Patent Application
20160303232
The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on May 17, 2016, is named MMJ_053PCCP_SL.txt and is 21,625 bytes in size.
Lung cancer is one the leading causes of cancer-related deaths worldwide. There were estimated to be 224,410 new cases diagnosed in 2014 alone, making up approximately 13% of all cancer diagnoses. For cases diagnosed during the period of 2003-2009, the 1- and 5-year survival rates were 43% and 17% respectively (“American Cancer Society Facts and Figures 2014”). Over 80% of lung cancers are non-small cell lung cancers (NSCLC), and nearly two thirds of these are diagnosed at an advanced stage. A platinum-based doublet regimen with a “third-generation” agent (paclitaxel, docetaxel, gemcitabine, vinorelbine, or pemetrexed) is considered standard of care worldwide for the treatment of advanced NSCLC. However, only one third of patients that receive this regimen reach an objective response during first-line therapy, and another 20-30% achieves stabilization of disease. Unfortunately, almost all such patients ultimately see progression of their disease.
Three agents that are currently approved for treatment of refractory (recurrent, i.e., second-line treatment) advanced NSCLC are docetaxel, pemetrexed, and erlotinib.
Docetaxel, brand names TAXOTERE®, DOCECAD®—IUPAC name 1,7β,10β-trihydroxy-9-oxo-5β,20-epoxytax-11-ene-2α,4,13α-triyl 4-acetate 2-benzoate 13-{(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoate}, is an anti-mitotic taxane anti-cancer therapeutic that is typically administered via a one-hour infusion every three weeks over ten or more cycles. The approved dose of docetaxel in the second-line treatment of NSCLC is 75 mg/m2 intravenously over 60 minutes once every 3 weeks. Docetaxel should be administered prior to seribantumab dosing.
Pemetrexed, brand name ALIMTA®—IUPAC name (2S)-2-{[4-[2-(2-amino-4-oxo-1,7-dihydro pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]amino}pentanedioic acid), is a folate antimetabolite currently approved for the treatment of pleural mesothelioma and non-small cell lung cancer. It is typically administered at a dose of 500 mg/m2 intravenously over 10 minutes on day 1 of each 21-day cycle.
Ovarian cancer, including epithelial ovarian cancer is a leading cause of cancer-related death in women, as are primary peritoneal carcinoma and fallopian tube carcinoma. Since ovarian cancer is relatively asymptomatic at its early stages, it often remains undiagnosed until the disease has reached an advanced stage. The standard treatment for advanced ovarian cancer includes surgery followed by chemotherapy with a platinum-based chemotherapeutic agent, e.g., cisplatin, carboplatin, oxaliplatin, and satraplatin, or with an antimicrotubule agent such as paclitaxel. Other drugs used to treat ovarian cancer include bevacizumab, carboplatin, cyclophosphamide, doxorubicin, gemcitabine, olaparib, and topotecan. Although standard treatments are often successful, many patients suffer a recurrence of the disease, often with expression of resistance to platinum-based regimens.
Seribantumab, an anti-ErbB3 Monoclonal Antibody Therapeutic
Seribantumab (previously MM-121 or Ab #6) is an human monoclonal anti-ErbB3 IgG2; see, e.g., U.S. Pat. Nos. 7,846,440; 8,691,771 and 8,961,966; 8,895,001, U.S. Patent Publication Nos., 20110027291, 20140127238, 20140134170, and 20140248280), as well as international Publication Nos. WO/2013/023043, WO/2013/138371, WO/2012/103341, and U.S. patent application Ser. No. 14/967,158.
Seribantumab is a recombinant human IgG2 mAb that binds an epitope on human ErbB3 with high specificity. The complete tetrameric structure of the IgG2 molecule is composed of 2 heavy chains (445 amino acids each) and 2 lambda light chains (217 amino acids each) held together by intrachain and interchain disulfide bonds. The amino acid sequence (see below) predicts a molecular weight of 143 kDa for the intact nonglycosylated monomer IgG2. Glycosylation analysis demonstrates N-linked glycosylation of seribantumab, which is predicted to contribute approximately 2.9 kDa to the molecular weight of the intact glycosylated seribantumab monomer. The predicted molecular weight of intact glycosylated seribantumab, 146 kDa, is within 0.2% of the actual molecular weight as experimentally determined by mass spectroscopy. The isolectric point of seribantumab is approximately 8.6 (major isoform as determined by isoelectric focusing electrophoresis).
Seribantumab is administered by intravenous infusion (e.g., over the course of one hour) and is supplied as a clear liquid solution in sterile, single-use vials containing 10.1 ml of seribantumab at a concentration of 25 mg/ml in an aqueous solution of 20mM histidine, 150mM sodium chloride, at a pH of about 6.5 (in the range of 6.2 to 6.8), to be stored at 2-8° C. Seribantumab comprises a heavy chain having the amino acid sequence of SEQ ID NO:7 and a light chain having the amino acid sequence of SEQ ID NO:8. Seribantumab comprises a heavy chain variable region (VH) and a light chain variable region (VL) encoded by the nucleic acid sequences set forth in SEQ ID NOs:9 and 11, respectively. Seribantumab comprises VH and VL regions comprising the amino acid sequences set forth in SEQ ID NOs:10 and 12, respectively. Seribantumab comprises CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO:1 (CDRH1) SEQ ID NO:2 (CDRH2) and SEQ ID NO:3 (CDRH3), and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO:4 (CDRL1) SEQ ID NO:5 (CDRL2) and SEQ ID NO:6 (CDRL3).
Treatment outcomes for NSCLC, ovarian cancer, primary peritoneal carcinoma and fallopian tube carcinoma are evaluated using standard measures for tumor response.
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm; Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters;
Progressive Disease (PD: At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression); and
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. (Note: a change of 20% or less that does not increase the sum of the diameters by 5 mm or more is coded as stable disease). To be assigned a status of stable disease, measurements must have met the stable disease criteria at least once after study entry at a minimum interval of 6 weeks.
