Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/08—Peptides having 5 to 11 amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/31—Somatostatins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
  • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
  • A61M5/178—Syringes
  • A61M5/20—Automatic syringes, e.g. with automatically actuated piston rod, with automatic needle injection, filling automatically
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• NET Neuroendocrine tumors
• GEP gastroenteropancreatic
• NET neuroendocrine carcinomas
• NET are further divided into grades according to their histopathologic characterization and to their proliferation (nuclear antigen Ki-67) index, see table 1:
• Table 1 Classification and grading criteria for neuroendocrine neoplasms of the gastrointestinal tract and hepatopancreatobiliary organs
• LCNEC large-cell neuroendocrine carcinoma
• MiNEN mixed neuroendocrine-non-neuroendocrine neoplasm
• NEC neuroendocrine carcinoma
• NET neuroendocrine tumors
• SCNEC small-cell neuroendocrine carcinoma
• GEP-NET gastroenteropancreatic neuroendocrine tumors
• GEP-NET may have the following primary tumor locations: stomach, duodenum, jejunum, ileum, pancreas, appendix, cecum, colon, and rectum.
• GEP-NET have a variable prognosis based on primary site of disease, degree of differentiation and grade, expression of somatostatin receptors, and presence of metastases at diagnosis.
• Well-differentiated, low-grade GEP-NET have prolonged survival compared to high-grade tumors, and pancreatic NET have more aggressive biology than NET arising in the small intestine.
• Surgical resection of the primary and metastatic lesions remains the mainstay of treatment of NET and the only way to obtain a cure.
• resection is often not possible as NET are frequently detected in a more advanced tumor stage when metastases have already developed.
• SSAs somatostatin analogues
• mTOR inhibitors mTOR inhibitors
• tyrosine kinase inhibitors sunitinib
• alkylating agents peptide radionuclide receptor therapy
• GEP-NETs gastroenteropancreatic neuroendocrine tumors
• PFS tumor progression or progression-free survival
• the approved dose of Sandostatin® LAR® for the treatment of advanced midgut NET is 30 mg/month, which is also the maximum approved dose for symptom control.
• the prescribing information in connection with Sandostatin® LAR® include several warnings relating to increased risk of cardiovascular adverse effects, such as bradycardia and arrhythmia; drug-drug interactions; increased risk of cholelithiasis, hypoglycemia, hyperglycemia, etc.
• This disclosure provides, in part, a lipid composition comprising 20 mg of octreotide or a pharmaceutically acceptable salt thereof for use in treating a gastroenteropancreatic neuroendocrine tumor, and wherein the composition is administered to a patient once every two weeks.
• a pre-filled syringe comprising a lipid composition comprising 20 mg of octreotide or a pharmaceutically acceptable salt thereof for use in treating a gastroenteropancreatic neuroendocrine tumor, and wherein the composition is administered to a patient once every two weeks.
• an autoinjector comprising a glass compartment containing a lipid composition comprising 20 mg of octreotide or a pharmaceutically acceptable salt thereof for use in treating a gastroenteropancreatic neuroendocrine tumor, and wherein the composition is administered to a patient once every two weeks.
• FIG. 1 illustrates the clinical trial design
• FIG. 2 shows the observed or predicted octreotide plasma concentrations, at steady state, based on predicted pharmacokinetic (PK) parameters and base on a population PK model, and observed PK parameters for Sandostatin LAR (Phase I) to healthy volunteers.
• PK pharmacokinetic
• Treating includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder, and the like.
• “Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
• the octreotide and its salts (compound) can be administered to a mammal, such as a human, but can also be other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g, rats, mice, guinea pigs, and the like).
• pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art.
• pharmaceutical composition refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
• the term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
• the compounds of the disclosure are administered in therapeutically effective amounts to treat a disease.
• a therapeutically effective amount of a compound is the quantity required to achieve a desired therapeutic and/or prophylactic effect, such as an amount which results in the treatment of neuroendocrine tumors.
• Steady state is the time during which the concentration remains stable or consistent when the drug is given repeatedly.
• the steady state for the administration of the octreotide compositions disclosed herein is estimated in healthy volunteers to be in the range of 2-3 months, such as about 2 months.
• the disclosure provides, in part, method of treating neuroendocrine tumors using lipid compositions disclosed herein.
• a method of treating at least one neuroendocrine tumor comprising, administering to a patient in need thereof a lipid composition comprising 20 mg of octreotide or a pharmaceutically acceptable salt thereof (e.g., chloride salt), wherein the lipid composition is administered to the patient once every two weeks, and wherein octreotide is the sole pharmaceutically active ingredient.
• a lipid composition comprising 20 mg of octreotide or a pharmaceutically acceptable salt thereof (e.g., chloride salt), wherein the lipid composition is administered to the patient once every two weeks, and wherein octreotide is the sole pharmaceutically active ingredient.
• the drug product in the present disclosure is 20 mg/ml octreotide (octreotide chloride).
• the IUPAC name is (4R,7S,10S,13R,16S,19R)-19-[(2R)-2-amino-3-phenylpropanamido]-10-(4- aminobutyl)-16-benzyl-N-[(2R,3R)-l,3-dihydroxybutan-2-yl]-7-[(lR)-l-hydroxyethyl]-13-[(lH- indol-3-yl)methyl]-6,9,12,15,18-pentaoxo-l,2-dithia-5,8,ll,14,17-pentaazacycloicosane-4- carboxamide.
• Octreotide has the following chemical structure: and the molecular weight is 1019.3 (free peptide, C 49 H 66 N 10 O 10 S 2 ).
• amino acid sequence of octreotide is H2N-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys- Thr-ol (Disulfide Bridge Cys2-Cys7).
• the lipid composition comprising 20 mg/ml octreotide (concentration based on free peptide), is based on glycerol dioleate and phosphatidylcholine as lipid excipients. Additional excipients in the lipid composition are ethanol (solvent), propylene glycol (co-solvent).
• the lipid composition optionally includes EDTA and ethanolamine as additional excipients.
• the water content of the lipid composition at release of the product is not more than (NMT) 1%, determined by USP ⁇ 921>.
• the lipid composition comprises octreotide chloride.
• W02008/152401 (the full disclosure of which is hereby incorporated herein by reference), see, e.g., examples 4 - 6 discloses a method for obtaining the octreotide chloride and subsequent formulation as a lipid composition. Further examples are disclosed in W02012/160213 (the full disclosure of which is hereby incorporated herein by reference), see, e.g., examples 1,2 and 8.
• the inactive excipients i.e., the lipids, glycerol dioleate and phosphatidyl choline, the solvent and co-solvent and the optional excipients EDTA and ethanolamine, and the octreotide chloride adds up to at least 80 wt.%, such as 85 wt.% of the total drug product.
• the rest are essentially by products, for example, originating from the lipids.
• Glycerol dioleate (GDO) may also contain monoglycerides (NMT 2%) and triglycerides (NMT 5%).
• the GDO used in the lipid composition should contain at least about 93% glycerol dioleate.
• Phosphatidyl choline may also contain lysophosphatidylcholine (NMT 3%) and triglycerides (NMT 2%). Generally, the phosphatidyl choline used in the lipid composition should contain at least about 94% phosphatidyl choline.
• the lipid formulation is provided in a pre-filled syringe, e.g., a glass syringe, equipped with a small needle compared to the comparative product (22G), and the drug product is not necessary to be reconstituted and considered ready-to-use.
• a pre-filled syringe e.g., a glass syringe, equipped with a small needle compared to the comparative product (22G)
• Suitable syringes may be those having a volume of about 0.5, about 0.75, about 1.0, about 1.25, and about 1.5 mL.
• One example is a 1 mL glass syringe, optionally equipped with a small needle compared to the comparative product (22G).
• Comparative drug product used herein are Sandostatin ® LAR ® (also referred to as octreotide LAR), which contains octreotide as the acetate salt. It is a long-acting octapeptide with pharmacologic properties mimicking those of the natural hormone somatostatin.
• Sandostatin LAR® Depot octreotide acetate for injectable suspension
• the excipients are poly(DL-lactide-co-glycolide) and mannitol (E421) in the vial.
• octreotide Carmellose sodium, mannitol (E421), Poloxamer 188 and water for injections as diluent/solvent.
• the octreotide is uniformly distributed within the microspheres which are made of a biodegradable glucose star polymer, D,L-lactic and glycolic acids copolymer. Sterile mannitol is added to the microspheres to improve suspendability.
• Sandostatin LAR may also be referred to as octreotide LAR, Oct LAR in the present disclosure. Sandostatin LAR is provided in a vial and in need of at least 30 min reconditioning before added to a syringe for intramuscular injection using a 20G needle.
• SOMATULINE DEPOT lanreotide
• SOMATULINE Autogel lanreotide
• ATG SOMATULINE Autogel
• Lanreotide acetate is chemically known as [cyclo S-S]-3-(2-naphthyl)-Dalanyl-L- cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-valyl-L-cysteinyl-L-threoninamide, acetate salt. Its molecular weight is 1096.34 (base) and its amino acid sequence is:
• Somatuline DEPOT is a prolonged-release formulation for deep subcutaneous injection. It contains the drug substance lanreotide acetate, water for injection and acetic acid (for pH adjustment). Somatuline ATG also needs to be reconditioned for more than 30 min before subcutaneous injection to a patient via a 18G/19G syringe.
• the present disclosure also relates to a lipid composition
• a lipid composition comprising, consisting essentially of, or consisting of 20 mg of octreotide or a pharmaceutically acceptable salt thereof, and glycerol dioleate (GDO), phosphatidyl choline (PC), ethanol, and optionally propylene glycol (PG).
• GDO glycerol dioleate
• PC phosphatidyl choline
• PG propylene glycol
• the lipid compositions may be substantially non-aqueous.
• the lipid compositions may form a depot composition upon contact with an aqueous fluid.
• the term “depot” relates to the composition which is formed upon exposure of the lipid composition to excess aqueous fluid, e.g., as occurs during numerous parenteral administration routes, such as administration in the subcutaneous tissue of a human patient.
• the depot typically has a much higher viscosity than the corresponding lipid composition and provides for the gradual release of the octreotide contained within the depot.
• GDO Glycerol dioleate
• the lipid composition contains glycerol dioleate (GDO).
• GDO may be present in the lipid composition in an amount ranging from 20 to 90 wt.% of the lipid composition (e.g., 30 to 70 wt.%, 33 to 60 wt.%, 43 to 60 wt.%, 38 to 43 wt.%).
• GDO may be derived from natural sources, there is generally a certain proportion of “contaminant” lipid having other chain lengths, etc.
• pure GDO is a di-ester of glycerol and two Cl 8:1 fatty acids. Any other diacyl glycerol is considered to be an impurity.
• GDO indicates any commercial grade of GDO with concomitant impurities (i.e., GDO of commercial purity). These impurities may be separated and removed by purification but, providing the grade is consistent, this is rarely necessary.
• GDO may be essentially chemically pure GDO, such as at least 70% pure GDO (e.g., at least 75% pure, at least 80% pure, at least 85% pure, at least 90% pure, at least 93%, at least 95% pure, at least 98% pure, at least 99% pure (area%).
• the diglycerides content of the glycerol dioleate is about 92% - 100%, such as about 93% to about 99%.
• the GDO used herein should have an oleic acid content (C18:l) of at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 98%, at least 99%).
• the diglyceride content is about 93% to about 99%, and the oleic acid content is about 88% to about 99% (area%).
• Any material used in the lipid composition, including GDO may potentially include unavoidable trace impurities of metals, optionally including heavy metals.
• a typical maximum concentration of heavy metals (or elemental impurities) in GDO is 5 ppm.
