TW201315481A - Dosage and administration of anti-ErbB3 antibodies in combination with paclitaxel - Google Patents

Abstract

Provided are methods and compositions for clinical treatment of breast cancer using anti-ErbB3 antibodies combined with paclitaxel.

Description

Dosage and administration of anti-ERBB3 antibody combined with paclitaxel

This application claims US Provisional Application No. 61/500,752, filed on June 24, 2011, US Provisional Application No. 61/596,102, filed on February 7, 2012, and No. 1252652, filed on March 23, 2012 Priority interest in French patent applications (all applications are hereby incorporated by reference).

The present invention relates to methods and compositions for the clinical treatment of breast cancer using anti-ErbB3 antibodies in combination with paclitaxel.

Despite improvements in breast cancer therapies and advanced treatment options, there is an urgent need to optimize existing therapies and develop promising new therapies to prolong the lives of patients while maintaining a high quality of life.

The ErbB3 receptor is a 148 kD transmembrane receptor and belongs to the ErbB/EGFR receptor tyrosine kinase family but is inactivated by kinase. The ErbB receptor forms homo- and heterodimeric complexes that affect the physiological functions of cells and organs by regulating ligand-dependent activation of multiple signal transduction pathways. It has been shown that heterodimers containing ErbB3 in tumor cells (such as ErbB2/ErbB3) are the most mitogenic and carcinogenic receptor complexes in the ErbB family. ErbB3 and other ErbB family members after binding to the physiological ligand-modulating protein (HRG) of the ErbB3 receptor (mainly ErbB2) forms a dimer. ErbB3/ErbB2 dimerization results in the phosphorylation of ErbB3 in the tyrosine residues contained in the cytoplasmic tail of the protein. Phosphorylation of these sites establishes an SH2 junction site for SH2 containing proteins, including PI3 kinase. Since ErbB3 has six tyrosine phosphorylation sites and YXXM sequences, these sites serve as excellent binding sites for phosphoinositide-3-kinase (PI3K) after phosphorylation, and binding will cause subsequent AKT pathways. Downstream activation, so the dimer complex containing ErbB3 is a potent activator of AKT. These six PI3K sites serve as powerful amplifiers for ErbB3 signal transmission. Activation of this pathway further induces several important biological processes involved in tumorigenesis, such as cell growth, migration, and survival.

There is evidence that modulators can occur in several different types of cancer: breast, ovarian, endometrial, colon, stomach, lung, thyroid, glioma, medulloblastoma, melanoma and Head and neck squamous cell carcinoma. In most of these tumor types, HRG controls growth, invasion, and angiogenesis by over-expressing or activating autocrine or paracrine loops. Treatments that control the growth of cancer cells can be provided by blocking the HRG binding to disrupt the autocrine loop of the regulatory protein or disrupting the ErbB2/ErbB3 dimer.

Compositions and methods for treating breast cancer in a human patient comprising administering an anti-ErbB3 antibody to paclitaxel in combination with a patient, wherein the combination will be administered (or for administration) according to a particular clinical dosage regimen.

A typical anti-ErbB3 antibody is Antibody A, as described below. In one embodiment, the anti-ErbB3 antibody comprises a heavy chain variable (VH) and/or a light chain variable (VL) region, encoded by the nucleic acid sequences set forth in SEQ ID NOs 1 and 3, respectively. In another embodiment, the antibody comprises a VH and/or VL region, and wherein the amino acid sequences listed in SEQ ID NOs 2 and 4, respectively, are included. In another embodiment, the antibody comprises CDRH1, CDRH2 and CDRH3 sequences, and these sequences comprise the amino groups listed in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3) The acid sequence, and/or the CDRL1, CDRL2 and CDRL3 sequences, and these sequences comprise the amino acid sequence set forth in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3). In another embodiment, an antibody that seeks to bind and/or incorporate the same epitope on human ErbB3 is used as the antibody described above. In a specific embodiment, the epitope comprises residues 92-104 of human ErbB3 (SEQ ID NO: 11). In another embodiment, the antibody competes with Antibody A for binding to human ErbB3, and at least 90% of the variable region amino acid sequence is identical to the anti-ErbB3 antibody described above.

Thus in one aspect, compositions and methods are provided for treating breast cancer in a human patient, wherein the method comprises administering to the patient an effective amount of the following: (a) an anti-ErbB3 antibody comprising CDRH1, CDRH2 and CDRH3 sequences, and wherein the sequences are Included are the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and the sequence of CDRL1, CDRL2 and CDRL3, and these sequences are listed in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and the amino acid sequence of SEQ ID NO: 10 (CDRL3), and (b) paclitaxel, wherein the method comprises at least one cycle, wherein one cycle lasts for 3 weeks, and at each The weekly dose of anti-ErbB3 antibody was 20 mg/kg during the week and the weekly dose of paclitaxel was 80 mg/m2. In one example, the anti-ErbB3 antibody is antibody A.

In one embodiment, the effective amount comprises administering an anti-ErbB3 antibody as a monotherapy before at least one of the above cycles.

In another embodiment, two weeks of anti-ErbB3 antibody monotherapy is administered wherein the anti-ErbB3 antibody is administered at a dose of 40 mg/kg at week 1 and 20 mg/kg at week 2.

In one embodiment, the breast cancer is ER positive and HER2 is non-overexpressing aggressive breast cancer.

In one embodiment, the breast cancer is a triple negative breast cancer.

In one embodiment, paclitaxel is administered immediately following the anti-ErbB3 antibody.

In one embodiment, the patient is pretreated with an anti-allergic agent prior to administration of paclitaxel.

In one embodiment, the hypoallergenic agent is selected from the group consisting of: 20 mg dexamethasone; 50 mg diphenhydramine; 300 mg cimetidine; 50 mg of lanitidine.

In another embodiment, the patient does not have a metastatic disease.

In another embodiment, the method further comprises at least an additional week The extra period is two weeks, and in each additional cycle, the dose of doxorubicin is 60 mg/m 2 and the dose of cyclophosphamide is 600 mg/m 2 .

In another embodiment, the breast cancer is ER positive and HER2 is non-overexpressing aggressive breast cancer.

In another embodiment, the breast cancer is a triple negative breast cancer.

In another embodiment, the breast cancer test is positive for the estrogen receptor with a Ki-67 index of 10% or more.

In another embodiment, the breast cancer is estrogen receptor positive and belongs to breast ductal carcinoma or pleomorphic lobular carcinoma.

In another embodiment, the breast cancer is an estrogen receptor positive breast cancer having greater than or equal to 1% of the breast cancer cell nucleus having an immune response against the estrogen receptor antibody.

In another embodiment, the breast cancer is ductal carcinoma.

In another embodiment, the breast cancer is an estrogen receptor negative breast cancer having less than 1% of the breast cancer cell nucleus having an immune response against the estrogen receptor antibody.

In another embodiment, the patient does not have a metastatic disease.

In another embodiment, the method includes four additional cycles.

In another embodiment, the patient receives further treatment with peg-filgrastim on day 2 of each additional cycle following administration of the above doxorubicin and cyclophosphamide.

In another embodiment, the patient subsequently undergoes surgery to remove cancerous tissue.

In another embodiment, the treatment produces at least one of the following effects: breast cancer tumor shrinkage; number of metastatic lesions decreases over time; complete response; partial response; stable condition; overall response rate increased; or pathological complete response.

In another aspect, the invention relates to a combination for the treatment of breast cancer in a human patient, the combination comprising a clinically proven safe and effective amount of: (a) an anti-ErbB3 antibody comprising CDRH1, CDRH2 and CDRH3 sequences, and wherein Included are the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and the sequence of CDRL1, CDRL2 and CDRL3, and these sequences are listed in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and the amino acid sequence of SEQ ID NO: 10 (CDRL3), and (b) paclitaxel, (c) doxorubicin and (d) cyclophosphazene amine.

