAR444881 monotherapy at doses of up to 10 mg/kg in 20 patients with advanced solid tumors, who were either refractory to or unsuitable for available treatments, demonstrate its favorable safety profile, including at the highest dose level tested so far.
Partial response (n=1) and stable disease assessments (n=5) were reported at SAR444881 doses of 1 mg/kg and above. The disease control rate was 30%. The one patient who had achieved a partial response (3 mg/kg cohort) was on treatment for 39 weeks at the preliminary data cutoff date, with a duration of response to date of 13.3 weeks. Median progression-free survival for the entire population was 1.8 months.
PK analyses suggested an increasing extent of saturation with increasing doses, manifesting by higher maximum serum concentrations, longer half-life, slower clearance and larger volume of distribution. PK exposure of SAR444881 was nearly linear and dose proportional from 2 mg/kg to 20 mg/kg in both Q2W and Q3W regimens based on population pharmacokinetic (PopPK) modeling. The PopPK/PD modeling suggested that maintaining a median target receptor occupancy (RO) exceeding 90% was achievable at 3 mg/kg or higher in both Q2W and Q3W regimens. Sustained saturated peripheral monocyte ILT2 receptor occupancy throughout the course of treatment, was noted in patients administered 3 mg/kg and 10 mg/kg of SAR444881. Preliminary analyses found that patients with a clinical benefit (PR or SD) had statistically significantly higher baseline levels of ILT2-positive NKT cells (p=0.0293). and treatment-associated downregulation of CCL7. Of note, high baseline levels of intra-tumoral ILT2 expression (90%) were seen in the patient who achieved a PR, along with significant increases in the levels of the cytokines CCL4, CXCL11, CCL23 and granzyme B. Analyses also demonstrated an upregulation of immune activation markers, such as CD69 and CD107a, on ILT2-expressing NK and T cells subsets and of the adhesion molecule CD62L on monocytes following SAR444881 treatment.
In summary, SAR444881 monotherapy appeared to be safe and well tolerated at doses up to 10 mg/kg. Preliminary signs of anti-tumor activity in this heavily pretreated, advanced cancer patient population were observed.
This Example describes preliminary safety, pharmacokinetic, and efficacy data for Part 1-Sub-Parts 1A-1C of the clinical study as described in Example 1.
The primary objectives of the study were to assess the safety and tolerability of SAR444881 when administered alone or in combination with pembrolizumab or cetuximab. The secondary objectives of the study were to assess the preliminary anti-tumor activity and to characterize the PK and immunogenicity of the treatments.
This study enrolled 76 patients (31 in Sub-Part 1A, 23 in Sub-Part 1B, and 22 in Sub-Part 1C) who had received ≥1 doses of SAR444881.
The average duration of treatment across Sub-Parts 1A, 1B, and 1C was 11 weeks. The most common treatment-related adverse events (AEs) were fatigue (19%) for Sub-Part 1A, nausea (17%) for Sub-Part 1B, and rash (50%) for Sub-Part 1C. Adverse events (AEs) in Sub-Part 1C included: rash in 11 patients (50%), dry skin in 7 patients (32%), fatigue in 7patients (32%), and dermatitis acneiform in 6 patients (27%). Serious treatment emergent AEs (TEAEs) were reported in 20 patients (26%), four of which were deemed to be treatment-related (see Table 5 below). No treatment-related dose-limiting toxicities or life-threatening/fatal treatment-related AEs were reported.
In assessing anti-tumor activity, one patient in Sub-Part 1A (3%), one patient in Sub-Part 1B (4%), and two patients in Sub-Part 1C (9%) achieved a partial response (see Table 5 below). The median progression free survival (PFS) in months was 1.8 (1.6-3.4) for Sub-Part 1A; 1.6 (1.5-2.1) for Sub-Part 1B; and 3.9 (1.8-NC) for Sub-Part 1C.
The 3 mg/kg and 10 mg/kg doses were identified as safe and exhibited anti-tumor activity, achieving high target receptor occupancy (>93%). All responders at 3-10 mg/kg bore tumors predicted to be insensitive or progressing after anti-PD-1 and/or cetuximab treatment. SAR444881 treatment at doses of ≥3 mg/kg led to upregulation of activation markers in monocytes and ILT2-expressing T and NK cell subsets. An increase in intratumoral necrosis and infiltration of CD8 T cell subsets was observed.
Based on these data, 10 mg/kg may be used as the initial dose of SAR444881 for dose optimization.
bOne SAE (back pain)
cTwo Grade 2 infusion-related reactions.
dGastroesophageal junction carcinoma
eColorectal cancer.
Treatment with SAR444881. alone or in combination with pembrolizumab or cetuximab, was well tolerated in patients with advanced solid tumors.
This application claims priority to U.S. Provisional Patent Application 63/513,037, filed Jul. 11, 2023; U.S. Provisional Patent Application 63/550,356, filed Feb. 6, 2024; and U.S. Provisional Patent Application 63/643, 156, filed May 6, 2024. The disclosures of those priority applications are incorporated by reference herein in their entirety.
| Number | Date | Country | |
|---|---|---|---|
| 63513037 | Jul 2023 | US | |
| 63550356 | Feb 2024 | US | |
| 63643156 | May 2024 | US |