• GDO may be replaced by, or combined with, at least one other lipid, e.g., at least one fatty acid and/or fatty acid ester (lipid).
• Fatty acids/bpids contain a polar carboxylic acid or ester “head group” with the hydrocarbon chain forming a non-polar “tail” group.
• Fatty acid esters are esterified fatty acids.
• Fatty acids or esters used in the lipid composition may be solid or liquid at room temperature and pressure.
• non-polar “tail” groups include C6-C32 alkyl and alkenyl groups, which are typically present as long chain carboxylic acids or the esters thereof.
• CX:Z indicates a hydrocarbon chain having X carbon atoms and Z unsaturations.
• Examples particularly include caproyl (C6:0), capryloyl (C8:0), capryloyl (C10:0), lauroyl (C12:0), myristoyl (C14:0), palmitoyl (C16:0), phytanoyl (C16:0), palmitoleoyl (C16:l), stearoyl (C18:0), oleoyl (C18:l), elaidoyl (C18:l), linoleoyl (Cl 8:2), linolenoyl (Cl 8: 3), arachidonoyl (C20:4), behenoyl (C22:0), and lignoceroyl (C24:9) groups.
• typical non-polar chains are based on the fatty acids of natural ester lipids, including caproic, caprylic, capric, lauric, myristic, palmitic, phytanic, palmitolic, stearic, oleic, elaidic, linoleic, linolenic, arachidonic, behenic, or lignoceric acids, or the corresponding alcohols.
• the lipid(s) may be saturated or unsaturated.
• the lipid(s) may comprise at least 1 wt.% unsaturated lipid (based on the total lipid content) (e.g., at least 5 wt.% (5-100%), at least 15 wt.% (15-100%), at least 30 wt.% (30-100%), at least 50 wt.% (50-100%), at least 80 wt.% (80-100%)).
• GDO may be replaced or combined with, for example, an edible lipid such as almond oil, avocado oil, butter, canola oil, castor oil, coconut oil, com oil, cottonseed oil, flaxseed oil, ghee, lard, linseed oil, macadamia oil, margarine, mustard oil, olive oil, palm oil, peanut oil, pumpkin seed oil, rice bran oil, safflower oil, sesame oil, soybean oil, sunflower oil, tea seed oil, vegetable oil, or walnut oil.
• an edible lipid such as almond oil, avocado oil, butter, canola oil, castor oil, coconut oil, com oil, cottonseed oil, flaxseed oil, ghee, lard, linseed oil, macadamia oil, margarine, mustard oil, olive oil, palm oil, peanut oil, pumpkin seed oil, rice bran oil, safflower oil, sesame oil, soybean oil, sunflower oil, tea seed oil, vegetable oil, or walnut oil.
• tocopherol which may be used to replace GDO.
• the at least one lipid may be present in the lipid composition in an amount ranging from 20 to 90 wt.% of the lipid composition (e.g., 30 to 70 wt.%, 33 to 60 wt.%, 43 to 60 wt.%, 38 to 43 wt.%). If the lipid composition contains both GDO and at least one additional lipid, the combination may also be present in the lipid composition in an amount ranging from 20 to 90 wt.% of the lipid composition (e.g., 30 to 70 wt.%, 33 to 60 wt.%, 43 to 60 wt.%, 38 to 43 wt.%).
• PC Phosphatidyl Choline
• the lipid composition also contains phosphatidyl choline (PC).
• PC is present in an amount ranging from 20 to 80 wt.% of the lipid composition (e.g., 30 to 70 wt.%, 33 to 55 wt.%, 35 to 55 wt.%, 38 to 43 wt.%).
• Ratios of GDO : PC may be 40:60 to 70:30 (e.g., 45:55 to 55:45, 40:60 to 54:46, 45:55 to 54:46, 47:53 to 53:47).
• Ratios of around 50:50 (e.g., 49:51 to 51 :49) may be highly effective.
• PC may be replaced by, or combined with, at least one other phospholipid.
• the phospholipids may be derived from a natural source.
• suitable sources of phospholipids include egg, heart (e.g., bovine), brain, liver (e.g., bovine), and plant sources, including vegetable PC, such as soybean.
• Such sources may provide one or more constituents of the PC and/or at least one other phospholipid.
• Any single PC or mixture thereof may be used according to the present disclosure, although egg, heart (e.g., bovine), brain, liver (e.g., bovine), and plant sources, including vegetable PC, such as soybean or any mixture thereof are used in most embodiments disclosed herein.
• the PC may be derived from soy.
• the PC may comprise 18:2 fatty acids as the primary fatty acid component with 16:0 and/or 18:1 as the secondary fatty acid components. These may be present in the PC at a ratio of between 1.5:1 and 6:1.
• PC having approximately 60-65% 18:2, 10 to 20% 16:0, 5-15% 18:1, with the balance predominantly other 16 carbon and 18 carbon fatty acids may be used, e.g., soy PC.
• the PC has a purity of not less than 90%, not less than 92%, not less than 94%, such as about 94% - 100% (based on dry weight).
• the maximum lysophosphatidylcholine content is about 3%, e.g., not more than 3%.
• the maximum triglycerides content is about 2%, such as not more than 2%.
• the PC used in the lipid composition has a purity of about 94% - 100% (based on dry weight), and contains not more than 3% lysophosphatidylcholine and optionally not more than 2% triglycerides.
• the PC component may comprise synthetic dioleoyl PC (DOPC).
• DOPC synthetic dioleoyl PC
• the PC component may contain at least 50% synthetic dioleoyl PC (e.g., at least 75% synthetic dioleoyl PC) and even essentially pure synthetic dioleoyl PC. Any remaining PC can be of any sort. DOPC may be more expensive.
• phospholipids are synthetic or highly purified PCs, such as dioleoyl phosphatidyl choline (DOPC), may, in alternative embodiments, be used as all or part of the phospholipid component.
• the synthetic dioleoyl PC may be l,2-dioleoyl-sn-glycero-3- phosphocholine, and other synthetic PC components include DDPC (1,2-Didecanoyl-sn-glycero- 3-phosphocholine); DEPC (l,2-Dierucoyl-sn-glycero-3-phosphocholine); DLOPC (1,2- Dilinoleoyl-sn-glycero-3-phosphocholine); DLPC (l,2-Dilauroyl-sn-glycero-3-phosphocholine); DMPC (l,2-Dimyristoyl-sn-glycero-3-phosphocholine); DOPC (l,2-Dioleoyl-sn-glycero-3-
• lipid slow-release matrices based on triacyl lipids that can form depot compositions on exposure to aqueous fluids without the need for a phospholipid component to be present, though in certain embodiments a phospholipid may also be present.
• Alternative embodiments include phosphatidylethanolamine (PE), phosphatidylserine, and phosphatidylinositol, instead of phosphatidyl choline.
• PE phosphatidylethanolamine
• phosphatidylserine phosphatidylserine
• phosphatidylinositol instead of phosphatidyl choline.
• the components should be biocompatible.
• PC such as soy PC and/or DOPC
• GDO are useful, since they are well tolerated and are broken down in vivo into components that are naturally present in the mammalian body.
• Appropriate amounts of each component suitable for the combination are those amounts indicated herein for the individual components in any combination. This applies also to any combinations of components indicated herein, where context allows.
• the at least one phospholipid may be present in the lipid composition in an amount ranging from 20 to 80 wt.% of the lipid composition (e.g., 30 to 70 wt.%, 33 to 55 wt.%, 35 to 55 wt.%, 38 to 43 wt.%). If the lipid composition contains both PC and at least one additional phospholipid, the combination may also be present in the lipid composition in an amount ranging from 20 to 80 wt.% of the lipid composition (e.g., 30 to 70 wt.%, 33 to 55 wt.%, 35 to 55 wt.%, 38 to 43 wt.%).
• Ratios of GDO and/or the at least one lipid other than GDO : PC and/or the at least one phospholipid other than PC may be 40:60 to 70:30 (e.g., 45:55 to 55:45, 40:60 to 54:46, 45:55 to 54:46, 47:53 to 53:47). Ratios of around 50:50 (e.g., 49:51 to 51 :49) may be highly effective.
• the lipid composition also contains the solvent ethanol .
• the ethanol may be replaced by, or combined with, at least one other biocompatible organic solvent. Since the lipid composition may generate a depot composition following administration (e.g., in vivo), typically upon contact with excess aqueous fluid, it is desirable that this solvent be tolerable to the subject and be capable of mixing with the aqueous fluid, e.g., body fluids, and/or diffusing or dissolving out of the lipid composition into the aqueous fluid. Therefore, solvents having at least moderate water solubility may be used.
• the lipid compositions include a polar co-solvent.
• the solvent in the lipid composition comprises, consists essentially of, or consists of at least one solvent selected from the group consisting of: alcohols, amines, amides, and esters. Therefore, the solvent may comprise at least a mono-alcoholic solvent, such as ethanol, propanol, iso-propanol, or mixtures thereof. In one embodiment, the solvent is ethanol.
• the lipid composition may also comprise, consist essentially of, or consist of a mono-alcoholic solvent (e.g., ethanol) and a polar co-solvent (e.g., propylene glycol).
• the amount of solvent in the lipid composition may affect several features, including, for example, the viscosity and the rate (and duration) of release. Therefore, the amount of solvent may be at least sufficient to provide a low viscosity mixture but may additionally be determined so as to provide the desired release rate. Typically, a level of 1 to 30% (e.g., 2 to 20%, 2 to 18%, 2 to 16%, 2 to 15%) solvent will provide suitable release and viscosity properties.
• the solvent e.g., EtOH
• a co-solvent e.g., PG
• the amount of solvent in the lipid compositions may be at least sufficient to provide a low viscosity mixture (e.g., a molecular solution) of the components of the lipid composition and can be determined for any particular combination of components by standard methods.
• a low viscosity mixture e.g., a molecular solution
• the solvent may be a single solvent (e.g., ethanol) or a mixture of suitable solvents (e.g., ethanol and PG) but will generally be of low viscosity.
• the solvent is a mixture of ethanol and propylene glycol, and no other solvent.
• the viscosity of the “low viscosity” solvent may be no more than 18 mPas at 20°C (e.g., no more than 15 mPas at 20°C, no more than 10 mPas at 20°C, no more than 7 mPas at 20°C).
• the solvent comprises a mono-alcoholic solvent (e.g., ethanol) and a polar co solvent.
• polar co-solvent defines a solvent having a dielectric constant (diel) of at least 28 at 25°C (e.g., at least 30 at 25°C) but is not water or any aqueous fluid. Examples include propylene glycol (diel -32), and N-methyl-2-pyrrolidone (NMP, diel -32). The levels of solvent recited herein may apply equally to mixtures of mono-alcoholic solvent and a polar co-solvent unless context permits otherwise.
• the solvent comprises, consists essentially of, or consists of a mixture of a mono-alcoholic solvent and a polar co-solvent.
• the polar co-solvent may be a di- alcoholic C3-C6 organic solvent, i.e., a C3-C6 organic solvent comprising two hydroxy groups.
• the di-alcoholic solvent may be propylene glycol.
• a polar co-solvent may be included at a level of 2 to 12 wt.% of the lipid composition (e.g., 3 to 10 wt.%, 4 to 9 wt.%). This level is counted as part of the ranges recited above for the solvent.
• the solvent comprises, consists essentially of, or consists of a mixture of ethanol and propylene glycol (PG), where PG is considered a co-solvent.
• the ratio of mono-alcoholic solvent to polar co-solvent solvent may be in the range 20:80 to 70:30 (w/w) (e.g., 30:70 to 70:30 (w/w), 40:60 to 60:40 (w/w)).