In one embodiment, the anti-ErbB3 antibody is Antibody A.

In another embodiment, the anti-ErbB3 antibody is administered by intravenous injection at a dose of 20 mg/kg per dose. In one embodiment, the antibody is administered by intravenous injection at a dose such that the average target serum concentration in the patient is about 300-350 (e.g., about 324) micrograms per milliliter.

In another aspect, the invention relates to a kit comprising a dose of an anti-ErbB3 antibody comprising CDRH1, CDRH2 and CDRH3 sequences, wherein the sequences comprise SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 ( CDRH2) and SEQ ID NO: 7 (CDRH3) amino acid sequence, and CDRL1, CDRL2 and CDRL3 sequences, and these sequences comprise SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), respectively. Amino acid sequence, and instructions for using the anti-ErbB3 antibody of the method of claim 1. In one embodiment, the anti-ErbB3 antibody is Antibody A.

In another embodiment, the kit comprises at least 500 mg of antibody.

In another embodiment, the kit comprises at least 1 mg of paclitaxel.

In another aspect, the invention pertains to an anti-ErbB3 antibody comprising SEQ ID NO: 5 (CDRH1), SEQ ID NO: 6 (CDRH2), SEQ ID NO: 7 (CDRH3), SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), and the anti-ErbB3 antibody is used in combination with paclitaxel for at least one cycle, wherein one cycle lasts for 3 weeks, and during the weekly period, the weekly dose of anti-ErbB3 antibody At 20 mg/kg, the weekly dose of paclitaxel is 80 mg/m2.

First, the definition

The words "subject" or "patient" as used herein refer to a human cancer patient.

As used herein, "effective treatment" refers to a treatment that produces a beneficial effect, such as at least one symptom improvement of a disease or disorder. The beneficial effects are reflected in the improvement above the baseline, ie before starting treatment according to the relevant method Improvements occurred above the measurement or observation. The beneficial effects are also reflected in the suppression, slowing, slowing or stabilization of the harmful progression of breast cancer markers. Effective treatment means that at least one type of breast cancer is relieved. For example, such effective treatment can reduce the patient's pain, reduce the size and/or number of lesions, and reduce or prevent breast cancer tumor metastasis, and/or slow the growth of breast cancer tumors.

The term "effective amount" refers to the amount of a drug that provides the desired biological, therapeutic, and/or prophylactic effect. This effect can be a reduction, amelioration, mitigation, mitigation, delay and/or alleviation of one or more signs, symptoms or causes, or any other desired change in the biological system. In the case of cancer, an effective amount comprises an amount sufficient to promote tumor atrophy and/or reduce tumor growth rate (e.g., inhibit tumor growth), or to prevent or delay the growth of other unhelpful cells. In some embodiments, the effective amount is an amount sufficient to delay tumor progression. In some embodiments, the effective amount is an amount sufficient to prevent or delay tumor recurrence. An effective amount can be administered in one or more administrations. An effective amount of a drug or composition can be: (i) reducing the number of cancer cells; (ii) reducing the tumor; (iii) inhibiting, delaying, slowing, and preventing the infiltration of cancer cells into the peripheral organs to some extent; (iv) inhibition ( That is, to some extent slow and prevent) tumor metastasis; (v) inhibit tumor growth; (vi) prevent or delay tumor emergence and/or recurrence; and/or (vii) reduce to some extent one or more of the cancer involved symptom. For example, an "effective amount" for therapeutic use is that the amount of antibody A and paclitaxel can clinically significantly improve or slow the progression of breast cancer.

The term "antibody" includes antibodies and antibody variants comprising at least one antibody-derived antigen binding site (such as the VH/VL region or Fv) that specifically binds to ErbB3. Antibodies include antibodies in known forms. For example, the antibody can be a human antibody, a humanized antibody, a bispecific antibody, or a chimeric antibody. The antibody may also be a Fab, Fab', ScFv, SMIP, Affibody®, Nanobody or Domain Antibody. The antibody may also be of any of the following isotypes: IgGl, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD, and IgE.

The term antibody variant as used herein includes naturally occurring antibodies which, upon alteration (e.g., by mutation, deletion, substitution or binding to a non-antibody portion), comprise at least one variant amino acid which alters the properties of the antibody. For example, numerous such variations known in the art can affect, for example, half-life, effector function, and/or immune response of a patient to an antibody. The term antibody variant also encompasses an artificial polypeptide construct comprising at least one antibody-derived binding site.

The term Ki-67 index as used herein refers to the ratio of tumor cells that exhibit immunoreactivity to antibodies (such as MIB-1), which specifically binds to Ki-67 (also known as MKI67), which is Ki-67. An intranuclear non-tissue protein that is present in growing, dividing cells but is absent during cell growth.

Pacific paclitaxel is a natural product with anti-tumor effects. The drug is produced by a semi-synthetic process of Taxus baccata . The chemical name of paclitaxel is 5β,20-epoxy-1,2α,4,7β,10β,13α-hexahydroxy taxane-11-ene-9-one-4,10-diacetate-2- Benzoate-13[(2'R,3'S)-N-benzimid-3-phenylisoserine. Pacific paclitaxel is marketed under the trade name Taxol®.

The term doxorubicin refers to a drug whose chemical name is (8 S , 10 S )-10-(4-amino-5-hydroxy-6-methyl-tetrahydroxy-2 H -pyran-2-氧基oxy)-6,8,11-trihydroxy-8-(2-hydroxyethyl)-1-methoxy-7,8,9,10-tetrahydrotetraphenyl-5,12-dione . Doxorubicin is marketed under the trade names Adriamycin PFS®, Adriamycin RDF® or Rubex®. Doxorubicin is an anthracycline antibiotic that is closely related to the natural product daunorubicin, and like all anthracyclines, it works by intercalating DNA. Generally, the drug is administered intravenously in the form of the hydrochloride salt. Doxorubicin is photosensitive, so its containers are often covered with aluminum and/or brown wax paper to avoid the effects of light.

The term cyclophosphamide refers to a drug whose chemical name is N , N -bis(2-chloroethyl)-1,3,2- Azaphosphorus cyclohexane-2-amine 2-oxide. Cyclophosphamide is marketed under the trade names Endoxan®, Cytoxan®, Neosar®, Procytox® or Revimumune®. Cyclophosphamide is a nitrogen mustardizing agent derived from the oxazophorines group. The alkylating agent adds an alkyl group (C _n H _2n+1 ) to the DNA, which attaches the alkyl group to the DNA guanine group at the nitrogen atom of the imidazole ring No. 7.

Second, anti-ErbB3 antibody

Useful antibiotics can be made using methods known in the art. ErbB3 antibody (or VH/VL domain derived therefrom). Alternatively, a technically recognized anti-ErbB3 antibody can also be used. For example, Ab#3, Ab #14, Ab#17, and Ab#19 described in U.S. 7,846,440 can be used. Antibodies that compete with any such antibody for binding to ErbB3 can also be used. Other technology-approved anti-ErbB3 antibodies that can be used include the antibodies disclosed in US 7,285,649, US20200310557 and US20100255010, as well as antibodies IB4C3 and 2D1D12 (U3Pharma Ag), both of which are described in US 2004/0197332; referred to as AMG888 (U3- 1287-U3 Pharma Ag and Amgen) anti-ErbB3 antibodies; and monoclonal antibody 8B8 as described in US 5,968,511. Other useful anti-ErbB3 antibodies are disclosed in the technical field of bispecific antibodies (see, for example, B2B3-1 or B2B3-2 in WO/2009/126920), and in US 7,846,440 and US 2010/0266584, all of which are The content is incorporated herein by reference. An example of such an antibody is antibody A having heavy and light chains, which contain the amino acid sequences listed in SEQ ID NOs 12 and 13, respectively. Antibody A is referred to as "Ab #6" in US 7,846,440.