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be non-pathological in size (<10 mm short axis). If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response;
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits; and
Progressive Disease (PD): Either or both of appearance of one or more new lesions and unequivocal progression of existing non-target lesions. In this context, unequivocal progression must be representative of overall disease status change, not a single lesion increase.
Other Exemplary Positive Responses
Patients treated with these methods may experience improvement in at least one sign of NSCLC or ovarian cancer, primary peritoneal carcinoma and fallopian tube carcinoma. Response may also be measured by a reduction in the quantity and/or size of measurable tumor lesions. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter is to be recorded) as >10 mm by CT scan (CT scan slice thickness no greater than 5 mm), 10 mm caliper measurement by clinical exam or >20 mm by chest X-ray. The size of non-target lesions, e.g., pathological lymph nodes can also be measured for improvement. Lesions can be measured using, e.g., x-ray, CT, or MM images. Microscopy, cytology or histology can be also used to evaluate responsiveness to a therapy. An effusion that appears or worsens during treatment when a measurable tumor has otherwise met criteria for response or stable disease can be considered to indicate tumor progression, but only if there is cytological confirmation of the neoplastic origin of the effusion.
Although the currently approved treatments for NSCLC ovarian cancer, primary peritoneal carcinoma and fallopian tube carcinoma provide some benefit, there is still much room for improvement, particularly for patients with advanced or metastatic disease. Thus more effective treatments for patients with advanced NSCLC, ovarian cancer, primary peritoneal carcinoma and fallopian tube carcinoma are needed. The present invention addresses this need and provides additional benefits.
Provided are compositions and methods for treating a cancer in a selected human patient, comprising administering to the patient a combination of an anti-ErbB3 antibody and a second anti-cancer therapeutic.
The cancer may be a non-small cell lung cancer (NSCLC) e.g., nonsquamous NSCLC, and the second anti-cancer therapeutic may be, e.g., docetaxel or pemetrexed, wherein the combination is administered (or is for administration) according to a particular clinical dosage regimen (i.e., at a particular dose amount and according to a specific dosing schedule). The cancer may instead be an ovarian cancer (e.g., persistent, recurrent, resistant, or refractory ovarian cancer) or the cancer may be primary peritoneal carcinoma or fallopian tube carcinoma and, for each of these the second anti-cancer therapeutic may be, e.g., paclitaxel, gemcitabine, irinotecan, liposomal irinotecan (e.g., nal-IRI) or liposomal doxorubicin, e.g., DOXIL®. In one embodiment, the cancer is a locally advanced or metastatic NSCLC that has progressed (i.e., is treatment refractory) after prior therapy with an organoplatinum agent. In one embodiment, the NSCLC is squamous cell carcinoma. In another embodiment, the cancer is EGFR wild-type.
In one aspect, a method of treating a cancer in an adult human patient is provided, the method comprising administering to the patient an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO:1 (CDRH1) SEQ ID NO:2 (CDRH2) and SEQ ID NO:3 (CDRH3), and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO:4 (CDRL1) SEQ ID NO:5 (CDRL2) and SEQ ID NO:6 (CDRL3), wherein the anti-ErbB3 antibody is administered as a first single dose of 3000 mg, regardless of patient body mass. In one embodiment, the first single dose is followed by at least one additional single dose, each of which at least one additional dose is administered three weeks after the immediately prior dose and is administered at a dosage of 3000 mg, regardless of patient body mass.
In a second aspect a method of treating a cancer patient who has a NSCLC tumor; and has progressed following treatment with no more than two systemic therapies for locally advanced or metastatic disease, of which one if which therapies was a platinum-based regimen is provided; the method comprising administering to the patient an effective amount of each of (1) an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO:1 (CDRH1) SEQ ID NO:2 (CDRH2) and SEQ ID NO:3 (CDRH3), and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO:4 (CDRL1) SEQ ID NO:5 (CDRL2) and SEQ ID NO:6 (CDRL3), and (2) docetaxel or pemetrexed.
In a third aspect a composition for treating a cancer in an adult human patient is provided, the composition comprising an antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO:1 (CDRH1) SEQ ID NO:2 (CDRH2) and SEQ ID NO:3 (CDRH3), and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO:4 (CDRL1) SEQ ID NO:5 (CDRL2) and SEQ ID NO:6 (CDRL3), wherein the composition is for administration as a first single dose of 3000 mg, regardless of patient body mass. In one embodiment, the composition is for administration as a first single dose of 3000 mg, regardless of patient body mass, followed by at least one additional single dose, each of which at least one additional dose is administered three weeks after the immediately prior dose and is administered at a dosage of 3000 mg, regardless of patient body mass.
In one embodiment, the cancer is non-small cell lung cancer (NSCLC). In another embodiment, the cancer is ovarian cancer.
In one embodiment, the patient has progressed following treatment with no more than two systemic therapies for locally advanced or metastatic disease, of which one was a prior platinum-based regimen. In another embodiment, the patient has progressed following treatment with no more than three systemic therapies for locally advanced or metastatic disease, of which one was a prior platinum-based regimen. In another embodiment, the human patient is treated following disease progression or recurrence after prior treatment with antineoplastic therapy (e.g., anti-cancer agent). In another embodiment, the human patient is treated after failure of an antineoplastic therapy. In another embodiment, the cancer is identified as a cancer that has acquired resistance to antineoplastic therapy.
In exemplary embodiments of any of the above aspects, the methods disclosed herein further comprise coadministration of an effective amount of a second anti-cancer therapeutic with the anti-ErbB3 antibody. In one embodiment, the second anti-cancer therapeutic is docetaxel, and wherein the effective amount of docetaxel is 75 mg/m2. In another embodiment the second anti-cancer therapeutic is pemetrexed, and wherein the effective amount is 500 mg/m2. In one embodiment, the effective amount of the docetaxel or pemetrexed is co-administered at least 30 minutes before the administration of the antibody.