• the amounts and ratio of ethanol and PG may have an effect on properties such as release of an active agent, viscosity of the lipid composition, etc., features which are all important characteristics of suitable lipid compositions for subcutaneous injection of an active agent to a patient in need thereof.
• the solvent is present at a level of 1 to 30 wt.% (e.g., 5 to 15 wt.%, 8 to 18 wt.%, 8 to 18 wt.%) and comprises, consists essentially of, or consists of a mixture of ethanol and PG, wherein the ratio of ethanol to PG (w/w) is in the range of 30:70 to 70:30 (w/w) (e.g., 40:60 to 60:40 (w/w)). Additional examples are about 4-10 wt.% ethanol and about 4-10 wt.% PG, e.g., about 5-8 wt.% of each.
• the total water level may remain at release of the lipid composition for sale at the levels describes herein (e.g., 1.0 wt.% or less, 0.1 to 1.0 wt.%).
• release in this context means released for administration to a patient, i.e., a pharmaceutical product approved by a regulatory agency, e.g., the FDA.
• release specification means the tests and limits against which raw material, intermediate, and final product are measured prior to use and/or release.
• the lipid composition may also optionally contain EDTA (“ethylenediamine tetraacetic acid” or “edetic acid”).
• EDTA ethylenediamine tetraacetic acid
• the term “EDTA” may represent ethylenediammetetraacetic acid as such.
• EDTA as indicated herein may include ethylenediammetetraacetic acid itself, EDTA analogues, and alkylammonium EDTA salts.
• “EDTA” herein thus includes “EDTA, analogues thereof, and alkylammonium EDTA salts,” whenever context allows. “EDTA” does not include the disodium salt of EDTA.
• EDTA analogues examples include:
• Iminodiacetic acid (IDA) - (NH(CH 2 C0 2 H) 2 ;
• Nitrilotriacetic acid (NT A) - NiCH 2 CO 2 H) 3 ;
• Pentetic acid* N(CH 2 C0 2 H) 2 CH 2 CH 2 N(CH 2 C0 2 H)CH 2 CH 2 N(CH 2 C0 2 H) 2 ;
• EDTA analogues and alkylammonium salts thereof are further disclosed and described in WO 2018/060212, which is hereby incorporated herein by reference.
• alkylammonium salt(s) of EDTA is provided by contacting the EDTA or analogue thereof with a suitable alkylamine, examples are:
• Ethanolamine “ETA” (NH2(CH2CH2OH):
• Diethanolamine “DiETA” (NH(OH 2 OH 2 OH) 2 ); meglumine (NH(CH 3 )CH 2 (CH0H) 4 CH 2 0H)); tris-hydroxymethylamine “TRIS” (N(CH 2 OH) 3 ); ethylenediamine (NH 2 CH 2 CH 2 NH 2 ); or serinol (NH 2 CH(CH 2 OH) 2 )
• the mass of the alkylammonium cation of Formula (I) may be below 500 amu (e.g., below 350, below 250 amu).
• Salts of EDTA containing the ethanolammonium ion (HOCH 2 CH 2 NH 3 ) may be used.
• the EDTA salt may be a salt of EDTA with ethanolamine (ETA) (e.g., EDTA with ETA only).
• the lipid composition may also contain EDTA salts comprising an anion of EDTA and at least one alkylammonium cation of the suitable alkylamine as previously described.
• EDTA and/or a structural analogue thereof and a suitable alkylamine e.g., ethylenediamine tetraacetic acid and ethanolamine, or ethylenediamine tetraacetic acid and diethanolamine
• a suitable alkylamine e.g., ethylenediamine tetraacetic acid and ethanolamine, or ethylenediamine tetraacetic acid and diethanolamine
• the provision of the alkylamine and the EDTA or structural analogues thereof enables substantial amounts of EDTA in the solution of lipid components. Further details are available in WO 2018/060212.
• the lipid composition may contain additional excipient(s).
• the octreotide dissolved in the lipid composition may gain stability (both storage and in vivo stability) by certain stabilizing additives.
• additives include, but are not limited to, sugars (e.g., sucrose, trehalose, lactose, etc.), polymers (e.g., polyols such as carboxy methyl cellulose), amino acids (such as methionine, glutamate, lysine, etc.), lipid-soluble acid components such as HC1, anionic lipids, and/or surface active agents (such as dioleoyl phosphatidyl glycerol (DOPG), palmitoyloleoyl phosphatidylglycerol (POPG), and oleic acid (OA)).
• DOPG dioleoyl phosphatidyl glycerol
• POPG palmitoyloleoyl phosphatidylglycerol
• OA oleic acid
• Single-dose formats such as pre-filled syringes comprising lipid compositions disclosed herein, must remain stable and potent in storage prior to use but are disposable after the single use.
• the substantially non-aqueous lipid compositions have enhanced storage stability at elevated temperatures, such as at 25°C or even 40°C. This offers advantages in terms of ease of transportation and storage (no need for refrigeration).
• a single dose format of the lipid composition may have stability such that after storage for 2 months at 25°C (with air in head space), the assayed octreotide concentration is at least 95% that of the initial assayed octreotide concentration, and after 3 months, the assayed octreotide concentration is at least 90% that of the initial assayed octreotide concentration, the lipid composition disclosed herein generally has an acceptable storage stability of twelve months or longer.
• a single dose format of the lipid composition may have a stability such that after storage for 2 months at 40°C (with air in head space), the assayed octreotide concentration is at least 85% that of the initial assayed octreotide concentration, and after 3 months, the assayed octreotide concentration is at least 80% that of the initial assayed octreotide concentration.
• the lipid compositions can optionally contain an antimicrobial or microbial- static agent, which includes bacteriostatic agents and preservative. Such agents include benzalkonium chloride, m-cresol, benzyl alcohol, or other phenolic preservatives. Typical concentrations as known in the art can be used. In most aspects and embodiments, there are no antimicrobial or microbial-static agents added.
• These additional components may be present in an amount of 0 to 5 wt.% (e.g., 0.01 to 5 wt.%), such as no more than 2% by weight, or no more than 1% by weight.
• the lipid composition comprises no additional excipient, only EDTA and an alkylamine.
• lipid compositions described in this disclosure will typically be stored in ready-to-use form, e.g., in syringes and possibly under refrigerated conditions. Syringes are often not completely air-tight meaning that the level of water in the lipid composition may increase to an appreciable level over time, e.g., over months, even if the initial level of water is insignificant.
• the initial absolute level of water in the lipid composition may be between 0 to 1.0 wt.% (e.g., less than 1.0 wt.%, less than 0.8 wt.%, less than 0.5 wt.%).
• the level of water may be in the range of 0.1 to 0.9 wt.%, such as 0.2 to 0.8 wt.%.
• These levels refer to the absolute level of water and not added levels of water. Any unavoidable trace of water present within the components of the lipid composition is included in this stated level of water.
• the absolute water level may be no more than 1.5 wt.%.
• Absolute levels of water can be measured by methods well known in the art, such as Karl Fischer titration.
• the water content may be measured according to the procedure in United States Pharmacopoeia (USP 40 - NF 35, USP ⁇ 921> Water determination, Method la).
• the lipid composition has a water content of between 0 to 1.0 wt.% (e.g., less than 1.0 wt.%, less than 0.8 wt.%, less than 0.5 wt.%) when the lipid composition product is released for sale (e.g., released for administration to a patient).
• the present disclosure relates to a method of treating at least one neuroendocrine tumor (NET) comprising, consisting essentially of, or consisting of administering to a patient in need thereof a lipid composition comprising 20 mg of octreotide or a pharmaceutically acceptable salt thereof, wherein the lipid composition is administered to the patient once every two weeks.
• NET neuroendocrine tumor
• the lipid composition which is described herein, may be administered to the patient once every two weeks as a single unit-dose, or in multi-dose formats.
• the at least one neuroendocrine tumor may be a gastroenteropancreatic neuroendocrine tumor (GEP-NET).
• GEP-NET gastroenteropancreatic neuroendocrine tumor
• the lipid composition may be administered to the patient by subcutaneous injection.
• the lipid composition may be administered to the patient by a syringe, a pre-filled syringe, an autoinjector, or a pen injector.
• the lipid composition may be administered to the patient not more than once every two weeks (or not more than once every week), and in a volume of about 1 mL.
• the lipid formulation may be provided in a pre-filled syringe, e.g., a 1 mL glass syringe, equipped with a small needle compared to the comparative product (22G), and the drug product is not necessary to be reconstituted and considered ready-to-use.
• a pre-filled syringe e.g., a 1 mL glass syringe, equipped with a small needle compared to the comparative product (22G), and the drug product is not necessary to be reconstituted and considered ready-to-use.
• the bioavailability of octreotide or a pharmaceutically acceptable salt thereof has been shown to be higher for a lipid composition of the present disclosure administered subcutaneously than for Sandostatin® LAR® which is administered as an intramuscular injection.
• octreotide release from a lipid composition of the present disclosure had a rapid onset of action, with an octreotide C max observed within approximately 4 to 24 hours after dosing. See Tiberg et al., British J. Clin. Pharmacol. 80(3):460-472 (2015). Thereafter, the plasma concentration slowly declined over time with therapeutic drug levels maintained for approximately 4 weeks, resulting in observable suppression of insulin-like growth factor- 1 over 4 weeks after dosing. Dose-proportional PK was observed in the dose range of 10 to 30 mg of the lipid composition. The bioavailability of octreotide was approximately 5 times higher for a lipid composition of the present disclosure than for Sandostatin® LAR®.
• the Phase 2 trial showed that switching from Sandostatin® LAR® (10 mg, 20 mg, or 30 mg) to a lipid composition comprising octreotide administered subcutaneously (20 mg once monthly or 10 mg every 2 weeks) was associated with maintenance or decrease in insulin-like growth factor- 1 levels (as compared to pre-switch values) and in maintenance of growth hormone levels in patients with acromegaly, and maintenance or improvement of symptom control, as measured by flushing episodes and bowel movements, in patients with NET. See Pavel et al., Cancer Chemotherapy and Pharmacology (2019) 83:375-385.
• the PK data from the trial confirmed the results from the trials in healthy volunteers and showed a higher exposure of octreotide after treatment with a lipid composition of the present disclosure than after treatment with Sandostatin® LAR®.
• the patient may have a maximum blood plasma concentration (Cmax) of octreotide (at steady state) of less than 45 ng/ml (e.g., less than 40 ng/ml, less than 35 ng/ml, less than 30 ng/ml), such as 3-45 ng/ml, such as 4-40 ng/ml, such as 5-35 ng/ml.
• Cmax blood plasma concentration
• the C max of octreotide at steady state is determined after 2 months of treatment.
• the concentration of octreotide may be determined using ultra high- performance liquid chromatography-tandem mass spectrometry, as described in Karnes et al, Journal of Chromatography B, 879 (2011) 2081-2088. Service labs, such as PPD laboratories (https://www.ppd.com/our-solutions/ppd-laboratories/bioanalytical-lab/), may be used. [00090]
• the patient may also have an average blood plasma concentration (CAV) of octreotide (at steady state) of 3 - 24 ng/ml (e.g., 4 - 20 ng/ml, 5 - 15 ng/ml, 5 - 10 ng/ml), for each administration of the lipid composition.
• CAV average blood plasma concentration
• the patient may also have a plasma concentration AUC of octreotide (at steady state) of 1300 - 6700 ng*h/ml (e.g., 1700 - 5000 ng*h/ml, 1700 - 3400 ng*h/ml), such as 1550 - 3500 ng*h/ml, such as 1600 - 3450 ng*h/ml, such as 1600 - 3400 ng*h/ml, for each administration of the lipid composition.