In one embodiment, the anti-ErbB3 antibody comprises a heavy chain variable (VH) and/or a light chain variable (VL) region, encoded by the nucleic acid sequences set forth in SEQ ID NOs 1 and 3, respectively. In another embodiment, the antibody comprises a VH and/or VL region, and wherein the amino acid sequences listed in SEQ ID NOs 2 and 4, respectively, are included.

In another embodiment, the antibody comprises CDRH1, CDRH2 and CDRH3 sequences, and these sequences are listed in SEQ ID NO: 5 (CDRH1) the amino acid sequence of SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and/or the CDRL1, CDRL2 and CDRL3 sequences, and these sequences are listed in SEQ ID NO: 8 (CDRL1) Amino acid sequences of SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3). In another embodiment, an antibody that seeks to bind and/or incorporate the same epitope on human ErbB3 is used as the antibody described above. In a specific embodiment, the epitope comprises residues 92-104 of human ErbB3 (SEQ ID NO: 11). In another embodiment, the antibody binds to human ErbB3 and at least 90% of the variable region sequences are identical to the antibodies described above.

In other embodiments, the antibody is a fully human monoclonal antibody, such as IgG2 that binds to ErbB3 and prevents HRG and EGF-like ligand-induced phosphorylation of ErbB3.

An anti-ErbB3 antibody, such as antibody A, can be produced in prokaryotic or eukaryotic cells using methods known in the art. In one embodiment, the antibody is produced in a cell line (eg, a CHO cell) capable of glycosylating the protein.

III. Pharmaceutical Composition

Pharmaceutical compositions suitable for administration to a patient are preferably in liquid form for intravenous administration.

In general, the compositions typically comprise a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable" as used herein means approved by a government regulatory agency and listed in the US Pharmacopoeia or related animals, especially humans. Other commonly recognized pharmacopoeia. The term "carrier" refers to a diluent, adjuvant, excipient or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids such as water and oil, including petroleum, animal, vegetable or synthetic products such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Aqueous solutions of water or saline, dextrose and glycerol can be used as carriers, especially for injectable solutions (for example comprising an anti-ErbB3 antibody and/or paclitaxel). Liquid compositions for parenteral administration can be administered by injection or continuous infusion. Routes of administration for injection or infusion include intravenous, intraperitoneal, intramuscular, intrathecal and subcutaneous. In one embodiment, both the anti-ErbB3 antibody and paclitaxel are administered intravenously (eg, separately or infused together for one hour).

Antibody A for intravenous infusion (eg, one hour of infusion) is in the form of a clear liquid solution placed in a sterile single-use vial containing 10.1 ml of Antibody A in 20 mmol of histidine, 150 mmol of chlorine The concentration in sodium is 25 mg/ml, the pH is 6.5, and the storage temperature should be 2-8 °C.

Paclitaxel Injection (USP) is a colorless to pale yellow transparent viscous solution. The preparation is a non-aqueous solution for dilution with an appropriate injection prior to intravenous infusion. Paclitaxel is available in 30 mg (5 ml), 100 mg (16.7 ml) and 300 mg (50 ml) multiple dose vials. Each milliliter of sterile, pyrogen-free solution contained 6 mg paclitaxel, 527 mg polyethylene glycol 35 castor oil, NF1 and 49.7% (v/v) absolute alcohol (USP).

The structural formula of paclitaxel is as follows:

Pacific paclitaxel is a white to beige crystalline powder having a molecular formula of C47H51NO14 and a molecular weight of 853.9. Paclitaxel is highly lipophilic, insoluble in water, and melts at around 216 ° C to 217 ° C.

Doxorubicin is supplied as a hydrochloride in the form of a sterile orange-red lyophilized powder containing lactose and a sterile isotonic injection containing sodium chloride. It may also be a sterile orange-red aqueous solution containing 0.9% sodium chloride. . Doxorubicin is only used for intravenous injection.

The structural formula of doxorubicin is as follows:

CYTOXAN® (Cyclophosphamide (USP) for injection) is a sterile white powder containing cyclophosphamide monohydrate. CYTOXAN Tablets (Cyclophosphamide Lozenges (USP)) are used orally and contain 25 mg or 50 mg of cyclophosphamide (anhydrous). Inactive ingredients in CYTOXAN Tablets are: gum arabic, FD&C blue 1 No., D&C Yellow No. 10 Aluminium, Lactose, Magnesium Stearate, Starch, Stearic Acid and Talc.

The structural formula of cyclophosphamide is as follows:

IV. Patient group

Provided herein are effective methods for treating HER2-negative breast cancer (breast cancer tumors tested to be HER2-negative). In one aspect, the patient has ER-positive (estrogen receptor-positive) HER2 non-overexpressing aggressive breast cancer. On the other hand, the patient has triple negative breast cancer (TNBC).

The characteristics of ER-positive HER2 non-overexpressing aggressive breast cancer are as follows: (A) Non-overexpression of HER2 is demonstrated by one of the following: immunohistochemical (IHC) staining results are 0 or 1+ indicating negative; or fluorescent in situ hybridization (FISH) results showed that the number of copies of the Her2 gene per core was less than 4, or the FISH ratio was less than 1.8; and (B) ER positive, defined as having/conforming for the following: Ki-67 index greater than or equal to 10% catheter or An ER-positive tumor of pleomorphic lobular carcinoma, defined as 1% of tumor nuclei have an immune response.

At the same time, the characteristics of TNBC are as follows: (A) HER2 non-overexpression is demonstrated by one of the following: immunohistochemical (IHC) staining results in 0 or 1+ indicating negative; or fluorescence in situ hybridization (FISH) results show that Nuclear nucleus Her2 gene copy number is less than 4, or FISH ratio is less than 1.8; and (B) breast ductal carcinoma; and (C) ER-negative PR-negative tumor, which is defined as <1% tumor cell check ER and/or PR has an immune response.

In another embodiment, the patient does not have a metastatic disease.

The patient may be tested or selected for one or more of the above clinical attributes before, during, and after treatment.

V. Combined therapy

As described herein, paclitaxel was administered with anti-ErbB3 antibody in combination with doxorubicin and cyclophosphamide as adjuvant therapy to achieve improved disease in breast cancer subjects. In one embodiment, the anti-ErbB3 antibody is Antibody A.

Auxiliary or combined administration (concomitant use) as used herein includes the simultaneous administration of the compound in the same or different dosage forms, or the administration of the compound alone (e.g., continuous administration). For example, the antibody can be administered concurrently with paclitaxel, at which time the antibody and paclitaxel are co-formulated. Or, antibodies can In combination with paclitaxel administration, both the antibody and paclitaxel are formulated separately and administered simultaneously or sequentially. For example, the antibody can be administered first, followed by paclitaxel, and vice versa. The preferred result of such simultaneous or sequential administration is that antibody A and paclitaxel can be present simultaneously in the patient being treated.

In another embodiment, the anti-ErbB3 antibody is a formulation for intravenous administration. In a particular embodiment, the anti-ErbB3 antibody is optionally administered at a dose of 40 mg/kg, 20 mg/kg, 12 mg/kg, 10 mg/kg, 6 mg/kg, and/or 3.2 mg/kg. In one embodiment, the dosage of the antibody will change over time. For example, the initial dose of an antibody may be higher, and then it may decrease over time. In another embodiment, the initial dose of the antibody is lower and then increased over time. In another embodiment, a dose of 40 mg/kg of Antibody A is administered weekly for 2 weeks; then a dose of 20 mg/kg of Antibody A and paclitaxel is administered in combination.