In a fourth aspect, a composition for treating a cancer in an adult human patient is provided, the composition comprising an antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO:1 (CDRH1) SEQ ID NO:2 (CDRH2) and SEQ ID NO:3 (CDRH3), and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO:4 (CDRL1) SEQ ID NO:5 (CDRL2) and SEQ ID NO:6 (CDRL3), wherein the composition is for administration as a first single dose of 3000 mg, regardless of patient body mass. In one embodiment, the composition is for administration as a first single dose of 3000 mg, regardless of patient body mass, followed by at least one additional single dose, each of which at least one additional dose is administered three weeks after the immediately prior dose and is administered at a dosage of 3000 mg, regardless of patient body mass. In another embodiment, the composition is for administration at a dose of 20 mg/kg. In one embodiment, the ovarian cancer is persistent, recurrent, resistant, or refractory ovarian cancer.
In a fifth aspect, a method of treating a cancer patient who has an ovarian tumor is provided, a primary peritoneal carcinoma or a fallopian tube carcinoma, the method comprising administering to the patient an effective amount of each of (1) an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO:1 (CDRH1) SEQ ID NO:2 (CDRH2) and SEQ ID NO:3 (CDRH3), and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO:4 (CDRL1) SEQ ID NO:5 (CDRL2) and SEQ ID NO:6 (CDRL3), and (2) paclitaxel, irinotecan, or gemcitabine.
In exemplary embodiments of any of the above aspects, the anti-ErbB3 antibody is seribantumab.
In one embodiment the treatment methods described herein comprise administering seribantumab in combination with one or more other antineoplastic agents (e.g., other chemotherapeutics, other anti-cancer agents, or other small molecule drugs).
In one embodiment, no more than three other anti-cancer therapeutics are administered within a treatment cycle. In another embodiment, no more than two other anti-cancer therapeutics are administered in combination with seribantumab within the treatment cycle. In another embodiment, no more than one other anti-cancer therapeutic is administered in combination with seribantumab within the treatment cycle. In another embodiment, no other anti-cancer therapeutic is administered in combination with seribantumab within the treatment cycle. In another embodiment, the other anti-cancer therapeutics may be administered either simultaneously or before or after administration of seribantumab.
A cancer to be treated by the methods and compositions disclosed herein includes cancers that are heregulin (HRG) positive cancers, optionally wherein HRG positivity is determined by a HRG RNA-ISH assay or a quantitative RT-PCR assay. In such assay a sample is determined to be positive if such assay reveals at least 1-3 dots per cell, wherein the cells are from patient tumor samples. In one embodiment, HRG positivity is based on an FDA-approved test. In one embodiment, the cancer is non-small cell lung cancer (NSCLC). In another embodiment, the cancer is locally advanced or metastatic. In another embodiment, the patient has progressed following treatment with no more than two systemic therapies for locally advanced or metastatic disease, one of which systemic therapies comprised a platinum-based regimen.
In one embodiment, the treatment of a cancer comprising the compositions and/or methods of any of the above aspects produces at least one therapeutic effect selected from the group consisting of: reduction in size of a tumor, reduction in metastasis, complete remission, partial remission, stable disease, increase in overall response rate, or a pathologic complete response.
Provided herein are methods for effective treatment of platinum refractory NSCLC (e.g., a locally advanced or metastatic NSCLC) in a human patient using a combination of seribantumab and either a taxane, (e.g., docetaxel) or a folate antimetabolite (e.g., pemetrexed).
A NSCLC patient selected for treatment is an adult patient who has failed at least one, but not more than three, systemic therapies for locally advanced or metastatic NSCLC, one which failed systemic therapies must have been a platinum-based therapy (e.g., a doublet therapy). In another aspect, the NSCLC patient has one or more NSCLC tumors that are positive for heregulin (HRG) mRNA as assessed by an RNA-ISH assay, as described in the Examples below. In one embodiment, the NSCLC tumor is positive for HRG as assessed by an FDA-approved test.
In another aspect, the invention provides methods for effective treatment of cancer (e.g., NSCLC) in a human patient in need thereof who previously received antineoplastic therapy and developed resistance to the antineoplastic therapy. For example, in one embodiment, the method comprises treating cancer in a human patient in need thereof who previously received antineoplastic therapy and developed resistance to the antineoplastic therapy by administering seribantumab and either a taxane, (e.g., docetaxel) or a folate antimetabolite (e.g., pemetrexed).
Seribantumab is to be co-administered with a taxane (e.g., docetaxel) or a folate antimetabolite (e.g., pemetrexed), to a selected subject with NSCLC. In another embodiment, seribantumab is to be co-administered with paclitaxel, irinotecan, or gemcitabine to a selected subject with an ovarian cancer, primary peritoneal carcinoma or fallopian tube carcinoma.
“Co-administer” refers to simultaneous or sequential administration of the seribantumab and the taxane or folate antimetabolite. When sequential, co-administration must occur within a timespan that is short enough so that both the seribantumab and the taxane or folate antimetabolite are simultaneously present in treated patients.
In one embodiment, seribantumab is co-administered with the taxane docetaxel. Docetaxel is approved for single agent use in treating breast cancer and NSCLC (post-platinum therapy), and in combination therapy for treatment of hormone refractory prostate cancer, NSCLC (in combination with cisplatin), gastric adenocarcinoma, and squamous cell carcinoma of the head and neck. The approved dose regimen of docetaxel for the treatment of NSCLC is 75 mg/m2, given intravenously over 1 hour, once every 3 weeks.
In another embodiment, seribantumab is co-administered with the folate antimetabolite pemetrexed, also marketed under the trade name ALIMTA®. ALIMTA is approved for combination therapy treatment of non-squamous cell NSCLC and mesothelioma. The recommended dose of ALIMTA is 500 mg/m2 i.v. on Day 1 of each 21-day cycle. Dose reductions may be needed if toxicity is observed in combination therapy regimens, and may be adjusted in subsequent cycles.