• AUC of octreotide at steady state of 1300 - 6700 ng*h/ml (e.g., 1700 - 5000 ng*h/ml, 1700 - 3400 ng*h/ml), such as 1550 - 3500 ng*h/ml, such as 1600 - 3450 ng*h/ml, such as 1600 - 3400 ng*h/ml, for each administration of the lipid composition.
• Administration of the lipid composition disclosed herein provides a drug depot comprising octreotide in the patient, wherein the depot may provide a release of octreotide to the patient over about two weeks and wherein the patient may have blood plasma levels of octreotide of at least about 3 ng/ml (e.g., at least about 4 ng/ml, at least about 5 ng/ml, at least about 6 ng/ml), for each administration of the lipid composition.
• the depot may be in the subcutaneous tissue of the patient.
• the lipid composition of the present disclosure may provide a progression-free survival (PFS) of at least 16 months (e.g., at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 21 months, at least 22 months, at least 23 months).
• PFS is defined as the time from the date of the first administration to the patient of the lipid composition of the present disclosure to the date of the first disease progression, determined according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1 ), or death to any cause, which occurs first.
• the lipid composition of the present disclosure may provide an improved progression- free survival (PFS) compared to Sandostatin® LAR® (30 mg administered intramuscularly every 4 weeks).
• PFS progression- free survival
• the present disclosure may also provide an improved or about the same PFS as Somatuline® Depot (Somatuline® Autogel) (120 mg administered subcutaneously every 4 weeks), again PFS is evaluated by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
• embodiments of the present disclosure may provide an improved PFS compared to Sandostatin® LAR® (30 mg administered intramuscularly every 4 weeks) and/or an increased or about the same PFS as Somatuline® Depot (Somatuline® Autogel) (120 mg administered subcutaneously every 4 weeks) in patients with, for example, unresectable/metastatic and well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NET).
• Somatuline® Depot Somatuline® Autogel
• GEP-NET gastroenteropancreatic neuroendocrine tumors
• the lipid composition administered once every second week and comprising 20 mg octreotide may provide an improved progression-free survival (PFS) compared to placebo or Sandostatin® LAR® (30 mg administered intramuscularly every 4 weeks), and/or increased or about the same progression-free survival as Somatuline® Depot (Somatuline® Autogel) (120 mg administered subcutaneously every 4 weeks), wherein the progression-free survival is determined radiologically according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
• PFS progression-free survival
• Somatuline® Depot Somatuline® Autogel
• the lipid composition administered once every second week and comprising 20 mg octreotide may provide an improved overall response rate (ORR) compared to Sandostatin® LAR® (30 mg administered intramuscularly every 4 weeks) and/or Somatuline® Depot (Somatuline® Autogel) (120 mg administered subcutaneously every 4 weeks) as determined according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
• the overall response rate may be selected from the group consisting of complete response and/or partial response.
• the lipid composition of the present disclosure may provide an improved disease control rate (DCR) compared to Sandostatin® LAR® (30 mg administered intramuscularly every 4 weeks) and/or Somatuline® Depot (Somatuline® Autogel) (120 mg administered subcutaneously every 4 weeks) as determined according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
• DCR disease control rate
• Sandostatin® LAR® (30 mg administered intramuscularly every 4 weeks
• Somatuline® Depot Somatuline® Autogel
• RECIST 1.1 Solid Tumors version 1.1
• the lipid composition of the present disclosure may provide an improved time to tumor response rate compared to Sandostatin® LAR® (30 mg administered intramuscularly every 4 weeks) and/or Somatuline® Depot (Somatuline® Autogel) (120 mg administered subcutaneously every 4 weeks) as determined according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
• the lipid composition of the present disclosure may provide an improved overall survival rate compared to Sandostatin® LAR® (30 mg administered intramuscularly every 4 weeks) and/or Somatuline® Depot (Somatuline® Autogel) (120 mg administered subcutaneously every 4 weeks) as determined by overall survival rates (i.e., the time from the date of the first administration to the date of death of the patient).
• the lipid composition may be administered to the patient once every two weeks until the patient experiences progressive disease (PD), determined radiologically according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), whereupon the lipid composition may then be administered to the patient once every week.
• PD progressive disease
• RECIST 1.1 Solid Tumors version 1.1
• the patient may have a maximum blood plasma concentration (Cmax) of octreotide (at steady state) of less than 45 ng/ml (e.g., less than 40 ng/ml, less than 35 ng/ml, less than 30 ng/ml), such as 3-45 ng/ml, such as 4-40 ng/ml, such as 5-35 ng/ml, for each once every administration.
• Cmax maximum blood plasma concentration
• the patient may have an average blood plasma concentration (CAV) of octreotide (at steady state) of 6 - 40 ng/ml (e.g., 7 - 30 ng/ml, 7 - 25 ng/ml), for each once every week administration.
• the patient may also have an average blood plasma concentration (CAV) of octreotide (at steady state) of 4 - 20 ng/ml for each once every week administration.
• CAV average blood plasma concentration
• the patient may have a plasma concentration AUC of octreotide (at steady state) of 1000 - 6700 ng*h/ml (e.g., 1000 - 5900 ng*h/ml, 1200 - 5000 ng*h/ml, 1200 - 4200 ng*h/ml), such as 1550 - 3500 ng*h/ml, such as 1600 - 3450 ng*h/ml, such as 1600 - 3400 ng*h/ml, for each once every week administration.
• a plasma concentration AUC of octreotide at steady state of 1000 - 6700 ng*h/ml (e.g., 1000 - 5900 ng*h/ml, 1200 - 5000 ng*h/ml, 1200 - 4200 ng*h/ml), such as 1550 - 3500 ng*h/ml, such as 1600 - 3450 ng*h/ml, such as 1600 - 3400
• Administration of the lipid composition may provide a drug depot comprising octreotide in the patient, wherein the depot may provide a release of octreotide to the patient over about 1 week and wherein the patient may have blood plasma levels of octreotide of at least about 5 ng/ml (e.g., at least about 7 ng/ml, at least about 8 ng/ml, at least about 10 ng/ml), for each once every week administration.
• the lipid composition of the present disclosure may be provided in a pre-filled syringe with no need for reconstitution.
• the lipid composition of the present disclosure also offers the option of self- or partner-administration and may be easier to handle and to administer, thereby potentially improving patient convenience and care.
• the method of administering the lipid composition of the present disclosure as a small- volume subcutaneous injection in, for example, a pre-filled syringe (i.e., eliminating the need for reconstitution) with, for example, a thin needle may provide a ready -to-use, long-acting octreotide formulation, with a higher octreotide bioavailability than Sandostatin® LAR®, and may lead to improved quality of patient care and treatment convenience.
• the present disclosure may not be appropriate for patients with long QT syndrome, a family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: [000109] Risk factors for Torsades de Pointes, including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically signifi cant/ symptomatic bradycardia; Treatment with concomitant medication(s) with a “known risk of Torsades de Pointes” per www.qtdrugs.org that cannot be discontinued or replaced with safe alternative medication at least 7 days or 5 half-lives (whichever is longer) before the first administration of the lipid composition of the present disclosure; or a baseline QTc interval corrected by Fridericia’s formula (QTcF) of >450 msec for male patients and >470 msec for female patients before the first administration of the lipid composition of the present disclosure.
• QTcF Fridericia’s formula
• the dosing of the lipid composition may not need to be interrupted for male patients having an average QTcF of 450 msec to 480 msec and for female patients having an average QTcF of 470 msec to 480 msec.
• the dosing of the lipid composition may need to be interrupted/paused/delayed until the average QTcF of the patient falls below 481 msec, whereupon the dosing of the lipid composition may resume.
• lipid composition comprising 20 mg of octreotide or a pharmaceutically acceptable salt thereof, herein the lipid composition is administered to the patient once every two weeks.
• the lipid composition is administered as a unit dose.
• the at least one neuroendocrine tumor is a gastroenteropancreatic neuroendocrine tumor.
• the octreotide or pharmaceutically acceptable salt thereof in the lipid composition is octreotide chloride.
• the octreotide or pharmaceutically acceptable salt thereof in the lipid composition is octreotide chloride, and the octreotide chloride is the only active ingredient in the lipid composition.
• the lipid composition comprises, consists essentially of, or consists of the octreotide or pharmaceutically acceptable salt thereof (e.g., octreotide chloride), glycerol dioleate, phosphatidylcholine, and ethanol.
• the lipid composition comprises, consists essentially of, or consists of the octreotide or pharmaceutically acceptable salt thereof (e.g., octreotide chloride), glycerol dioleate, phosphatidylcholine, ethanol, and propylene glycol.
• the lipid composition comprises, consists essentially of, or consists of the octreotide or pharmaceutically acceptable salt thereof (e.g., octreotide chloride), glycerol dioleate, phosphatidylcholine, ethanol, and EDTA.
• the lipid composition comprises, consists essentially of, or consists of the octreotide or pharmaceutically acceptable salt thereof (e.g., octreotide chloride), glycerol dioleate, phosphatidylcholine, ethanol, propylene glycol, and EDTA.
• octreotide chloride e.g., octreotide chloride
• glycerol dioleate e.g., glycerol dioleate
• phosphatidylcholine e.g., ethanol, propylene glycol, and EDTA.
• the lipid composition comprises, consists essentially of, or consists of the octreotide or pharmaceutically acceptable salt thereof (e.g., octreotide chloride), glycerol dioleate, phosphatidylcholine, ethanol, propylene glycol, EDTA, ethanolamine and/or diethanolamine.
• octreotide chloride e.g., octreotide chloride
• glycerol dioleate e.g., octreotide chloride
• glycerol dioleate e.g., glycerol dioleate
• phosphatidylcholine e.g., ethanol, propylene glycol, EDTA, ethanolamine and/or diethanolamine.
• At least 80 wt.% of the lipid composition may comprise the octreotide or pharmaceutically acceptable salt thereof (and any other optional active ingredients) and lipid(s), phospholipid(s), solvents , and, if present, EDTA (allowing for any impurity inherent in these components).
• At least 85 wt.% of the lipid composition may comprise the octreotide (e.g., octreotide chloride), at least one lipid (e.g., glycerol dioleate), at least one phospholipid (e.g., phosphatidylcholine), at least one biocompatible organic solvent (e.g., ethanol and propylene glycol), and EDTA.
• octreotide e.g., octreotide chloride
• at least one lipid e.g., glycerol dioleate
• at least one phospholipid e.g., phosphatidylcholine
• biocompatible organic solvent e.g., ethanol and propylene glycol
• These lipid compositions may have an initial (at release of the drug product) water of content of less than 1.0 wt.% (e.g., less than 0.9 wt.%, less than 0.8 wt.%, less than 0.7 wt.%, less than 0.6 wt.%, less than 0.5 wt.%), and/or a water content of less than 1.0 wt.% (e.g., less than 0.9 wt.%, less than 0.8 wt.%, less than 0.7 wt.%, less than 0.6 wt.%, less than 0.5 wt.%) at the release of the lipid composition product for sale.
• 1.0 wt.% e.g., less than 0.9 wt.%, less than 0.8 wt.%, less than 0.7 wt.%, less than 0.6 wt.%, less than 0.5 wt.%
• At least 85 wt.% of the lipid composition consists of octreotide chloride, glycerol dioleate, phosphatidylcholine, ethanol, and propylene glycol.
• At least 86 wt.% of the lipid composition consists of octreotide chloride, glycerol dioleate, phosphatidylcholine, ethanol, propylene glycol, EDTA, and the lipid composition has a water content of less than 1.0 wt.% at the release of the lipid composition product for sale.