VI. Treatment plan

For example, a suitable treatment regimen includes: (A) weekly administration of an anti-ErbB3 antibody to a patient (ie, a human subject) within 14 weeks (administered at a dose of 40 mg/kg for the first two weeks and 20 mg for the next 12 weeks) /kg); and (B) administration of paclitaxel once a week to the patient during the last 12 weeks of administration of the anti-ErbB3 antibody.

In one embodiment, paclitaxel is used in combination with an amount of Antibody A, which is administered once every seven days. Pacific paclitaxel suitable The weekly dose is 80 mg/m2.

In another embodiment, Antibody A is administered a total of 14 times over a 14 week period, ie, weekly. The dosing cycle can be repeated as necessary.

In another embodiment, the dose of the antibody A antibody is unchanged per administration. In another embodiment, each dose of the antibody is administered differently. For example, the maintenance (or subsequent) dose of the antibody can be greater than or equal to the loading dose administered for the first time. In another embodiment, the maintenance dose of the antibody can be less than or equal to the loading dose.

In one embodiment, the anti-ErbB3 antibody monotherapy is administered prior to at least one anti-ErbB3 antibody/pacliol combination therapy cycle. In one embodiment, the anti-ErbB3 antibody is administered monotherapy for 2 weeks, wherein the anti-ErbB3 antibody is administered at a dose of 40 mg/kg for the first week and 20 mg/kg for the second week.

VII. Results

Responses to therapy may include: pathological complete response (pCR) - the absence of invasive cancer in the breast and lymph nodes after initial systemic treatment.

Complete response (CR): All non-target lesions disappeared. The short axis of any pathological lymph node (whether target lymph node or non-target lymph node) is reduced by <10 mm; partial response (PR): the total size of the target lesion is reduced by more than 30% compared with the sum of the baseline diameters; the condition is stable (SD): during the study period Minimum diameter sum ratio In contrast, the sum of lesion diameters has shrunk but has not reached partial response, or increased but did not progress to disease; or, at the same time, incomplete/non-disease progression refers to the presence of one or more non-target lesions and/or tumor markers persisting Above normal.

Disease progression (PD) refers to a 20% increase in the sum of the target lesions compared to the smallest size sum during the study period (eg, the baseline sum is the smallest of the study period, and the baseline sum must also be included). In addition to a relative increase of 20%, the sum of absolute values must exceed 5 mm. The presence of one or more new lesions is also considered progression; in typical outcomes, at least one of the breast cancer-related signs can be improved in patients treated as described herein.

In one embodiment, the patient so treated exhibits a pathological complete response, a complete response, a partial response, or a stable condition.

In another embodiment, the patient so treated has a tumor shrinkage and/or a decrease in growth rate, i.e., tumor growth is inhibited. In another embodiment, the amount of adverse cell proliferation is decreased or inhibited. In another embodiment, one or more of the following may occur: a decrease in the number of cancer cells; a decrease in tumor volume; a suppression, delay, slowing or cessation of proliferation of peripheral cells by cancer cells; slowing or suppression of tumor metastasis; Tumor growth is inhibited; tumor recurrence is blocked or delayed; one or more cancer-related symptoms are somewhat relieved.

In other embodiments, this improvement is measured by a reduction in the number of measurable tumor lesions and/or a reduction in volume. A measurable lesion is one that accurately measures the diameter of at least one dimension of the lesion (the longest diameter will be recorded): measured by CT scan (the thickness of the CT scan is less than 5 mm). 10 mm; or 10 mm measured with a caliper during clinical examination; or >20 mm by chest X-ray. The size of non-target lesions (such as pathological lymph nodes) can also be used as an indicator of improvement. In one embodiment, the lesion can be measured through chest x-ray or CT or MRI film.

In other embodiments, the therapeutic response can be assessed using cytology or histology. If the measurable tumor meets the criteria for response or stable disease, consider any cytological confirmation of any neoplastic effusion that occurs or worsens during treatment to identify it as a response or a stable condition (the effusion may be a side effect of treatment) ) or disease progression.

In some embodiments, administration of an effective amount of an anti-ErbB3 antibody and paclitaxel according to any of the methods described herein can result in at least one of the following effects: breast tumor volume reduction; number of metastatic lesions decreases over time; complete remission; partial remission The condition is stable; the overall response rate is increased; or the pathology is completely responsive. In some embodiments, the similar clinical benefit rate achieved by the provided treatment method (clinical benefit rate = complete response rate + partial response rate + disease stability rate) 6 months) is more desirable than the clinical benefit rate of paclitaxel alone. In other embodiments, the increase in clinical benefit rate is about 20%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or higher compared to paclitaxel alone.

VIII. Kit and unit dosage form

Also provided herein are kits comprising: a pharmaceutical composition comprising an anti-ErbB3 antibody (e.g., Antibody A); and a pharmaceutically acceptable carrier in a therapeutically effective amount as employed by the foregoing methods. The kit may also include instructions such as a dosing regimen as needed to enable a medical practitioner (such as a doctor, nurse or patient) to administer the composition contained in the kit to a patient suffering from breast cancer. In an embodiment, the kit further comprises paclitaxel. In another embodiment, the kit includes a syringe.

The kit may optionally comprise a plurality of single dose pharmaceutical composition packs containing an effective amount of an antibody (e.g., Antibody A) for use in a single administration as described above. If desired, the kit can include the instruments or devices required to administer the pharmaceutical composition. For example, the kit can provide one or more prefilled syringes containing an amount of antibody A that is about 100 times the dose administered in the above method (in milligrams per kilogram). Where necessary, the kit may further comprise paclitaxel in a desired unit dosage form, such as a unit dosage form sold by a paclitaxel pharmaceutical manufacturer, for administration. In another embodiment, the kit may further comprise cyclophosphamide and doxorubicin.

The following examples are for illustrative purposes only, and are not to be construed as limiting the scope of the invention as disclosed herein. .

Example Example 1. Phase 1 trial of specific gynecological and breast cancer

A Phase 1 trial of a combination of antibody A and paclitaxel for specific gynaecological and breast cancer patients to assess the safety and tolerability of a combination of antibody A and paclitaxel, and to determine the combination of antibody A and paclitaxel The maximum tolerated dose and the associated dose-limiting toxicity of the combination.

In the study, both paclitaxel and antibody A antibodies were administered once a week. A combination of a fixed dose of paclitaxel (80 mg/m 2 per week) and any of the following doses of antibody A: i) 12 mg/kg per week for the first week and 6 mg/kg per week thereafter; Ii) Week 1 is 20 mg/kg per week, thereafter 12 mg/kg per week; or iii) Week 1 is 40 mg/kg per week, followed by 20 mg/kg per week. One treatment cycle in the study consisted of a weekly treatment of 4 weeks. The cycle will be repeated every 4 weeks.

Patients participating in Phase 1 studies must be identified as having locally advanced/metastatic or recurrent ovarian epithelial cancer, fallopian tube cancer, primary peritoneal cancer, endometrial cancer, or localized late/metastatic confirmed by cytology or histology Sexual Her2 does not overexpress breast cancer. Such patients with ovarian, fallopian tube, primary peritoneal or endometrial cancer must have evidence that the disease has relapsed or persisted after receiving initial chemotherapy, and that it has previously received at least one platinum-containing chemotherapy regimen (or After high-dose therapy, consolidation therapy, or prolonged treatment after surgery or non-surgical evaluation Delivery). The ovarian, fallopian tube, or primary peritoneal cancer of these patients has been identified as a platinum-resistant cancer or a refractory cancer as described herein. Patients with Her2 non-overexpression breast cancer must have evidence that they have previously received at least one locally advanced or metastatic cancer treatment but the disease still relapses or persists and must demonstrate that it does not have Her2 non-over-expressing cancer (by the field) It is known by known methods that the results are negative if the IHC staining is 0 or 1+, the FISH results show that the number of copies of the Her2 gene per core is less than 4 or the FISH ratio is less than 1.8).