In another embodiment, no more than three other anti-cancer therapeutics are administered in combination with seribantumab within a treatment cycle. In another embodiment, no more than two other anti-cancer therapeutics are administered in combination with seribantumab within the treatment cycle. In another embodiment, no more than one other anti-cancer therapeutic is administered in combination with seribantumab within the treatment cycle. In another embodiment, no other anti-cancer therapeutic is administered in combination with seribantumab within the treatment cycle. In another embodiment, the other anti-cancer therapeutics may be administered either simultaneously or before or after administration of seribantumab.
As used herein, “antineoplastic agent” refers to agents that have the functional property of inhibiting a development or progression of a neoplasm in a human, particularly a malignant (cancerous) lesion, such as a carcinoma, sarcoma, lymphoma, or leukemia. Inhibition of metastasis is frequently a property of antineoplastic agents.
A selected patient having advanced or metastatic NSCLC is treated on day 1 of at least one 21-day treatment cycle. Prior to the first treatment cycle, the patient undergoes a pre-treatment regimen. The regimen is specific to the upcoming chemotherapeutic treatment (e.g., pemetrexed or docetaxel) and is designed to mitigate pemetrexed- or docetaxel-related toxicity. Docetaxel pre-treatment comprises premedication with a corticosteroid such as dexamethasone (e.g., 8 mg twice daily) for three days, starting one day prior to docetaxel administration. Pemetrexed pre-treatment comprises premedication with a low-dose oral folic acid preparation (or multivitamin containing folic acid) on a daily basis, starting at least seven days before the start of the first 21-day cycle. On day 1 of each 21-day cycle, the patient will receive a standard dose of docetaxel or pemetrexed intravenously at least 30 minutes prior to the administration of seribantumab. Seribantumab is then administered intravenously over 90 minutes (on day 1 of the first 21-day cycle) or 60 minutes (on day 1 of any subsequent 21-day cycle).
As used herein, the term “fixed dose” (also known as a “flat dose” or a “flat-fixed dose”) is used refer to a measured dose that is administered to an adult patient without regard for the weight or body surface area (BSA) of the patient. The fixed dose is therefore not provided as a mg/kg (weight-based) dose, or as a mg/m2 (BSA) dose, but rather as an absolute amount of an agent (e.g., mgs of the anti-ErbB3 antibody) to be administered to an adult patient in a single administration.
A patient treated in accordance with the disclosed protocols may exhibit CR, PR, or SD with respect to target lesions. In another embodiment, the patient so treated experiences tumor shrinkage and/or decrease in growth rate, i.e., suppression of tumor growth. In another embodiment, tumor cell proliferation is reduced or inhibited. Alternately, one or more of the following can indicate a beneficial response to treatment: the number of cancer cells can be reduced; tumor size can be reduced; cancer cell infiltration into peripheral organs can be inhibited, retarded, slowed, or stopped; tumor metastasis can be slowed or inhibited; tumor growth can be inhibited; recurrence of tumor can be prevented or delayed; one or more of the symptoms associated with cancer can be relieved to some extent. Other indications of a favorable response include reduction in the quantity and/or size of measurable tumor lesions or of non-target lesions.
Also provided are kits that include, in an inner container (e.g., a vial) contained within an outer container (e.g., a bag, clamshell or box), a composition comprising an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences comprising the amino acid sequences set forth in SEQ ID NO:1 (CDRH1) SEQ ID NO:2 (CDRH2) and SEQ ID NO:3 (CDRH3), and CDRL1, CDRL2, and CDRL3 sequences comprising the amino acid sequences set forth in SEQ ID NO:4 (CDRL1) SEQ ID NO:5 (CDRL2) and SEQ ID NO:6 (CDRL3) and a pharmaceutically acceptable carrier, in a therapeutically effective unit dosage form (e.g., as a single dose) for use in the preceding methods. Optionally, the anti-ErbB3 antibody is seribantumab. Unit dosage forms will typically comprise an amount of drug, optionally slightly above the dosage amount (e.g., 3000 mg) to facilitate removal of the required amount from the inner container. This dosage amount may comprise multiple vials, e.g., 12×10.1 mL vials or 6×20 mL vials. Each vial in a kit should comprise the same lot number. The kits can optionally also include instructions, comprising, e.g., administration parameters and schedules, to allow a practitioner (e.g., a physician or nurse) to administer the antibody composition (and other drugs, if any) contained therein to NSCLC patients in accordance with the methods taught herein. In one embodiment, the kit further comprises docetaxel and/or pemetrexed, e.g., each in a separate container, optionally in single dose unit dosage form. The kit may further contain diluents, instruments, or devices necessary for administering the pharmaceutical composition(s) e.g., one or more of a container of sterile diluent, e.g., saline or dextrose solution for injection; a syringe or syringes (e.g. pre-filled syringes); a catheter, a hypodermic (IV) needle, an IV infusion set.
The following examples are merely illustrative and should not be construed as limiting the scope of this disclosure in any way as many variations and equivalents will become apparent to those skilled in the art upon reading the present disclosure.
All patents, patent applications and publications cited herein are incorporated herein by reference in their entireties.
Heregulin (HRG) RNA-ISH is performed as described below and in pending international application No. PCT/US2014/072594, “Biomarker Profiles for Predicting Outcomes of Cancer Therapy with ErbB3 Inhibitors and/or Chemotherapies,” filed 29 Dec. 2014, with the exception of the core needle biopsy analysis in Example 3.