• the lipid composition is administered by a syringe, a pre-filled syringe, an autoinjector, or a pen injector.
• the lipid composition is administered by subcutaneous inj ection.
• the lipid composition is administered not more than once every two weeks, and in a volume of about 1 mL.
• the patient has a maximum blood plasma concentration (C max ) of octreotide (at steady state) of less than 45 ng/ml, such as less than 40 ng/ml, less than 35 ng/ml, or less than 30 ng/ml, for each administration.
• C max maximum blood plasma concentration
• the patient has a maximum blood plasma concentration (Cm ax ) of octreotide (at steady state) of 3-45 ng/ml, such as 4-40 ng/ml, such as 5-35 ng/ml, for each administration.
• Cm ax maximum blood plasma concentration of octreotide (at steady state) of 3-45 ng/ml, such as 4-40 ng/ml, such as 5-35 ng/ml, for each administration.
• the patient has an average blood plasma concentration (CAV) of octreotide (at steady state) of 3 - 24 ng/ml, such as 4 - 20 ng/ml, such as 5 - 15 ng/ml or 5 - 10 ng/ml, for each administration.
• CAV blood plasma concentration
• the patient has an average blood plasma concentration (CAV) of octreotide (at steady state) of 4 - 20 ng/ml for each administration.
• CAV average blood plasma concentration
• the patient has a plasma concentration AUC of octreotide (at steady state) of 1300 - 6700 ng*h/ml, such as 1700 - 5000 ng*h/ml or 1700 - 3400 ng*h/ml, for each administration.
• the patient has a plasma concentration AUC of octreotide (at steady state) of 1550 - 3500 ng*h/ml, such as 1600 - 3450 ng*h/ml, such as 1600 - 3400 ng*h/ml, for each administration.
• administering the lipid composition comprising 20 mg of octreotide provides a drug depot comprising octreotide in the patient, said depot providing a release of octreotide to the patient over about two weeks and wherein the patient has blood plasma levels of octreotide of at least about 3 ng/ml, such as at least about 4 ng/ml, about 5 ng/ml, or about 6 ng/ml, for each administration.
• the depot is in the subcutaneous tissue of the patient.
• the lipid composition is administered to the patient once every two weeks until the patient experiences progressive disease (PD), determined radiologically according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), whereupon the lipid composition is optionally administered to the patient once every week.
• PD progressive disease
• RECIST 1.1 Response Evaluation Criteria in Solid Tumors version 1.1
• the method provides a progression-free survival of at least 16 months, such as at least 17 months, such as at least 18 months, such as at least 19 months, such as at least 20 months, such as at least 21 months, such as at least 22 months, such as at least 23 months.
• the method provides an improved progression-free survival (PFS) compared to Sandostatin® LAR®.
• PFS progression-free survival
• the method provides an improved progression-free survival (PFS) compared to placebo or Sandostatin® LAR®, and/or increased or about the same progression-free survival as Somatuline® Depot (Somatuline® Autogel), wherein the progression- free survival is determined radiologically according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
• PFS progression-free survival
• Somatuline® Depot Somatuline® Autogel
• the method provides an improved overall response rate (ORR) compared to Sandostatin® LAR® as determined according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
• the overall response rate is selected from the group consisting of complete response and/or partial response.
• the method provides an improved disease control rate (DCR) compared to Sandostatin® LAR® as determined according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
• DCR disease control rate
• the patient has a maximum blood plasma concentration (C max ) of octreotide (at steady state) of less than 45 ng/ml, such as less than 40 ng/ml, less than 35 ng/ml, or less than 30 ng/ml, for each once every administration.
• C max maximum blood plasma concentration
• the patient has a maximum blood plasma concentration (Cm ax ) of octreotide (at steady state) of 3-45 ng/ml, such as 4-40 ng/ml, such as 5-35 ng/ml, for each once every administration.
• Cm ax maximum blood plasma concentration of octreotide (at steady state) of 3-45 ng/ml, such as 4-40 ng/ml, such as 5-35 ng/ml, for each once every administration.
• the patient has an average blood plasma concentration (CAV) of octreotide (at steady state) of 6 - 40 ng/ml, such as 7 - 30 ng/ml or 7 - 25 ng/ml, for each once every week administration.
• CAV blood plasma concentration
• the patient has an average blood plasma concentration (CAV) of octreotide (at steady state) of 4 - 20 ng/ml for each once every week administration.
• CAV average blood plasma concentration
• the patient has a plasma concentration AUC of octreotide (at steady state) of 1000 - 6700 ng*h/ml, such as 1000 - 5900 ng*h/ml, such a 1200 - 5000 ng*h/ml, or 1200 - 4200 ng*h/ml, for each once every week administration.
• AUC of octreotide at steady state of 1000 - 6700 ng*h/ml, such as 1000 - 5900 ng*h/ml, such a 1200 - 5000 ng*h/ml, or 1200 - 4200 ng*h/ml, for each once every week administration.
• the patient has a plasma concentration AUC of octreotide (at steady state) of 1550 - 3500 ng*h/ml, such as 1600 - 3450 ng*h/ml, such as 1600 - 3400 ng*h/ml, for each once every week administration.
• administering the lipid composition comprising 20 mg of octreotide provides a drug depot comprising octreotide in the patient, said depot providing a release of octreotide to the patient over about 1 week and wherein the patient has blood plasma levels of octreotide of at least about 5 ng/ml, such as at least about 7 ng/ml, about 8 ng/ml, or about 10 ng/ml, for each once every week administration.
• a pre-filled syringe comprising the aforementioned lipid composition and/or any of its disclosed variations.
• an autoinjector comprising a glass compartment containing the aforementioned lipid composition and/or any of its disclosed variations.
• the glass compartment of the autoinjector is part of a pre-filled syringe.
• kits for the administration of octreotide or a pharmaceutically acceptable salt thereof having one or more containers comprising 20 mg of octreotide or a pharmaceutically acceptable salt thereof, wherein the octreotide or a pharmaceutically acceptable salt in the one or more containers is administered according to the aforementioned method and/or any of its disclosed variations.
• a method of treating at least one neuroendocrine tumor comprising, administering to a patient in need thereof a lipid composition comprising 20 mg of octreotide or a pharmaceutically acceptable salt thereof, wherein the lipid composition is administered to the patient once every two weeks.
• E3 The method of El or E2, wherein the at least one neuroendocrine tumor is a gastroenteropancreatic neuroendocrine tumor.
• E4 The method of any one of E1-E3, wherein the octreotide or a salt thereof is octreotide chloride.
• E5. The method of E4, wherein the octreotide chloride is the sole active agent in the lipid composition.
• E6 The method of any one of E1-E5, wherein the lipid composition further comprises glycerol dioleate, phosphatidylcholine, and ethanol.
• E7 The method of E6, wherein the lipid composition further comprises propylene glycol.
• E9 The method of E8, wherein the lipid composition further comprises ethanolamine and/or diethanolamine.
• E10 The method of any one of E1-E9, wherein at least 85 wt% of the lipid composition consists of octreotide chloride, glycerol dioleate, phosphatidylcholine, ethanol, and propylene glycol.
• Ell. The method of any one of E1-E10, wherein at least 86 wt% of the lipid composition consists of octreotide chloride, glycerol dioleate, phosphatidylcholine, ethanol, propylene glycol, EDTA, and the lipid composition has a water content of less than 1.0 wt% at the release of the product for sale.
• E12 The method of any one of El-Ell, comprising administering the lipid composition by a syringe, a pre-filled syringe, an autoinjector, or a pen injector.
• E12 The method of any one of E1-E12, administering the lipid composition by subcutaneous injection.
• El 4. The method of any one of El -El 3, comprising administering the lipid composition not more than once every two weeks, and in a volume of about 1 mL.
• El 5 The method of any one of El -El 4, wherein the patient has a maximum blood plasma concentration (Cmax) of octreotide (at steady state) of less than 45 ng/ml, such as less than 40 ng/ml, less than 35 ng/ml, or less than 30 ng/ml, for each administration.
• Cmax maximum blood plasma concentration
• El 6. The method of any one of El -El 5, wherein the patient has a maximum blood plasma concentration (Cmax) of octreotide (at steady state) of 3-45 ng/ml, such as 4-40 ng/ml, such as 5-35 ng/ml, for each administration.
• Cmax maximum blood plasma concentration
• E17 The method of any one of E1-E16, wherein the patient has an average blood plasma concentration (CAV) of octreotide (at steady state) of 3 - 24 ng/ml, such as 4 - 20 ng/ml, such as 5 - 15 ng/ml or 5 - 10 ng/ml, for each administration.
• CAV blood plasma concentration
• E18 The method of any one of E1-E17, wherein the patient has an average blood plasma concentration (CAV) of octreotide (at steady state) of 4 - 20 ng/ml for each administration.
• CAV average blood plasma concentration
• El 9. The method of any one of El -El 8, wherein the patient has a plasma concentration AUC of octreotide (at steady state) of 1300 - 6700 ng*h/ml, such as 1700 - 5000 ng*h/ml or 1700 - 3400 ng*h/ml, for each administration.
• E20 The method of any one of El -El 9, wherein the patient has a plasma concentration AUC of octreotide (at steady state) of 1550 - 3500 ng*h/ml, such as 1600 - 3450 ng*h/ml, such as 1600 - 3400 ng*h/ml, for each administration.
• E21 The method of any one of E1-E20, wherein administering the lipid composition comprising 20 mg of octreotide provides a drug depot comprising octreotide in the patient, said depot providing a release of octreotide to the patient over about two weeks and wherein the patient has blood plasma levels of octreotide of at least about 3 ng/ml, such as at least about 4 ng/ml, about 5 ng/ml, or about 6 ng/ml, for each administration.
• E22 The method of E21, wherein the depot is in the subcutaneous tissue of the patient.
• E23 The method of any one of E1-E22, wherein the lipid composition is administered to the patient once every two weeks until the patient experiences progressive disease (PD), determined radiologically according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), whereupon the lipid composition is optionally administered to the patient once every week.
• PD progressive disease
• RECIST 1.1 Solid Tumors version 1.1
• E24 The method of any one of E1-E23, wherein the method provides a progression-free survival of at least 16 months, such as at least 17 months, such as at least 18 months, such as at least 19 months, such as at least 20 months, such as at least 21 months, such as at least 22 months, such as at least 23 months.
• E25 The method of any one of E1-E24, wherein the method provides an improved progression-free survival (PFS) compared to Sandostatin® LAR®.
• PFS progression-free survival
• E26 The method of any one of E1-E25, wherein the method provides an improved progression-free survival (PFS) compared to placebo or Sandostatin® LAR®, and/or increased or about the same progression-free survival as Somatuline® Depot (Somatuline® Autogel), wherein the progression-free survival is determined radiologically according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
• PFS progression-free survival
• Somatuline® Depot Somatuline® Autogel
• E27 The method of any one of E1-E26, wherein the method provides an improved overall response rate (ORR) compared to Sandostatin® LAR® and/or improved or about the same ORR as Somatuline® Depot (Somatuline® Autogel) as determined according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
• ORR overall response rate
• E28 The method of E27, wherein the overall response rate is selected from the group consisting of complete response and/or partial response.
• E29 The method of any one of E1-E28, wherein the method provides an improved disease control rate (DCR) compared to Sandostatin® LAR® and/or improved or about the same DCR as Somatuline® Depot (Somatuline® Autogel) as determined according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
• DCR disease control rate
• E30 The method of any one of E23-E29, wherein the patient has a maximum blood plasma concentration (Cmax) of octreotide (at steady state) of less than 45 ng/ml, such as less than 40 ng/ml, less than 35 ng/ml, or less than 30 ng/ml, for each once every administration.