A summary of the initial response is shown in Figure 1-2. As shown in Figure 1, 13 of the ovarian cancer patients who had received combination therapy showed clinical benefit (stable or partial response).

In an expanded group of 24 patients, an alternative dosing regimen will be tested, as detailed in Table 2. Patients in the first group of dose levels will be recruited first. After 6 cases have been recruited, two dose groups will be recruited, followed by recruitment of dose levels 3 and 4.

Patients who administered Antibody A in a QOW (every two weeks) regimen would not receive Antibody A at Weeks 2 and 4 of each cycle.

Example 2. Phase 2 trial of HER2-negative breast cancer

A Phase 2 trial of antibody A and paclitaxel in combination with HER2-negative breast cancer patients was designed to demonstrate the efficacy of administration of Antibody A in a neoadjuvant therapy with paclitaxel.

aims

The main objective of this study was to identify patients with human primary epidermal growth factor receptor 2 (HER2)-negative primary breast cancer who were treated with doxorubicin plus cyclophosphamide after weekly treatment with antibody A plus paclitaxel. Pathological complete response to doxorubicin plus cyclophosphamide in combination with weekly paclitaxel alone (pCR) rate.

The secondary objectives of this study were to define the toxicity characteristics of the treatment group; to determine the clinical activity of the treatment group in which the tumor was removed based on the residual cancer load index; to evaluate the changes in the postoperative Ki-67 tumor marker in the residual disease; And the pharmacokinetics of paclitaxel; defining the immunogenicity of antibody A; assessing the distribution of a marker (based on a pre-specified combination of one or a group of biomarkers) predicts whether it can benefit from treatment (pCR Subgroups that are improved and measured; and assess changes in pharmacodynamic markers below and explore the effects of these changes with antibody A exposure and antitumor activity in pre- and post-treatment tumor tissues tErb3, pErbB3, pAKT, and pERK The association.

Additional targets for the study include: assessing the relevant pharmacodynamic changes of antibody A and/or paclitaxel acting on other downstream targets of the key pro-survival pathway, and assessing other markers from serum or tumor tissue samples that can be used to predict confrontation Response/resistance of body A (measured by pCR and RCB index).

Research design

This study was a multicenter, open-label, randomized Phase II study designed to study the use of antibody A combined with chemotherapy in the treatment of HER2-negative breast cancer patients before surgery. See Figure 3. Patients will be randomized to receive 12 weeks of paclitaxel-conjugated antibody A or paclitaxel alone, followed by 4 cycles of doxorubicin plus cyclophosphamide and surgery. This test is intended to prove Ming: For patients with Her2-negative locally advanced breast cancer who can undergo surgery, the addition of Antibody A to paclitaxel in their neoadjuvant therapy is more effective than paclitaxel alone.

Two groups of patients will be enrolled in the study: Group 1: Patients with ER-positive HER2 non-overexpressing aggressive breast cancer (ER-positive tumors are defined as 1% of tumor nuclei have an immune response); Group 2: patients with triple-negative disease (ER-negative tumors are defined as <1% of tumor nuclei with immune response).

A total of 200 patients participated in the study, 100 in each group. Patients will be eligible for screening for up to 28 days, during which time they will complete all screening procedures. Through a computerized IVR system, eligible patients will be randomly assigned to the following therapy group at a 2:1 ratio (1 cycle = 3 weeks):

̇ Treatment group A: Initially 2 weeks of antibody A introduction, followed by 4 cycles of paclitaxel plus antibody A treatment, followed by 4 cycles of doxorubicin and cyclophosphamide

̇ treatment group B: 4 cycles of paclitaxel treatment, followed by 4 cycles of doxorubicin and cyclophosphamide

One treatment cycle, weekly for 3 weeks, was treated with paclitaxel or paclitaxel plus antibody A. Doxorubicin and cyclophosphamide are administered once every 2 weeks. If the patient is proven to have radioactive or clinical disease progression or intolerable toxicity, the study therapy can be discontinued before the specified number of cycles is completed.

Once the patient completes the study therapy, it will be followed up on the 30th day (±15 days) after the treatment is discontinued.

After the screening period and the third week of paclitaxel treatment, a core biopsy will be collected (patients in treatment group A [antibody A treatment group] may refuse biopsy after receiving paclitaxel plus antibody A for 3 weeks). Patients randomized to treatment group A will undergo an additional core biopsy after 2 weeks of antibody A introduction.

Treatment and safety assessment

Antibody A plus paclitaxel or paclitaxel alone was administered intravenously once a week (± 2 days) for one hour for 12 weeks. Doxorubicin plus cyclophosphamide was administered intravenously once every 2 weeks for 4 hours. At the discretion of the physician, the patient is required to undergo other chemotherapy and/or radiation therapy in the removal of the tumor.

The patient will continue to receive treatment until surgery.

standard constrain

The patient has not received any treatment for this cancer, including chemotherapy, surgery (except for diagnostic biopsy), radiation therapy, hormonal therapy, or research products. After a diagnostic biopsy, clinical or radiologically detectable breast disease is defined as having a longest diameter greater than or equal to 2 cm (T2, T3 or T4).

Patients will be enrolled in a group of triple-negative breast cancer and ER-positive HER2 non-overexpressive invasive breast cancer. It should be noted that ER positive is defined as 1% of tumor nuclei have an immune response, while ER positives are defined as <1% of tumor nuclei with immune responses (Hammond 2010).

Patients must have/become: confirmed by histology as locally advanced ER-positive HER2 non-overexpressing aggressive breast cancer (Group 1) or invasive triple-negative breast cancer (Group 2).

Group 1: (ER-positive HER2 non-overexpressive invasive breast cancer) HER2 non-overexpression status has been demonstrated to be one of the following: immunohistochemical (IHC) staining results are 0 or 1+ indicating negative; or fluorescent Hybridization (FISH) results showed that the number of copies of the Her2 gene per nucleus was less than 4; or the FISH ratio was less than 1.8 ER positive tumors should have / be: Ki-67 index equal to or greater than 10% breast ductal carcinoma or pleomorphic lobules Cancer ER-positive tumors are defined as 1% of tumor nuclei have an immune response Group 2: (three-negative breast cancer) HER2 non-overexpression status has been demonstrated to be one of the following: immunohistochemical (IHC) staining results are 0 or 1+ indicating negative; or fluorescent Position hybridization (FISH) results showed that the number of copies of Her2 gene per nucleus was less than 4; or the FISH ratio was less than 1.8

In addition, the triple negative tumor should be: ductal carcinoma of the breast

ER-negative PR-negative tumors are defined as <1% of tumor cells that have an immune response to ER and/or PR.

Exclusion criteria

Patients who have the following conditions should not participate in the study: there is evidence of metastatic disease; active infection or unexplained fever of >38.5 °C during screening visits or on the first day of scheduled dosing, in the opinion of the investigator It may affect the patient's participation in the trial or the results of the study (researchers may decide to recruit patients with tumor fever at their discretion); patients are known to be allergic to any component of Compound A, or to allergic reactions to all human monoclonal antibodies; Association of cardiac function classification (NYHA) grade III or IV congestive heart failure or left ventricular ejection fraction (LVEF) is less than 55%; (has a significant history of heart disease (ie uncontrolled blood pressure, unstable angina, myocardial development within 1 year) Patients with infarction or ventricular heart rhythm requiring medication are also excluded; have a history of severe allergic reactions to paclitaxel or other drugs formulated with Cremaphor® EL; pregnant or breastfeeding; have any other condition, and the researcher believes that It is likely that the patient will interfere with the patient's ability to sign informed consent, cooperate with and participate in the study, or interpret the outcome of the intervention or require chronic consolidation. Alcohol treatment.