RNA-ISH Assay
In this assay, FFPE tumor samples are scored for HRG RNA levels using the following variant of an Advanced Cell Diagnostics® (“ACD” Hayward, Calif.) RNAscope® assay. Specifically, cells are permeabilized and incubated with a set of oligonucleotide “Z” probes (see, e.g., U.S. Pat. No. 7,709,198) specific for HRG. Using “Z” probes, as well as using multiple sets of probes per transcript, increases the specificity of the assay over standard ISH methods. One HRG probe set that can be used in this assay is ACD Part Number 311181. Another HRG probe set prepared by ACD (and used in RNAscope® assays) includes 62 probes (31 pairs), each 25 bases in length, that target a 1919 base long region of the HRG transcript comprising nucleotides 442-2977 of SEQ ID NO:42 and that together detect 15 separate HRG isoforms (α, β1, β1b, β1c, β1d, β2, β2b, β3, β3b, γ, γ2, γ3, ndf43, ndf34b, and GGF2). Following Z probe incubation, a pre-amplifier is added that can only hybridize to a pair of adjacent Z probes bound to the target transcript. This minimizes amplification of non-specific binding. Several sequential amplification steps are then performed based on sequence-specific hybridization to the pre-amplifier, followed by enzyme-mediated chromogenic detection that enables semi-quantitative measurement of HRG RNA levels in the tumor tissue.
Step 1: FFPE tissue sections are deparaffinized and pretreated to block endogenous phosphatases and peroxidases and to unmask RNA binding sites. Step 2: Target-specific double Z probes are applied, which specifically hybridize to the target RNA at adjacent sequences. Step 3: Targets are detected by sequential applications of a preamplifier oligonucleotide, amplifier oligonucleotides, a final HRP-conjugated oligonucleotide, and DAB. Step 4: Slides are visualized using a light microscope and scored by a pathologist.
To score the assay, a reference tissue microarray (TMA) of four cell lines is stained alongside the tumor sample. These cell lines express different levels of HRG, ranging from low to high. A pathologist then assigns the patient sample a score based on a visual comparison with the reference TMA.
1. Sample Preparation and Staining
Patient sample preparation and pathologist review procedures are similar to qIHC assays. Upon biopsy or surgical resection, patient tumor samples are immediately placed in fixative (10% neutral buffered formalin) typically for 20-24 hours at room temperature. Samples are then transferred to 70% ethanol and embedded in paraffin as per standard hospital procedures. Before the assay is performed, 4μm sections of the sample are prepared and mounted on positively charged 75×25 mm glass slides. These are baked for improved tissue adhesion (10-30 min at 65° C.), dipped in paraffin for tissue preservation, and stored at room temperature under nitrogen. One of the sections is used for routine H&E staining, which a pathologist reviews for tumor content, quality, and clinical diagnosis. The pathologist differentiates areas of tumor, stroma, and necrosis. Following this review, an adjacent or nearby tissue section (within 20 μm of the H&E section) is used for the assay.
Pretreat solutions, target probes, and wash buffers for RNAscope® assays are obtained from ACD. The assay can be run manually, or using a VENTANA autostainer (Discovery XT). For the manual assay, 40° C. incubations are performed in a metal slide tray inside a HybEZ oven (ACD). For the automated assay, incubation temperatures are controlled by the autostainer. ACD software is usede to run the RNAscope® assays on the VENTANA autostainer.
To begin the assay, samples are deparaffinized by baking at 65° C. for 30 min, followed by sequential immersion in xylenes (2×20 min) and 100% ethanol (2×3 min). After air-drying, tissues are covered with Pretreat1 solution, which blocks endogenous enzymes (phosphatases and peroxidases which would produce background with chromogenic detection reagents), incubated for 10 min at room temperature, then rinsed twice by immersion in dH2O. Slides are then incubated in boiling Pretreat2 solution for 15 min, which unmasks binding sites, and transferred immediately to containers of dH2O.
After washing by immersion in dH2O (2×2 min), tissue is covered with Pretreat3 solution and incubated in a HybEZ oven at 40° C. for 30 min. Pretreat3 solution contains a protease, which strips the RNA transcripts of protein and exposes them to the target probes. After washing the slides 2×2 min in dH2O, the tissues are covered with the 15 isoform-detecting HRG RNAscope® probes described above. Serial tissue sections are incubated with positive control probes (protein phosphatase 1B (PP1B) ACD Part Number 313901), negative control probes (bacterial gene DapB—ACD Part Number 310043), or HRG probes for 2 h at 40° C. Slides are washed (2×2 min) with 1× RNAscope® wash buffer before incubating with Amp1 reagent. Amp1 incubation conditions (30 min, 40° C.) favor binding only to pairs of adjacent probes bound to RNA transcripts. Slides are washed by immersion in RNAscope® wash buffer before incubating with subsequent amplification reagents.
For signal amplification, each of the sequentially applied reagents binds to the preceding reagent and amplifies the signal present at the previous step. Amplification steps may include Amp2 (15 min, 40° C.), Amp3 (30 min, 40° C.), Amp4 (15 min, 40° C.), Amp5 (30 min, room temperature), and Amp6 (15 min, room temperature). The final reagent, Amp6, can be conjugated to horseradish peroxidase (HRP). To visualize the transcripts, the slides are then incubated with the ACD staining reagent, which contains diaminobenzidine (DAB), for 10 min at room temperature. Chromogen development is stopped by rinsing with dH2O. Nuclei are then counterstained with hematoxylin, which is blued with dilute ammonium chloride. Stained slides are immersed in 80% ethanol (2×5 min), 100% ethanol (2×5 min), and xylenes (2×5 min) before coverslipping with Cytoseal non-aqueous mounting medium (Thermo Scientific, 8312-4).
2. Generation of Biomarker Values
The biomarker values to be generated are a composite of pathologist scores. To score the assay, a TMA comprising plugs of four different cell lines is included in each staining run. Cell line plugs are prepared prior to generating a TMA. Cultured cells grown to a sub-confluent density are harvested by trypsinization, rinsed in PBS, and fixed for 16-24 hr at 4° C. before rinsing in PBS and resuspending in 70% ethanol. Cells are then centrifuged for 1-2 minutes at approximately 12,000 rpm to produce a dense cell pellet, which is then coated with low-melting point agarose. The agarose pellets are stored in 70% ethanol at 4° C., and embedded in paraffin before constructing the TMA.