• Cmax maximum blood plasma concentration
• E31 The method of any one of E23-E30, wherein the patient has a maximum blood plasma concentration (C max ) of octreotide (at steady state) of 3-45 ng/ml, such as 4-40 ng/ml, such as 5-35 ng/ml, for each once every administration.
• C max maximum blood plasma concentration
• E32 The method of any one of E23-E31, wherein the patient has an average blood plasma concentration (C AV ) of octreotide (at steady state) of 6 - 40 ng/ml, such as 7 - 30 ng/ml or 7 - 25 ng/ml, for each once every week administration.
• CAV average blood plasma concentration
• E34 The method of any one of E23-E33, wherein the patient has a plasma concentration AUC of octreotide (at steady state) of 1000 - 6700 ng*h/ml, such as 1000 - 5900 ng*h/ml, such a 1200 - 5000 ng*h/ml, or 1200 - 4200 ng*h/ml, for each once every week administration.
• AUC of octreotide at steady state
• E35 The method of any one of E23-E34, wherein the patient has a plasma concentration AUC of octreotide (at steady state) of 1550 - 3500 ng*h/ml, such as 1600 - 3450 ng*h/ml, such as 1600 - 3400 ng*h/ml, for each once every week administration.
• E36 The method of any one of E23-E35, wherein administering the lipid composition comprising 20 mg of octreotide provides a drug depot comprising octreotide in the patient, said depot providing a release of octreotide to the patient over about 1 week and wherein the patient has blood plasma levels of octreotide of at least about 5 ng/ml, such as at least about 7 ng/ml, about 8 ng/ml, or about 10 ng/ml, for each once every week administration.
• E37 A lipid composition comprising 20 mg of octreotide or a pharmaceutically acceptable salt thereof for use in treating at least one neuroendocrine tumor, and wherein the composition is administered to a patient once every two weeks.
• E38 The composition of E37, wherein the at least one neuroendocrine tumor is a gastroenteropancreatic neuroendocrine tumor.
• E39 The composition of E37 or E38, wherein the octreotide or a salt thereof is octreotide chloride.
• E40 The composition of E39, wherein the octreotide chloride is the sole active agent in the lipid composition.
• E41 The composition of any one of E37-E40, wherein the lipid composition further comprises glycerol dioleate, phosphatidylcholine, and ethanol.
• E42 The composition of E41, wherein the lipid composition further comprises propylene glycol.
• E43 The composition of any one of E37-E42, wherein the lipid composition further comprises EDTA.
• E44 The composition of any one of E37-E43, wherein the lipid composition further comprises ethanolamine and/or diethanolamine.
• E45 The composition of any one of E37-E44, wherein at least 85 wt% of the lipid composition consists of octreotide chloride, glycerol dioleate, phosphatidylcholine, ethanol, and propylene glycol.
• E46 The composition of any one of E37-E45, wherein at least 86 wt% of the lipid composition consists of octreotide chloride, glycerol dioleate, phosphatidylcholine, ethanol, propylene glycol, EDTA, and the lipid composition has a water content of less than 1.0 wt% at the release of the product for sale.
• E47 The composition of any one of E37-E46, comprising administering the lipid composition by a syringe, a pre-filled syringe, an autoinjector, or a pen injector.
• E48 The composition of any one of E37-E47, administering the lipid composition by subcutaneous injection.
• E49 The composition of any one of E37-E48, comprising administering the lipid composition not more than once every two weeks, and in a volume of about 1 mL.
• E50 The composition of any one of E37-E49, wherein the patient has a maximum blood plasma concentration (C max ) of octreotide (at steady state) of less than 45 ng/ml, such as less than 40 ng/ml, less than 35 ng/ml, or less than 30 ng/ml, for each administration.
• C max maximum blood plasma concentration
• E51 The composition of any one of E37-E50, wherein the patient has a maximum blood plasma concentration (Cm ax ) of octreotide (at steady state) of 3-45 ng/ml, such as 4-40 ng/ml, such as 5-35 ng/ml, for each administration.
• Cm ax maximum blood plasma concentration of octreotide (at steady state) of 3-45 ng/ml, such as 4-40 ng/ml, such as 5-35 ng/ml, for each administration.
• E52 The composition of any one of E37-E51, wherein the patient has an average blood plasma concentration (CAV) of octreotide (at steady state) of 4 - 20 ng/ml, such as 5 - 15 ng/ml or 5 - 10 ng/ml, for each administration.
• CAV blood plasma concentration
• E53 The composition of any one of E37-E52, wherein the patient has an average blood plasma concentration (CAV) of octreotide (at steady state) of 4 - 20 ng/ml for each administration.
• CAV average blood plasma concentration
• E54 The composition of any one of E37-E53, wherein the patient has a plasma concentration AUC of octreotide (at steady state) of 1300 - 6700 ng*h/ml, such as 1700 - 5000 ng*h/ml or 1700 - 3400 ng*h/ml, for each administration.
• E55 The composition of any one of E37-E54, wherein the patient has a plasma concentration AUC of octreotide (at steady state) of 1550 - 3500 ng*h/ml, such as 1600 - 3450 ng*h/ml, such as 1600 - 3400 ng*h/ml, for each administration.
• E56 The composition of any one of E37-E55, wherein administering the lipid composition comprising 20 mg of octreotide provides a drug depot comprising octreotide in the patient, said depot providing a release of octreotide to the patient over about two weeks and wherein the patient has blood plasma levels of octreotide of at least about 3 ng/ml, such as at least about 4 ng/ml, about 5 ng/ml, or about 6 ng/ml, for each administration.
• E57 The composition of E56, wherein the depot is in the subcutaneous tissue of the patient.
• E58 The composition of any one of E37-E57, wherein the lipid composition is administered to the patient once every two weeks until the patient experiences progressive disease (PD), determined radiologically according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), whereupon the lipid composition is optionally administered to the patient once every week.
• PD progressive disease
• RECIST 1.1 Solid Tumors version 1.1
• E59 The composition of any one of E37-E58, wherein the administration of the composition provides a progression-free survival of at least 16 months, such as at least 17 months, such as at least 18 months, such as at least 19 months, such as at least 20 months, such as at least 21 months, such as at least 22 months, such as at least 23 months.
• E60 The composition of any one of E37-E59, wherein the method provides an improved progression-free survival (PFS) compared to Sandostatin® LAR®.
• PFS progression-free survival
• E61 The composition of any one of E37-E60, wherein the administration of the composition provides an improved progression-free survival (PFS) compared to placebo or Sandostatin® LAR®, and/or increased or about the same progression-free survival as Somatuline® Depot (Somatuline® Autogel), wherein the progression-free survival is determined radiologically according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
• PFS progression-free survival
• Somatuline® Depot Somatuline® Autogel
• E62 The composition of any one of E37-E61, wherein the administration of the composition provides an improved overall response rate (ORR) compared to Sandostatin® LAR® and/or imporved or about the same ORR as Somatuline® Depot (Somatuline® Autogel) as determined according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
• ORR overall response rate
• Somatuline® Depot Somatuline® Autogel
• E63 The composition of E62, wherein the overall response rate is selected from the group consisting of complete response and/or partial response.
• E64 The composition of any one of E37-E53, wherein the administration of the composition provides an improved disease control rate (DCR) compared to Sandostatin® LAR® and/or improved or about the same DCR as Somatuline® Depot (Somatuline® Autogel) as determined according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
• DCR disease control rate
• Somatuline® Depot Somatuline® Autogel
• E65 The composition of any one of E58-E64, wherein the patient has an average blood plasma concentration (CAV) of octreotide (at steady state) of 6 - 40 ng/ml, such as 7 - 30 ng/ml or 7 - 25 ng/ml, for each once every week administration.
• CAV average blood plasma concentration
• E66 The composition of any one of E58-E65, wherein the patient has an average blood plasma concentration (CAV) of octreotide (at steady state) of 4 - 20 ng/ml for each once every week administration.
• CAV blood plasma concentration
• E67 The composition of any one of E58-E66, wherein the patient has a plasma concentration AUC of octreotide (at steady state) of 1000 - 6700 ng*h/ml, such as 1000 - 5900 ng*h/ml, such a 1200 - 5000 ng*h/ml, or 1200 - 4200 ng*h/ml, for each once every week administration.
• AUC of octreotide at steady state
• E68 The composition of any one of E58-E67, wherein the patient has a plasma concentration AUC of octreotide (at steady state) of 1550 - 3500 ng*h/ml, such as 1600 - 3450 ng*h/ml, such as 1600 - 3400 ng*h/ml, for each once every week administration.
• AUC of octreotide at steady state
• E69 The composition of any one of E58-E68, wherein administering the lipid composition comprising 20 mg of octreotide provides a drug depot comprising octreotide in the patient, said depot providing a release of octreotide to the patient over about 1 week and wherein the patient has blood plasma levels of octreotide of at least about 5 ng/ml, such as at least about 7 ng/ml, about 8 ng/ml, or about 10 ng/ml, for each once every week administration.
• E70 A pre-filled syringe comprising a lipid composition according to any one of
• E71 An autoinjector comprising a glass compartment containing the lipid composition of any one of E37-E69.
• E72 The autoinjector of E71, wherein the compartment is part of a pre-filled syringe.
• E73 A kit for the administration of octreotide or a pharmaceutically acceptable salt thereof having one or more containers comprising 20 mg of octreotide or a pharmaceutically acceptable salt thereof, wherein the octreotide or a pharmaceutically acceptable salt in the one or more containers is administered according to the method of any one of E1-E36.
• NET Neuroendocrine tumors
• GEP gastroenteropancreatic
• neuroendocrine neoplasms are divided into NET and neuroendocrine carcinomas (NEC) based on their molecular differences (2).
• NET are further divided into grades according to their histopathologic characterization and to their proliferation (nuclear antigen Ki-67) index; see Table 1 above.
• GEP -NET may have the following primary tumor locations: stomach, duodenum, jejunum, ileum, pancreas, appendix, cecum, colon and rectum.
• GEP-NET The diagnosis of GEP-NET is established pathologically. Patients are further characterized according to the clinical presentation, including whether symptoms related to tumor hormone secretion are present. Carcinoid syndrome is the most notable cluster of symptoms related to secretion of serotonin and other vasoactive peptide hormones. It is characterized by abdominal pain and cramping, severe diarrhea and flushing, and potential cardiac abnormalities. Carcinoid syndrome is more frequent in patients with advanced disease (6).
• Radiology imaging plays an important role in the staging and characterization of somatostatin receptor expression in NET.
• Conventional cross-sectional imaging using computed tomography (CT) or magnetic resonance imaging (MRI) scans plays a key role in the assessment of location and extent of the disease.
• CT computed tomography
• MRI magnetic resonance imaging
• GEP-NET have a variable prognosis based on primary site of disease, degree of differentiation, grade, expression of somatostatin receptors, and presence of metastases at diagnosis.
• Well-differentiated, lower-grade GEP-NET have prolonged survival compared to high- grade tumors, and pancreatic NET generally have more aggressive biology than NET arising in the small intestine.
• Retrospective analyses have demonstrated that the median overall survival for pancreatic NET ranges from 2 to 5.8 years, while NET in the small intestine have a median overall survival of almost 8 years (4, 7, 8).
• Surgical resection of the primary lesions remains the mainstay of treatment for NET and the only way to obtain a cure.
• resection is often not possible as NET are frequently detected in a more advanced tumor stage when metastases have already developed (1).