Dose level

Antibody A was administered weekly. The study drug should be placed at room temperature prior to administration. Do not shake the vial of the study drug. The appropriate amount of the study drug was taken from the vial, diluted with 250 ml of normal saline (0.9%), and then administered as a intravenous infusion solution with a low protein-bound 0.22 micron line filter. The first infusion time was 90 minutes or more. , all subsequent infusions are more than 60 minutes.

The dose administered by the patient over the entire cycle will be calculated using the body weight before the start of the cycle. The first dose of Antibody A was administered at a dose of 40 mg/kg. After this loading dose, 20 mg/kg of Antibody A will be administered weekly. If the patient's weight change reaches 10%, a new total dose will be calculated to reflect this change.

Pacific paclitaxel is a colorless to pale yellow transparent viscous solution. The preparation is a non-aqueous solution for dilution with an appropriate injection prior to intravenous infusion. Paclitaxel is available in 30 mg (5 ml), 100 mg (16.7 ml) and 300 mg (50 ml) multiple dose vials. Each milliliter of sterile, pyrogen-free solution contained 6 mg of paclitaxel, 527 mg of pure Cremophor® EL ^* (polyethylene glycol castor oil), and 49.7% (v/v) of anhydrous alcohol (USP).

The paclitaxel bottle should be stored in its original outer box and stored in the dark at 20° to 25°C (68° to 77°F).

Paclitaxel is administered at a dose of 80 mg/m3 per week for 60 minutes or more per intravenous infusion. For receiving antibody A For patients, paclitaxel should be administered immediately after administration of Antibody A. All patients should receive pre-administration before administration of paclitaxel to prevent severe allergic reactions. Prodrug administration can consist of 20 mg (oral) dexamethasone administered at about 12 and 6 hours prior to paclitaxel dosing; 50 mg (intravenous) diphenhydramine (or equivalent) in paclitaxel Administration 30 to 60 minutes prior to dosing; and 300 mg of cimetidine (intravenous) or 50 mg of methotrexate (intravenous) administered 30 to 60 minutes prior to paclitaxel administration.

Doxorubicin and cyclophosphamide

The product is supplied in the form of a hydrochloride salt, which is expressed as a sterile orange-red lyophilized powder containing lactose, and a sterile isotonic injection containing sodium chloride, which is only used for intravenous injection. The lyophilized cyclophosphamide for injection is a sterile white lyophilized cake or partially broken mass containing 75 mg of mannitol per 100 mg of cyclophosphamide (anhydrous).

Doxorubicin should be stored at 15° to 30°C (59° to 86°F) in the dark. All unused parts should be discarded.

Cyclophosphamide should be stored at a temperature of 25 ° C (77 ° F) or below. This product can be temporarily placed at a temperature of up to 86 ° F (30 ° C), but should be avoided at temperatures above 30 ° C (86 ° F).

Doxorubicin was administered as a separate intravenous injection via intravenous injection at a dose of 60 mg/m 2 per dose. All patients will receive doxorubicin once every 2 weeks for a total of 4 cycles.

Cyclophosphamide is administered intravenously at a dose of 600 mg/flat Square meter. All patients will receive cyclophosphamide once every 2 weeks for a total of 4 cycles.

It is recommended that Group 2 patients (TNBC) receive pegylated filgrastim on the second day after doxorubicin and cyclophosphamide administration per cycle.

Dose adjustment

The infusion response is defined as follows in accordance with the National Cancer Institute (NCI) Common Adverse Event Terminology Criteria (CTCAE; Version 4.0).

The study unit policy or the following treatment guidelines are used to control the infusion response.

For patients with grade 1 or 2 infusion reactions, the rate can be reduced (over 90 minutes) during the infusion.

For patients who have a grade 1 or 2 infusion reaction for the second time, 10 mg of dexamethasone is administered by intravenous injection. For subsequent infusion, pre-administration should be given by intravenous injection of 50 mg of diphenhydramine hydrochloride, intravenous injection of 10 mg of dexamethasone, and oral administration of 650 mg of acetaminophen.

For patients randomized to the antibody A treatment group, if a grade 3 or 4 infusion reaction occurs, anti-antibody A antibody analysis is performed on any patient who has an infusion response to antibody A as close as possible to the onset of the infusion reaction. Anti-antibody A antibody analysis should also be obtained at the time of disappearance of the reaction and 28 days (± 2 days) after the reaction.

Toxicity control

If there is a grade 1 or 2 toxicity that may be associated with antibody A treatment, then it will be decided whether to continue treatment. If the patient develops a grade 3 or higher toxicity that may be associated with antibody A treatment, further treatment with antibody A should be controlled until the toxicity drops to level 1 or baseline. If the treatment of antibody A stops for 28 consecutive days and the toxicity is not relieved to At baseline or level 1, the patient should discontinue the study.

Depending on the toxicity, the dose of Antibody A in the future can be 15 mg/kg.

Before starting treatment with paclitaxel, the patient's ANC should be >1000/m3. If the patient develops a grade 2, 3 or 4 toxicity or if ANC < 1000 / cubic meter, the weekly dose can be postponed. Toxicity restored to After level 1 and / or ANC At 1000/m3, paclitaxel administration can be resumed. It is not recommended to reduce the dose of paclitaxel.

For doxorubicin and cyclophosphamide, the starting dose can be reduced if necessary. Doxorubicin can be reduced from a starting dose of 60 mg/m2 to 50 mg/m2. Cyclophosphamide can be reduced from a starting dose of 600 mg/m2 to 500 mg/m2.

Before starting treatment with doxorubicin/cyclophosphamide, patients with no G-CSF should have an ANC >1200/m3. Patients receiving G-CSF should have an ANC of >1000/m3 to begin treatment with doxorubicin/cyclophosphamide. Patients with grade 3 or 4 non-hematologic toxicity or febrile neutropenia (with or without G-CSF) should be reduced to level A.

Incidence assessment

The assessment may include a physical examination (as appropriate) through a two-dimensional measurement of the breast mass and any axillary lymph nodes and/or standard imaging modalities (CT scans, MRI scans, ultrasound). Patients who are tracked by radiology need to scan only once every two cycles.

Pharmacokinetic assessment

For patients receiving antibody A, serum levels of antibody A and paclitaxel should be measured in a central analytical laboratory using enzyme-linked immunosorbent assay (ELISA). In order to better understand the PK and safety properties of Compound A in combination with paclitaxel, it is also possible to measure additional analytes. Instructions for handling and shipping PK serum samples are found in the research manual.

Biomarker assessment

The following assessments were included in part of routine research tracking for all patients participating in the study:

Serum biomarker

Blood samples were taken for exploratory studies to further define and correlate the characteristics of potential biomarkers that can assess the response, potential resistance, and toxicity of antibody A production. The sample is used to perform a specific biomarker analysis, or if there is still a sample remaining after performing the analysis, the remaining sample will be saved by the sponsor for use as a future biomarker analysis associated with Antibody A. When informed consent is given, the patient can refuse to save the remaining samples.

Research core slice

Before the first dose, two weeks after the introduction of antibody A monotherapy (for patients in treatment group A) and paclitaxel +/- antibody A therapy (patients in treatment group A can refuse to live at this time) Tissue examination) A biopsy performed 3 weeks later collected tumor samples from the patient. Samples collected through the above biopsy will be compared, and analysis will be performed to find biomarkers predictive of response to antibody A; Ki-67 analysis will also be performed on all sections intensively.