The arrays are constructed, e.g., using a Manual Tissue Arrayer (MTA-1, Beecher Instruments), with which a 0.6 mm punch is used to take a portion of the cell pellet and plug it into an empty recipient paraffin block. The pathologist uses the images of the TMA to provide a score ranging from 0 (undetectable) to 4 (high). The pathologist provides two scores for the top two populations of tumor cells, and one score for the top population of stromal cells (when available), along with the percentage of cells in each population. So, for example, a patient sample may have 20% tumor with a score of 3, 40% tumor with a score of 2, and 60% stroma with a score of 2. Scores are provided for the target probe (HRG), as well as the positive control probe (PP1B) and the negative control probe (DapB).
RNA-ISH assays and biomarker analysis are performed as described above. These studies indicate that 9 out of 25 EGFR wild-type NSCLC cell lines are responsive to HRG: they exhibit increased cell proliferation in response to exogenously added HRG, as measured by a CellTiter Glo® luminescent cell viability assay (Promega) using 3D spheroid cultures (
Two HRG-responsive cell lines and two non-responsive cell lines were selected to assess the single agent activity of seribantumab in subcutaneous mouse xenografts. The mice were dosed with 300 μg seribantumab every three days (Q3D). As shown in
As depicted in
Analysis of tumor samples from previous randomized phase II clinical trials of seribantumab in breast and ovarian cancer indicated that a CT level of HRG expression of −5 relative to reference genes as measured by quantitative RT-PCR (per PCT/US2014/072594, discussed above) was a threshold value for seribantumab activity. In patients with HRG expression at or above the threshold (≧−5), increased PFS was observed in patients treated with seribantumab co-administered with standard-of-care therapy. Since this threshold roughly corresponds to the presence of detectable HRG-encoding RNA, The Cancer Genome Atlas (TCGA; http://cancergenome.nih.gov/) dataset was analyzed to determine the prevalence of detectable HRG expression in a wide variety of solid tumors (
In addition, HRG expression was assessed using an RNA in situ hybridization (RNA-ISH) assay (also per PCT/US2014/072594) in pre-treatment core needle biopsies obtained from patients enrolled in a study of seribantumab in EGFR wild-type NSCLC (MM-121-01-101). Overall, 54% of the samples scored 1+ (i.e., 1-3 dots/cell (visible at 20-40× magnification) or higher (
Population pharmacokinetic (PK) analyses support using a fixed dosing regimen for seribantumab.
Analysis by simulation: To evaluate optimal dosing regimens, population analysis was used to estimate the point estimates and variabilities of pharmacokinetic parameters, and to evaluate the source of the variabilities, including their relationships with body weight. The resulting estimates were used to compare fixed dosing and weight-based dosing regimens. For fixed dosing strategies, comparable dose is simulated by assuming the weight-based dose times the median of weight in the population (72 kg), rounded to the next 500 mg (vial size). The simulation results show comparable variability between both fixed-dosing and weight-based dosing regimens, suggesting no benefits of reduced PK variability with weight-based dosing (higher concentrations are predicted for the dose regimens of 10 mg/kg equivalent only because of rounding up doses to the next 500 mg). For example, a weight-based dosing of 20 mg/kg Q2W and a corresponding fixed dose of 1.5 g Q2W have comparable maximum, minimum, and average steady-state concentration levels and variability. This result can be explained as a consequence that clearance increased less than proportionally to weight (i.e., the estimated proportionality between log10 of clearance and weight was 0.203). This proportionality results in higher-weight patients being overdosed by a weight-based regimen (which assumed a proportionality constant of one between log10 of clearance and weight).
A simulation study, conducted by comparing the simulated pharmacokinetics (averaged and minimum concentration) at different dose intervals, indicates an every 3 week regimen is optimal. A dose regimen of 3 g Q3W is predicted to have: 1) comparable maximum concentration (Cmax) to 40 mg/kg Q3W; 2) comparable minimum concentration (Cmin) to 20 mg/kg Q2W; and 3) average steady-state concentration in between 20 mg/kg Q2W (the dose studied in previous NSCLC study) and 20 mg/kg Q1W (the dose studied in previous ovarian and breast cancer studies). Therefore, this simulation study suggests that a seribantumab dose regimen of 3 g Q3W should improve compliance and convenience while maintaining the pharmacokinetic levels within the bounds of the exposures observed from previously studied effective seribantumab doses (40 mg/kg loading+20 mg/kg Q1W or +20 mg/kg Q2W). To evaluate the contribution of loading dose, concentration trajectories of simulated dose regimens with and without loading dose are compared. The loading dose is limited to a maximum of 3 g (a corresponding fixed dose for a 40 mg/kg). The results show comparable pharmacokinetics with and without a loading dose, and therefore, support the regimen without loading dose.
Experimental: The pharmacokinetics of seribantumab were evaluated using population pharmacokinetic analysis from 499 patients who had been treated with seribantumab. 4925 data points from the combined phase I and phase II studies of seribantumab were analyzed. These pharmacokinetic data were described using a two-compartment model, with estimated parameters provided in Table 1. Covariate selection evaluated potential relationships between baseline covariates (sex, race, age, weight, intended-dose, and study/indication) and volume of distribution and clearance. The results indicated significant relationships between weight, sex, and clearance, with the final parameter estimates provided in Table 1. The model assumed a proportional relationship between the log of clearance (CL) and weight, and obtained an estimated proportionality constant of 0.203. In the presence of the relationship between weight and clearance, no significant relationship between volume (V) and weight (WT) were observed.
To evaluate the benefit of weight-based dosing, a simulation study was conducted by comparing pharmacokinetics with weight-based and fixed-dose regimens. Post-hoc estimates of PK parameters from each of the 499 patients were used in the simulation. The simulated dose for the fixed dosing regimen was chosen by rounding up to the closest 500 mg dose unit. The simulation results showed comparable variability between both fixed-dosing and weight-based dosing regimens, suggesting no benefits of the reduced PK variability with weight-based dosing (
Accordingly, seribantumab will be administered at a fixed dose of 3 g/3000 mg on day 1 of each 21-day cycle in sync with the chemotherapy regimens outlined in the study below.