• SSAs somatostatin analogues
• mTOR mammalian target of rapamycin
• sunitinib tyrosine kinase inhibitors
• PRRT peptide receptor radionuclide therapy
• the dose of octreotide LAR for the treatment of advanced midgut NET is 30 mg/month, which is also the maximum approved dose for symptom control.
• Higher doses of octreotide up to 120 mg have been used for symptom control in patients who no longer respond adequately to standard doses. Higher doses have also been used for tumor control, though results from controlled studies are lacking (17).
• Three studies have investigated the antiproliferative efficacy of above-standard doses of either octreotide LAR (up to 160 mg every 2 weeks) or lanreotide (up to 15 mg/day), showing disease stabilization in 37 to 75% of the patients (18-20).
• CAM2029 (‘octreotide subcutaneous depot’) is anovel and long-acting pharmaceutical formulation of octreotide for subcutaneous (SC) administration. Compared to Sandostatin LAR, which is administered as an intramuscular (IM) injection and which needs to be reconstituted before injection, CAM2029 is provided in a pre-filled syringe with no need for reconstitution. CAM2029 also offers the option of self- or partner-administration and may be easier to handle and to administer, thereby potentially improving patient convenience and care. In addition, the bioavailability of octreotide has been shown to be higher for CAM2029 than for Sandostatin LAR (see below).
• the non-clinical development program for CAM2029 includes bridging studies of toxicity, pharmacokinetics (PK) and local tolerability.
• PK pharmacokinetics
• the FluidCrystal ® vehicle and the excipient glycerol dioleate have been evaluated.
• the main effects observed in these studies were reversible injection-site reactions, which were noted with the FluidCrystal vehicle, CAM2029 formulations, and glycerol dioleate.
• Body weight decreases were also observed, which is consistent with the pharmacology of octreotide.
• the maximum plasma concentration (C max ) of octreotide after administration of CAM2029 in dogs was higher than after administration of an equivalent dose of Sandostatin LAR, without any apparent difference in toxicity.
• CAM2029 The safety of CAM2029 is supported by the available extensive database (pharmacology, PK, safety, and toxicity) of octreotide (see further details in the Investigator’s Brochure [IB]) (29).
• the clinical program for CAM2029 includes 3 completed Phase 1 trials in healthy volunteers (a single-dose trial [HS-05-194] and 2 repeated-dose trials [HS-07-291 and HS-11- 411]), and 1 completed, repeated-dose, Phase 2 trial (HS-12-455) in patients with acromegaly or functioning NET previously treated with Sandostatin LAR.
• CAM2029 is currently being studied in US and Europe in 2 multinational Phase 3 trials in patients with acromegaly.
• a Phase 1 trial is also ongoing, in which the PK of octreotide after administration of CAM2029 with an autoinjector is investigated.
• the target population in the current trial comprises adult patients with histologically confirmed, advanced (unresectable and/or metastatic), and well-differentiated NET of presumed GEP origin.
• SSAs octreotide and lanreotide
• the current trial aims to confirm efficacy and safety of CAM2029 (octreotide SC depot) as compared to Investigator’s choice of comparator (octreotide LAR or lanreotide ATG) for the treatment of patients with well-differentiated GEP-NET.
• Octreotide products (Sandostatin IR and Sandostatin LAR) have well-characterized profiles of efficacy and safety with over 30 years of clinical use.
• CAM2029 has the same active ingredient (octreotide) as Sandostatin IR and Sandostatin LAR and has been shown to have a safety profile similar to Sandostatin LAR in previous Phase 1 and 2 clinical trials (29).
• Lanreotide is another SSA approved for the treatment of acromegaly and NET and is available in a microsphere formulation (sustained release) and a saturated aqueous solution (lanreotide ATG; Somatuline Autogel [Somatuline Depot in the US]).
• Lanreotide has been on the market for almost 20 years and its efficacy and safety are well established.
• patients will be randomized to 1 of 2 treatment groups: CAM2029 20 mg every 2 weeks or one of the comparator products (30 mg octreotide LAR or 120 mg lanreotide ATG) every 4 weeks.
• Patients will be treated with the investigational medicinal products (IMP; i.e. CAM2029, octreotide LAR or lanreotide ATG) until disease progression, at which time patients in both the CAM2029 treatment group and the comparator treatment group will have the option to switch to treatment with CAM202920 mg once weekly.
• the shorter dosing interval could potentially result in a higher somatostatin-receptor saturation and may further improve the clinical outcomes.
• CAM2029 as a ready -to-use, long-acting formulation that is administered as a small-volume SC injection in a pre-filled syringe (i.e. eliminating the need for reconstitution) with a thin needle and with higher bioavailability of octreotide than for octreotide LAR, is expected to lead to improved quality of patient care and treatment convenience.
• CAM2029 in the abdomen or thigh is allowed after appropriate training under the supervision of trained trial personnel and after the patient or their partner has been judged capable to administer CAM2029.
• a “partner” may be a spouse, parent, child, or sibling, or any other person whom the patient trusts to administer the injection.
• Home administration of CAM2029 is also allowed in the trial, which will further facilitate the treatment with CAM2029.
• the CAM2029 drug product is based on the FluidCrystal injection depot technology.
• CAM2029 and other products based on this technology have been extensively investigated in Phase 1 to Phase 3 clinical trials.
• the buprenorphine-containing product Buvidal ® which is based on the FluidCrystal injection depot technology, was approved by the European and Australian authorities in November 2018 for treatment of opioid dependence. All clinical trials reported to date have demonstrated good or very good local tolerability, with generally mild or moderate transient injection-site reactions, such as injection site pain, pruritus, erythema, swelling and induration, at low incidence.
• the safety profile of Buvidal is also favorable based on post marketing experience with more than 7,200 patient-years of exposure as of 30-Nov-2020.
• CAM2029 The active substance in CAM2029 (octreotide) is well documented. Octreotide products have been in clinical use for more than 30 years.
• ADRs adverse drug reactions
• GI disorders such as nausea, diarrhea, abdominal pain, flatulence and constipation
• headache cholelithiasis
• hyperglycemia injection-site reactions
• the most commonly reported ADRs were headache and GI disorders, such as diarrhea and abdominal pain.
• Injection site reactions e.g.
• the patients will be followed closely with several safety assessments throughout the trial. Parameters that will be monitored regularly include vital signs, hematology laboratory assessments, blood chemistry (including renal and liver function, and thyroid hormones), urinalysis, electrocardiogram (ECG), and gallbladder ultrasound. Patients will be regularly and carefully monitored for AEs, including those that have been observed for Sandostatin IR and Sandostatin LAR. A Data Monitoring Committee (DMC) will be established and the DMC will conduct periodic reviews of safety data from the trial. In addition, the protocol provides specific guidance for IMP discontinuation and safety follow-up for ADRs, liver toxicity (increased liver enzyme values) and QT prolongation.
• DMC Data Monitoring Committee
• sampling for measurement of octreotide plasma concentrations will be conducted in patients who receive CAM2029 or octreotide LAR. Blood samples will also be taken for qualification and quantification of anti-octreotide antibodies to assess for potential immunogenicity.
• the Sponsor will, in collaboration with the contract research organization (CRO) managing the trial, prepare a specific COVID-19-related risk assessment and mitigation plan to be followed during the trial.
• CRO contract research organization
• CAM2029 has been found to be well tolerated in clinical trials conducted to date.
• AE adverse event
• ATG autogel
• BIRC Blinded Independent Review Committee
• CR complete response
• DCR disease control rate
• ECG electrocardiogram
• ECOG Eastern Cooperative Oncology Group
• EORTC QLQ-C30 European Organization for Research and Treatment of Cancer’s Core Quality of Life Questionnaire
• GEP-NET gastroenteropancreatic neuroendocrine tumors
• LAR long-acting release
• ORR overall response rate
• PFS progression-free survival
• PFS2 progression-free survival 2
• PFS-ext progression-free survival in the Extension Treatment Period
• PGI-S Patient Global Impression of Severity
• PK pharmacokinetics
• PR partial response
• PROs patient-reported outcomes
• QLQ-GINET21 Quality of Life Questionnaire - Neuroendocrine Carcinoid Module
• RECIST 1.1 Response Evaluation Criteria in Solid Tumors version 1.1
• SD stable disease
• SF-36 Short Form-36
• TSQM Treatment Satisfaction
• FDG fluorodeoxy glucose
• Randomization will be stratified by the following:
• Tumor origin pancreas versus other GI origin
• Patients randomized to the CAM2029 treatment group may self-administer CAM2029 or have CAM2029 administered by their partner.
• the feasibility of self- or partner-administration of CAM2029 under the supervision of a trained trial personnel will be assessed. If the trial personnel consider the patients or their partners competent to administer CAM2029, they may continue to administer CAM2029 every 2 weeks. If CAM2029 is not self- or partner-administered, trial personnel will perform the administrations at the clinic. Self- or partner-administration at home is allowed after 3 supervised and successful administrations.
• Next-line therapy may be started after the End-of-treatment Visit at the Investigator’s discretion.
• BIRC BIRC confirms PD during treatment with the IMP (CAM2029/comparator) in the Randomized Treatment Period
• patients in both treatment groups may be switched to receive treatment with CAM202920 mg once weekly in an Extension Treatment Period, if the Investigator considers it beneficial for the patient.
• the End-of-treatment Visit may be the same visit as the first visit in the Extension Treatment Period. During this period, tumor progression will be evaluated every 12 weeks. Safety will be evaluated continuously and plasma samples for assessment of octreotide concentration will be taken. Patient-reported treatment satisfaction will be assessed using a general questionnaire and health-related quality of life parameters will be assessed by PROs.
• Patients may self-administer CAM2029 or have CAM2029 administered by their partner.
• the feasibility of self- or partner-administration of CAM2029 will be assessed by a trained trial personnel before self- or partner administration of CAM2029 once weekly may be performed. If CAM2029 is not self- or partner-administered, trial personnel will perform the administrations at the clinic. Self- or partner-administration at home is allowed after 3 supervised and successful administrations.
• the eCRF should be completed, giving the date and reason for stopping the treatment. If a withdrawal occurs, or if the patient fails to return for visits, the Investigator must determine the primary reason for a patient’s premature withdrawal from the trial and record this information on the End-of-extension-treatment eCRF page. The End-of-extension-treatment Visit is not considered the end of the trial.
• Next-line therapy may be started after the End-of-extension-treatment Visit at the Investigator’s discretion.
• the reason for trial completion should be recorded in the eCRF. If a patient starts a new anti-neoplastic therapy before progression, every attempt should be made to perform tumor evaluation until disease progression. All n p w anti-neoplastic therapies given after the last dose of the IMP must be recorded in the eCRF until disease progression, death, lost to follow-up, or withdrawal of consent occur.
• Survival information can be obtained via phone, and information will be documented in the source documents and relevant eCRFs.
• the target population in the current trial comprises adult patients with histologically confirmed, advanced (unresectable and/or metastatic), and well-differentiated NET of presumed GEP origin.
• SSAs octreotide and lanreotide
• NET NET of presumed GEP origin.
• SSAs octreotide and lanreotide
• Grade 3 NET there is currently no standard of care for patients with well- differentiated, Grade 3 NET.
• use of SSA can be considered.
• PFS defined as the time from randomization to the first documented progression or death (whichever occurs first)
• PFS is a recommended primary endpoint for NET trials (33) and has been used in many NET trials investigating effects on tumor proliferation (15, 16, 21, 23). This endpoint requires smaller sample sizes and shorter trials as compared to e.g. overall survival.
• the primary PFS endpoints will be assessed by a BIRC using standard criteria (RECIST 1.1).
• RECIST 1.1 As a secondary endpoint, PFS assessed by local Investigators will also be evaluated.