Statistical considerations

The primary endpoint of this study was pCR. The difference in pCR rates between the 2 treatment groups in each group will be estimated. After calculation, the confidence interval of the estimated difference is 80%.

Secondary endpoints included residual cancer burden, changes in residual disease Ki-67 index at the time of surgery, molecular biomarkers associated with antibody A therapy, PK, immunogenicity, and toxicity. All efficacy evaluations are based on a measurable group. The residual cancer load index can be measured using the MD Anderson Residual Tumor Burden Calculator and is also reported to have 95% CI. The results were provided separately by the treatment groups of each group.

All patients who received at least one study protocol will be included in the safety analysis. Toxicity was assessed on the basis of CTCAE (version 4.0). The incidence and type of grade 3 and grade 4 adverse events (AE, including serious adverse events (SAE)) will be summarized using a descriptive statistics list. The toxicity frequency is based on the CTCAE list.

Statistical assumptions and sample size determination

The trial was designed to estimate the trial and there was no formal hypothesis test. The primary analysis will consist of estimating the difference in pCR rates between treatment groups in each patient group and the 80% confidence interval (CI) for the calculated difference.

For the TN group, 100 patients were enrolled and assigned 2:1 (67 to the antibody-treated group and 33 to the control group). If the putative pCR rate of the control group is 35%, and the antibody A treatment group is 55%, the probability that 80% CI will exclude no effect is about 73%. If the pCR rate of the antibody A treatment group is 57%, the probability will increase to 80%. If the pCR rate of the antibody A treatment group is 62%, the probability will increase to 90%, while the pCR rate of the control group is still 35%.

For the ER-positive/HER2-negative group, 100 patients were enrolled and assigned 2:1 (67 to the antibody-A treatment group and 33 to the control group). If the putative pCR rate of the control group is 10%, and the antibody A treatment group is 25%, the probability that 80% CI will exclude no effect is about 71%. If the pCR rate of the antibody A treatment group is 28%, the probability will increase to 80%. If the pCR rate of the antibody A treatment group is 32%, the probability will increase to 90%, while the pCR rate of the control group is still 10%.

Statistical and analytical plan

This study has 2 patient groups.

The efficacy of sputum can be estimated: this group includes all patients who received at least 6 doses of study drug after surgery. This group is the primary group for all efficacy analysis parameters.

̇ Safety Analysis Group: The Safety Analysis Group includes all randomly assigned patients who have received at least 1 study drug infusion (including partial doses). This group is used for security analysis. All analyses performed using this group are based on actual accepted treatment.

Efficacy analysis

The primary end point of this study was pathological complete response (pCR), which was defined as the disappearance of invasive cancer of the chest and lymph nodes after initial systemic therapy. After 12 weeks of treatment with antibody A + paclitaxel or paclitaxel alone, followed by 4 cycles of doxorubicin + cyclophosphamide, the patient will undergo a tumor resection. Tumor tissue mass/tissue samples were examined locally to understand the pCR rate and to quantify residual disease for secondary endpoint analysis.

The primary analysis consisted of estimating the difference in pCR rates between treatment groups in each patient group, including the 80% CI calculated using the positive approximation.

For the secondary efficacy endpoint, the residual tumor burden index can be measured at the time of tumor resection using the MD Anderson Residual Tumor Burden Calculator. The residual tumor burden index was summarized by a treatment group that also reported 95% CI. Ki-67 tumor markers in residual disease were obtained at the time of surgery. Changes in Ki-67 tumor markers in residual disease at the time of surgery compared to the time point of previous biopsy studies Can be summarized by treatment group.

For safety endpoints, treatment-induced AEs were reported by treatment group, by patient, by NCI CTCAE grade, and by the "Medical Dictionary for Regulatory Activities" (MedDRA) system organ classification and preferred terminology. A separate list is used to present total AE, SAE, AE associated with antibody A, and grade 3/4 AE. If possible, abnormal test values are assessed according to the NCI CTCAE rating. The assessment of the corrected QT interval is based on Fridericia's calibration method (QTcF). The CTCAE standard applies to QTcF. The incidence of anti-antibody A immunogenicity was summarized by the treatment group.

Pharmacokinetic (PK) analysis

Serum concentrations can be used to determine PK parameters by using standard non-compartment model techniques. PK parameters can be aggregated using descriptive statistics, including a median, mean, and 95% confidence interval for dose level parameters. The pharmacokinetic parameters will include the maximum serum concentration (Cmax) of the drug, the time to reach Cmax (tmax), the area under the concentration time curve (AUC), the AUC (AUCt) of the last observed concentration at time t, and the clearance rate. (CL), volume of distribution (Vdss) in steady state, and terminal elimination half-life (t1/2) (if applicable).

Pharmacodynamics and biomarker data analysis

Tumor tissue blocks or clean slides containing tumor tissue can be The initial diagnosis begins with the collection of patients and is then processed to obtain quantitative measurements of predictive biomarkers for antibody A sensitivity. Biomarkers are screened by immunohistochemistry and are measured by receptors EGFR (ErbB1), Her-2-neu (Erb-B2), Her-3 (Erb-B3), and by reverse transcriptase polymerase chain reaction (RT). -PCR) Measurement of the expression of the messenger RNA of the ligands betacellulin and neuregulin-1.

To assess the pharmacodynamics of the antibody A combination, patient tumor sampling will be performed directly from the core sections extracted from the obtained surgical specimens prior to the first administration, at the end of the patient's first treatment cycle, and after completion of the study treatment. TErbB3, pErbB3, pAKT, and pERK levels will be analyzed for pre- and post-treatment samples. These tumor samples will be analyzed as paired samples (measured before and after treatment for each patient). Data were characterized by the mean concentration of pre-treatment groups and a 95% confidence interval and the mean of the standardized changes from baseline for the paired samples and a 95% confidence interval.

In addition, biomarker measurements were obtained from serum samples taken at baseline and throughout the study to assess whether serum markers were associated with tumor sample analysis results and/or overall efficacy outcomes (eg, neuregulin).

The primary purpose of biomarker analysis is to assess the potential predictive use of each or any combination of alternate biomarkers measured at baseline (pre-treatment). The initial method of assessment is to check if the treatment effect has changed due to any biomarkers. In this regard, logic The regression model was applied as a result, specifying the treatment, the biomarkers involved, and the interaction between the indicated treatment and biomarkers as covariates. If there is an interaction, as the alpha=0.10 test determines that the therapeutic effect changes due to biomarkers, the biomarker can be potentially predicted and further examined.

The efficacy of treatment interactions with biomarkers was found to be assessed by simulation. It is assumed that the biomarker values (or variants) are normally distributed through the public variance, and the biomarkers are predictive, while the biomarker values differ only between responders and non-responders in the antibody A treatment group. It is further hypothesized that all patients will be effectively pre-treatment measurements of the biomarkers involved, and the pCR rates in the antibody-treated and single-chemotherapy groups in the TN patient group are 55% and 35%, respectively, whereas antibodies in the ER-positive group The pCR rates of the A treatment group and the single chemotherapy group were 25% and 10%, respectively. If the mean biomarker value differs by a factor of 1.5 from the responder and non-responders in the antibody A treatment group, the effect of the interaction between the biomarker and the treatment in the TN group based on the alpha=0.10 test is approximately 88%, 63% in the ER positive group. If the mean difference is 2 times the standard deviation, the efficacy of the TN group will increase to 97%, while the ER positive group will increase to 77%. However, if the mean difference is as small as 1 standard deviation, the efficacy of the TN group will fall to 67%, while the ER positive group will fall to 40%.

If an appropriate biomarker threshold can be determined, other indicators can be assessed through the treatment group, including positive predictive value, negative predictive, and sensitivity. And specificity.