Title: A Phase 2 Study of Seribantumab (MM-121) in Combination with Docetaxel (D) or Pemetrexed (P) versus D or P Alone in Patients with Heregulin Positive (HRG+), Locally Advanced or Metastatic Non-Small Cell Lung Cancer.
BACKGROUND: The role of the HER3 receptor and its ligand heregulin (HRG) in the progression of multiple cancers has been well established. Seribantumab (MM-121) is a fully human, monoclonal IgG2 antibody that binds to the HRG domain of HER3, blocking HER3 activity. In retrospective analyses of prior seribantumab Phase 2 studies, high levels of HRG mRNA appeared to predict poor outcome when patients received standard of care (SOC) treatment. Addition of seribantumab to SOC improved progression-free survival (PFS) in patients with HRG positive (HRG+) tumors, consistent with the hypothesis that blockade of HRG-induced HER3 signaling by seribantumab can restore sensitivity to SOC impacted by HRG.
METHODS: In the current randomized, open-label, international, Phase 2 study, NSCLC patients will be screened for HRG using an RNA in situ hybridization assay on a recent biopsy tissue sample. Approximately 560 patients will be screened to support randomization of approximately 280 HRG+ patients in a 2:1 ratio to receive seribantumab plus investigator's choice of docetaxel (D) or pemetrexed (P), or D or P alone. Patients will be wild-type for EGFR and ALK and will have progressed following one to three systemic therapies for locally advanced and/or metastatic disease, including one platinum-containing regimen and anti-PD-1/PD-L1 where available and clinically indicated. The primary endpoint is overall survival (OS). Secondary endpoints include PFS, objective response rate and time to progression.
Approximately 227 OS events are required to have ≧80% power to detect a 3-month improvement in median OS with seribantumab plus D or P versus D or P alone with a baseline median OS assumption of 6 months (hazard ratio ≦0.67), using a one-sided, stratified log-rank test at a significance level of 0.025. An interim analysis for stopping due to futility or efficacy will be conducted when 50% of final OS events have been reported.
This study is a randomized, open-label, international, multi-center, phase II study in adult patients with NSCLC that has progressed following no more than two systemic therapies for locally advanced or metastatic disease, of which one must have been a platinum-based doublet therapy.
Following signing informed consent and evaluation of initial eligibility criteria, all patients will provide a tissue sample (which meets the requirements for collection and processing as outlined in the study lab manual) to a central lab facility for HRG testing. It is important that no systemic therapy is administered between the date of acquisition of the tissue sample and screening for this study in order to accurately assess a patient's HRG status. If adequate tissue is not available, patients should undergo a fine needle aspirate (FNA) or core needle biopsy (CNB) to acquire the necessary tissue for HRG testing. For these procedures, investigators are asked to choose an easily accessible tumor lesion to minimize any possible risk associated with the collection of the tissue. As a general guideline, if the selected procedural location of the core needle biopsy or FNA has an established serious complication rate of >2% at the institution completing the procedure, this is considered a high risk procedures and should be avoided. Upon receipt of a tissue sample at the central lab, the investigational site will be informed of the results within 7 days. Patients with a positive HRG status will be eligible for the interventional study population. Patients with tumors that show no staining for HRG will not continue further screening procedures and will be eligible for the observational group as outlined below.
Baseline data will be collected which includes demographics, disease characteristics and previous treatments. In addition, data regarding subsequent anti-cancer therapies received and OS will be collected. Patients are free to participate in any study and seek any care suitable.
By the time all screening procedures have been completed and determination of eligibility for treatment randomization (HRG positive, interventional group), the investigator must select the chemotherapy backbone (docetaxel or pemetrexed) most appropriate for each patient based on current presentation and medical history. Patients will be randomized in a 2:1 ratio (experimental arm versus comparator arm) using an Interactive Web Response System (IWRS). Randomization will be stratified based on the chemotherapy backbone (docetaxel or pemetrexed) and number of prior systemic therapies for locally advanced or metastatic disease (1 or 2). Within the interventional group, patients will be assigned to Arm A or Arm B:
Treatment must start within 7 days following randomization. Patients are expected to be treated until investigator-assessed progressive disease or unacceptable toxicity. Tumor assessments will be measured and recorded by the local radiologist every 6 weeks (+/−1 week) and evaluated using the RECIST guidelines (version 1.1). All patients, including any patient that comes off treatment for reasons other than RECIST 1.1 assessed progressive disease, should have an additional scan 6 weeks (+/−1 week) following treatment termination. In addition, an independent central review of scans will be conducted to support secondary efficacy objectives. All images for patients in the interventional group will be submitted to a central imaging facility for this purpose and will be assessed by independent reviewers in accordance with the Imaging Charter. After patients come off treatment, survival information and information about subsequent therapies will be collected until death or study closure, whichever occurs first.
Safety has been established for the combination of seribantumab+pemetrexed, and seribantumab has been administered in combination with taxanes (paclitaxel and cabazitaxel) at the standard doses with no maximum tolerated dose (MTD) reached. However, as no data is available for the combination of seribantumab and docetaxel, enrollment into this backbone will be paused after the twelfth patient has been randomized to docetaxel or seribantumab+docetaxel and completed one full cycle of treatment, and the emerging safety data on both arms will be reviewed by investigators, medical monitors and representatives from the sponsor. Additional input may be gathered from the DMC before continuing enrollment. The DMC will continue to monitor safety data in accordance with the DMC Charter on a quarterly basis.