Pharmacodynamic (PD) changes in intra- and inter-group biomarkers (eg, tErbB3, pErbB3, pAKT, and pERK) will be assessed using paired pre- and post-treatment patient biopsies. A pre-treatment tumor biopsy is expected for all patients. Two weeks after monotherapy, a second biopsy was forced in the antibody A treatment group, and the third biopsy was performed 3 weeks after the combination of antibody A and paclitaxel. A second biopsy was also mandated in the paclitaxel treatment group 3 weeks after treatment.

A one-sample T test was used to assess the effect of PD in each group after 2 weeks of monotherapy and 2 weeks of monotherapy with the paclitaxel-treated group in the antibody A treatment group. The analysis was performed in individual and combined groups within each group assuming consistent changes in biomarkers within the intergroup.

A two-sample T-test was used to assess the presence of differences between groups of biomarkers PD within the group after 2 weeks of monotherapy with antibody A alone and after 3 weeks of monotherapy with paclitaxel alone. The same type of analysis was used to compare the effect of biomarker PD in the group after 3 weeks of combined therapy in the antibody A treatment group and 3 days after receiving paclitaxel monotherapy in the paclitaxel group.

Those skilled in the art will recognize that numerous equivalents of the specific embodiments described herein can be determined and carried out using only routine experiment. Such equivalents are included in the following claims. Disclosed in the independent claims Combinations of any of the embodiments are within the scope of the disclosure.

All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety.

Figure 1 shows the response of a cancer patient receiving antibody A and paclitaxel combination therapy. Group 1: MM-121 20 mg/kg (load), 12 mg/equivalent dose once a week; paclitaxel 80 mg/m2. Group 2: MM-121 40 mg/kg (load), 20 mg/equivalent dose once a week; paclitaxel 80 mg/m2. Expanded group 1: MM-121 40 mg/kg (load), 20 mg/equivalent dose once a week; paclitaxel 80 mg/m2. Expanded group 2: MM-121 20 mg/kg (load), 12 mg/equivalent dose once a week; paclitaxel 80 mg/m2. Expanded group 3: MM-121 40 mg/kg once every two weeks; paclitaxel 80 mg/m2.

Figure 2 shows the response of a cancer patient receiving antibody A combined with paclitaxel, as shown by the sum of diameters (%).

Figure 3 shows a schematic of the Phase 2 clinical trial.

<110> KUBASEK, WILLIAM MOYO, VICTOR NERING, RACHEL DHINDSA, NAVREET PEARLBERG, JOSEPH TABAH-FISCH, ISABELLE

<120> Dosage and administration of anti-ERBB3 antibody combined with paclitaxel

<130> MMJ-035PC

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<141> Attached at the same time

<150> 61/500,752

<151> 2011-06-24

<150> 61/596,102

<151> 2012-02-07

<150> FR1252652

<151> 2012-03-23

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Claims (24)

A method of treating breast cancer in a human patient comprising administering to the patient an effective amount of: (a) an anti-ErbB3 antibody comprising CDRH1, CDRH2 and CDRH3 sequences, and wherein the sequences comprise SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and the amino acid sequence of SEQ ID NO: 7 (CDRH3), and the CDRL1, CDRL2 and CDRL3 sequences, and these sequences comprise SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3) amino acid sequence, and (b) paclitaxel, wherein the method comprises at least one cycle, wherein one cycle lasts for 3 weeks, and during the weekly period, the weekly dose of anti-ErbB3 antibody is 20 The weekly dose of milligrams per kilogram of paclitaxel is 80 mg/m2. The method of claim 1, wherein the anti-ErbB3 antibody is antibody A. The method of claim 1 or 2, wherein the effective amount comprises administering an anti-ErbB3 antibody as a monotherapy before at least one of the cycles described above. The method of any one of claims 1 to 3, wherein the anti-ErbB3 antibody is administered monotherapy for 2 weeks, wherein the anti-ErbB3 antibody is administered at a dose of 40 mg/kg at the first week, and the second week 20 Mg/kg. The method of any one of claims 1 to 4 wherein the breast cancer test is positive for the estrogen receptor and the breast cancer is HER2 non-overexpressing invasive breast cancer. The method of any one of claims 1 to 5 wherein the breast cancer is triple negative breast cancer. The method of any one of claims 1 to 6, wherein paclitaxel is administered immediately after the anti-ErbB3 antibody. The method of any one of claims 1 to 7, wherein the patient is pretreated with an anti-allergic agent prior to administration of paclitaxel. The method of claim 8, wherein the hypoallergenic agent is selected from the group consisting of 20 mg dexamethasone; 50 mg diphenhydramine; 300 mg cimetidine; and 50 mg methylamine Furfuryl. The method of any one of claims 1 to 9, wherein the patient does not have a metastatic disease. The method of any one of claims 1 to 10, wherein the method further comprises at least one additional cycle, wherein the additional cycle is two Week, while in each additional cycle, the dose of doxorubicin was 60 mg/m2 and the dose of cyclophosphamide was 600 mg/m2. The method of claim 11, wherein the breast cancer test is positive for estrogen receptors, and the breast cancer is HER2 non-overexpressing invasive breast cancer. The method of claim 11, wherein the breast cancer is triple-negative breast cancer. The method of any one of claims 11 to 13, wherein the method comprises four additional cycles. The method of claim 11, wherein the patient receives further treatment with pegylated filgrastim on the second day of each additional cycle after administration of the above doxorubicin and cyclophosphamide. For example, in the method of claim 11, wherein the patient is subsequently operated to remove the cancerous tissue. The method of any one of claims 1 to 16, wherein the treatment produces at least one of the following effects: the tumor volume is reduced; the number of metastatic lesions decreases with time; complete response; partial response; stable condition; overall response The rate is increased; or the pathology is completely responsive. A composition for treating breast cancer in a human patient, the composition comprising a clinically proven safe and effective amount of: (a) an anti-ErbB3 antibody comprising CDRH1, CDRH2 and CDRH3 sequences, and wherein these sequences are listed in SEQ ID NO : 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and the amino acid sequence of SEQ ID NO: 7 (CDRH3), and the CDRL1, CDRL2 and CDRL3 sequences, and these sequences are listed in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and the amino acid sequence of SEQ ID NO: 10 (CDRL3), and (b) paclitaxel, (c) doxorubicin and (d) cyclophosphamide. The composition of claim 18, wherein the anti-ErbB3 antibody is antibody A. The composition of claim 18 or 19, wherein the antibody is administered in an intravenous dose of 20 mg/kg per dose. A kit comprising a dose of an anti-ErbB3 antibody comprising CDRH1, CDRH2 and CDRH3 sequences, wherein the sequences comprise SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 The amino acid sequence of (CDRH3), and the CDRL1, CDRL2 and CDRL3 sequences, and these sequences comprise SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), respectively. Amino acid Sequences, and instructions for using the anti-ErbB3 antibody in the method of claim 1 of the scope of the patent application. As in the kit of claim 21, the kit contains at least 500 mg of antibody. As in the kit of claim 21, the kit contains at least 1 mg of paclitaxel. An anti-ErbB3 antibody comprising SEQ ID NO: 5 (CDRH1), SEQ ID NO: 6 (CDRH2), SEQ ID NO: 7 (CDRH3), SEQ ID NO: 8 (CDRL1), SEQ ID NO: 9 (CDRL2 And SEQ ID NO: 10 (CDRL3), wherein the anti-ErbB3 antibody is used in combination with paclitaxel for at least one cycle, wherein one cycle is for 3 weeks, and during the weekly period, the weekly dose of anti-ErbB3 antibody is 20 mg/kg. The weekly dose of paclitaxel is 80 mg/m2.