For inclusion in the trial, all patients will have/be: cytologically or histologically confirmed NSCLC, with either metastatic disease (stage IV); Stage IIIB disease not amenable to surgery with curative intent; disease progression or evidence of recurrent disease documented by radiographic assessment following the last systemic therapy; received one prior platinum-based regimen for the management of primary or recurrent disease; clinically eligible for intended chemotherapy, docetaxel or pemetrexed, once every three weeks per the investigator's judgment; available recent tumor specimen, collected following completion of most recent therapy; a lesion amenable to either core needle biopsy or fine needle aspiration; greater than or equal to eighteen years of age; and able to provide informed consent or have a legal representative able to do so. To be included in the interventional group, patients will have/be: a positive in situ hybridization (ISH) test for heregulin with a score of ≧1+, as determined by centralized testing; measureable disease in accordance with RECIST v1.1; ECOG performance status (PS) of 0 or 1; Screening ECG without clinically significant abnormalities; Adequate bone marrow reserve as evidenced by ANC >1,500/μl, platelet count >100,000/μl, and hemoglobin >9 g/dL; adequate renal function as evidenced by a serum/plasma creatinine <1.5×ULN for patients receiving docetaxel and a creatinine clearance ≧45 mL/min for patients receiving pemetrexed; for patients receiving pemetrexed: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≦2.5×ULN (≦5×ULN is acceptable if liver metastases are present); for patients receiving docetaxel: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≦1.5×ULN, Alkaline phosphatase (AP) <2.5 ULN and serum/plasma total bilirubin within normal institutional limits.
Women of childbearing potential, as well as fertile men and their partners, must be willing to abstain from sexual intercourse or to use an effective form of contraception during the study (an effective form of contraception is an oral contraceptive or a double barrier method) and for 90 days following the last dose of study drug(s), or greater, as in accordance with the label requirements or institutional guidelines for docetaxel/pemetrexed.
Patients will meet all the inclusion criteria listed above and none of the following exclusion criteria:
a) Known Anaplastic Lymphoma Kinase (ALK) gene rearrangement or presence of exon 19 deletion or exon 21 (L858R) substitution of the EGFR gene
b) Pregnant or lactating
c) Prior radiation therapy to >25% of bone marrow-bearing areas
d) Received >2 prior systemic anti-cancer drug regimen for locally advanced disease
e) Patients who have received prior docetaxel for advanced/metastatic disease are not eligible for the docetaxel-containing chemotherapy backbone
f) Patients who have received prior pemetrexed for advanced/metastatic disease and/or maintenance therapy are not eligible for the pemetrexed-containing chemotherapy backbone
g) Received other recent antitumor therapy including:
h) CTCAE grade 3 or higher peripheral neuropathy
i) Presence of an unexplained fever >38.5° C. during screening visits that does not resolve prior
j) Symptomatic CNS metastases or CNS metastases requiring steroids
k) Use of strong CYP3A4 inhibitors for patients considered for the docetaxel backbone.
l) Any other active malignancy requiring systemic therapy
m) Known hypersensitivity to any of the components of MM-121 or previous hypersensitivity reactions to fully human monoclonal antibodies
n) History of severe allergic reactions to docetaxel or pemetrexed
o) Known hypersensitivity to polysorbate (Tween®) 80 or arginine
p) Clinically significant cardiac disease, including: symptomatic congestive heart failure, unstable angina, acute myocardial infarction within 1 year months of planned first dose, or unstable cardiac arrhythmia requiring therapy (including torsades de pointes).
q) Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals, known human immunodeficiency virus (HIV) infection, or active B or C infection.
r) Patients who are not appropriate candidates for participation in this clinical study for any other reason as deemed by the investigator.
The anti-tumor efficacy of seribantumab and a chemotherapeutic agent (e.g. irinotecan, gemcitabine, or paclitaxel) either alone (i.e., as a monotherapy) or in combination, in tumor-bearing mice was evaluated using human ovarian epithelial carcinoma OVCAR8 cells (NCI) implanted as xenografts in nu/nu nude, Crl:NU-Foxn1nu mice. In these xenograft studies, the mice were obtained from Charles River Laboratories. The mice were housed in Tecniplast® Individually Ventilated polycarbonate (Makrolon®) Cages (IVC) set in climate-controlled rooms and had free access to food and acidified water. A cell suspension of 8×106 cells/mouse, mixed 1:1 in reduced growth factor Matrigel™ (BD Biosciences, Cat #354230) and PBS was implanted by subcutaneous injection into the left flank of female, 4-5 week old nu/nu nude, Crl:NU-Foxn1nu mice. Tumors were allowed to reach 250 mm3 in size before randomization.
A combination therapy study was performed to demonstrate the effects of various combinations of a fixed dose of seribantumab, irinotecan HCl, gemcitabine, and paclitaxel.
Mice were randomized as above into 8 groups of 10 mice each. Five groups were treated with i.p. doses of a single agent alone, as follows: (1) seribantumab (300 μg Q3D), (2) irinotecan HCl (6.25 mg/kg Q7D), (3) gemcitabine (25 mg/kg Q7D), (4) paclitaxel (10 mg/kg Q7D), or (5) PBS (Q3D) alone (Control). Three groups were treated with a combination therapy of (1) seribantumab and paclitaxel, (2) seribantumab and irinotecan HCl, and (3) seribantumab and gemcitabine, with the doses described above. Treatment continued for three weeks. Tumors were measured twice weekly and tumor volume calculated.
As shown in
While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features set forth herein. The disclosure of each and every US, international, or other patent or patent application or publication referred to herein is hereby incorporated herein by reference in its entirety.
This application is a continuation-in-part of International Application No. PCT/US2016/027933 (filed Apr. 15, 2016), which claims priority to, and the benefit of, U.S. Provisional Application No. 62/149,271 (filed Apr. 17, 2015). The contents of the aforementioned applications are hereby incorporated by reference in their entireties.
| Number | Date | Country | |
|---|---|---|---|
| 62149271 | Apr 2015 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/US2016/027933 | Apr 2016 | US |
| Child | 15156603 | US |