• Other secondary efficacy endpoints in the trial include commonly used endpoints in NET trials, such as overall survival, overall response rate (ORR), disease control rate (DCR), and time to tumor response.
• octreotide plasma concentration and the need for symptomatic rescue treatment will be assessed in the trial and the proportion of patients/partners who are judged competent to self- or partner-administer CAM2029 will be evaluated. Health- related quality of life and patient satisfaction with treatment will be assessed using selected PROs.
• PFS-ext defined as the time from date of randomization to documented progression or death from any cause in the Extension Treatment Period, whichever occurs first
• PFS2 defined as time from date of randomization to documented progression as per RECIST 1.1 on next-line therapy or death from any cause, whichever occurs first
• the immunogenicity of CAM2029 will be assessed.
• the selection of the CAM2029 dose is based on the results of completed Phase 1 and Phase 2 trials in healthy volunteers and in patients with acromegaly or NET.
• a dose of 20 mg CAM2029 every 4 weeks has been identified as a suitable starting and maintenance dose for the ongoing Phase 3 trials in patients with acromegaly.
• NET a higher octreotide exposure is proposed to reach therapeutic concentrations.
• 20 mg of CAM2029 will be administered every 2 weeks until the patient experiences PD. Thereafter, the patient will have the option to increase the dosing frequency to 20 mg CAM2029 once weekly, if further increased dosing with CAM2029 is considered possibly beneficial for the patient.
• Predicted octreotide plasma concentrations for the treatment regimens 20 mg CAM2029 every 2 weeks and 20 mg CAM2029 once weekly are shown in FIG. 2 and predicted PK parameters at steady state are presented in Table 3. Observed PK data for 30 mg CAM2029 every 4 weeks (trial HS-11-411) are added in FIG. 2 and Table 3, as a comparison. The predicted Cmax,ss for 20 mg CAM2029 every 2 weeks (18 ng/mL) and 20 mg CAM2029 once weekly (22 ng/mL) are below the observed C ma x, S s for 30 mg CAM2029 every 4 weeks (geometric mean 28.5 ng/mL, trial HS-11-411), in which such exposure was well tolerated by the subjects.
• the predicted Cmax,ss values are below the C ma x, S s at the no-observed-adverse-effect- level (NOAEL) of 60 mg CAM2029 every 4 weeks in the 6-month study in dogs (mean C ma x, S s of 101.6 ng/mL; study TO-07-278).
• the predicted systemic exposure (AUC ss ), described as average plasma concentration during a dosing interval at steady state (C av,ss AUC ss /dose interval), for 20 mg CAM2029 every 2 weeks (6.4 ng/mL) is somewhat higher than that observed for 30 mg CAM2029 every 4 weeks (geometric mean 5.09 ng/mL, Table 3).
• Table 3 Observed or predicted PK parameters of octreotide after administration of 2 doses of 20 mg CAM2029 every 2 weeks, 4 doses of 20 mg CAM2029 once weekly, and 1 dose of 30 mg CAM2029 (trial HS-11-411) to healthy volunteers
• AUC ss area under the plasma concentration-time curve at steady state
• Cav ss : average plasma concentration during a dosing interval at steady state
• C max ss : maximum plasma concentration at steady state
• PK pharmacokinetic
• qlw once weekly
• q2w every 2 weeks
• q4w every 4 weeks
• the overall survival follow-up will end at the latest 2 years after the primary PFS analysis. At that time, the final analysis of trial data will be conducted. All available data from all patients up to that cut-off date will be analyzed. [000327] The overall end of trial is defined as the last protocol-specified contact with the last patient ongoing in the trial.
• Previous treatment with more than 1 cycle (where 1 cycle means ⁇ 28 days on treatment) of targeted therapies such as mTOR inhibitors (e.g. sirolimus, temsirolimus, or everolimus) or vascular endothelial growth factor inhibitors (e.g. sunitinib, lenvatinib, or cabozantinib), or more than 1 cycle of chemotherapy or interferon for GEP -NET
• mTOR inhibitors e.g. sirolimus, temsirolimus, or everolimus
• vascular endothelial growth factor inhibitors e.g. sunitinib, lenvatinib, or cabozantinib
• Active hepatitis Patients with no significant viral load, no acute signs of inflammation, and no clinical necessity for therapy are allowed, at the Investigator’s discretion b.
• Known gallbladder or bile duct disease, or acute or chronic pancreatitis c.
• Symptomatic cholelithiasis d.
• Clinically active or chronic liver disease, including liver cirrhosis of Child-Pugh class B or C Patients with poorly controlled diabetes, as evidenced by hemoglobin Ale (HbAlc) >8.0% Cardiac history or current diagnosis of cardiac disease indicating significant risk of safety for patients participating in the trial, such as uncontrolled or significant cardiac disease, including any of the following: a.
• Presence of active or suspected acute or chronic uncontrolled infection including active human immunodeficiency virus (HIV) infection, or with a history of compromised immune system
• Screen failures are defined as patients who consent to participate in the trial but are not subsequently randomized in the trial.
• a minimal set of screen failure information is required to ensure transparent reporting of screen failure participants to meet the publishing requirements of the Consolidated Standards of Reporting Trials and to respond to queries from regulatory authorities.
• Minimal information includes demography, eligibility criteria, possible other screen failure information, and any SAE.
• Patients who do not meet the eligibility criteria may be screened one more time and should receive a new screening number. If the patient is re-screened, the informed consent form (ICF) must be re-signed before re-screening procedures are performed. The eCRF should clearly indicate that the patient has been re-screened and the original screening number. However, if e.g. abnormal laboratory findings are considered by the Investigator to be temporary and not reflective of the patient’s usual state, the patient may be re-tested once within the screening period (keeping the original screening number). The decision to re-screen or re-test will be made on a case by case basis by the Investigator in consultation with the Medical Monitor. Applicable screening information and results obtained during the first screening may be used for eligibility assessments during re-screening.
• ICF informed consent form
• ATG autogel
• IM intramuscular
• IMP investigational medicinal product
• IR immediate-release
• LAR long-acting release
• NIMP non-investigational medicinal product
• SC subcutaneous
• CAM202920 mg will be administered once weekly as an SC injection. Rescue medication may also be used in the same way as in the Randomized Treatment Period.
• CAM2029 may be self-administered by the patient or administered by the patient’s partner.
• a “partner” may be the patient’s spouse, parent, child, or sibling etc. or any other person that the patient trusts to administer the injection.
• Self- or partner-administration of CAM2029 in the abdomen or thigh is allowed after appropriate training under the supervision of adequately trained trial personnel.
• the first self- or partner-administration should preferably be performed on Day 1.
• the trial personnel will document that the patient or partner understands the administration instructions, performs the injection correctly, and administers a full dose (see the Manual of Procedures for a checklist of the feasibility of self- or partner-administration). If the patients or their partners are considered competent to administer CAM2029, they may continue with the self- or partner-administration. If CAM2029 is not self- or partner-administered, trial personnel will administer CAM2029. If the partner who is administering CAM2029 is replaced, the new partner must undergo appropriate training, as described above.
• the first 3 doses will be self- or partner-administered at the clinic. Starting from the second dose in Month 2, CAM2029 may be self- or partner-administered at home on Day 15 of each month.
• the Investigator will dispense an appropriate number of investigational treatment packages for home administrations. The patients will use a patient diary to record the dose(s), date(s), and exact time(s) of administration, the injection site, and who performed the injection. At the next visit, the patients will return the used syringes and packaging to the trial personnel. The trial personnel will document the administration dates and confirm whether the full dose was administered. Detailed instructions will be provided separately. Patients will be asked to return any unused medication and packaging on a regular basis or at the End-of-treatment Visit at the latest to ensure proper drug accountability.
• a missed dose during treatment every 2 weeks is defined as a case when the full dose is not taken ⁇ 3 days from the scheduled day of the dosing. If a dose is missed, the patient should continue treatment with the next scheduled dose as planned.
• Extension Treatment Period Patients who self- or partner-administered CAM2029 20 mg every 2 weeks in the Randomized Treatment Period may continue to self- or partner-administer CAM202920 mg once weekly during the Extension Treatment Period. CAM2029 will be injected in the abdomen or in the thigh. Self- or partner-administration at home may be performed from the second dose in Month 1.
• the first self- or partner-administration of CAM2029 in the Extension Treatment Period should preferably be performed on Day 1 of the Extension Treatment Period. Trained trial personnel will document that the patient or partner understands the administration process, performs the injection correctly and administers a full dose (see detailed instructions above). The first 3 doses will be self- or partner-administered at the clinic. Starting from the fourth dose in Month 1, the patients may self-administer CAM2029 or receive the administration of CAM2029 from their partner at home.
• CAM2029 is administered at home during the Extension Treatment Period, the Investigator will dispense an appropriate number of investigational treatment packages for home administrations.
• the patients will record the dose(s), date(s) and exact time(s) of administration, the injection site and who performed the injection in a patient diary.
• the patients will return the used syringes and packaging to the trial personnel.
• the trial personnel will document that the patient or partner understands the administration instructions, performs the injection correctly, and administers a full dose. Detailed instructions will be provided separately. Patients will be asked to return any unused medication and packaging on a regular basis or at the End-of-extension-treatment Visit at the latest to ensure proper drug accountability.
• a missed dose during the once-weekly treatment is defined as a case when the full dose is not taken ⁇ 2 days from the scheduled day of the dosing. If a dose is missed, the patient should continue treatment with the next scheduled dose as planned.
• Octreotide LAR 30 mg will be administered every 4 weeks in the Randomized Treatment Period by a trained HCP.
• Octreotide LAR will be administered as an IM injection in the gluteus as per local practice and regulation. Alternating injections sites (right and left gluteus) should be used for the injections.
• Lanreotide ATG 120 mg will be administered every 4 weeks in the Randomized Treatment Period by a trained HCP.
• Lanreotide ATG will be administered as a deep SC injection in the gluteus or thigh as per local practice and regulation. Alternating injections sites (right and left gluteus or thigh) should be used for the injections.
• Octreotide IR as rescue medication may be self-injected for symptom rescue as per local practice during the trial and at the Investigator’s discretion, up to a maximum of 600 ⁇ g per day. Patients who are unable to achieve symptom control at the maximum allowed dose are advised to contact their Investigator for guidance. Administration of octreotide IR must be avoided within 24 hours before each clinic visit. [000375] The patients will record the dose(s), date(s), and exact time(s) of administration of octreotide IR in a patient diary.
• the Sponsor will provide octreotide LAR and lanreotide ATG through a central vendor, who will obtain the marketed drug and label it in accordance with applicable regulatory requirements.
• the vendor will be responsible for distribution of octreotide LAR and lanreotide ATG to the trial sites.
• the IMP (CAM2029 and comparator products) must be received by designated personnel at the trial site, handled and stored safely and properly, and kept in a secured location to which only the Investigator and designated trial personnel have access.
• the IMP should be stored in accordance with the storage conditions specified on the labels.
• Patients will be recruited by methods chosen at the discretion of the sites. Each site will maintain a screening log of all screened patients.
• Tumor origin pancreas versus other GI origin
• the Investigator (or his/her designated personnel) will maintain an Injection Log detailing the dates and quantities of IMP administered to each patient, as well as an Accountability Log detailing dates and quantities of CAM2029 dispensed to and returned by each patient in case of administration at home.
• the monitor will verify drug accountability during the trial.
• CAM2029 will be self- or partner-administered or administered by designated trial personnel during the trial. Patients will be allowed to self-administer or to have CAM2029 administered by his/her partner from the first injection. Starting with the second injection in Month 2 in the Randomized Treatment Period or the fourth injection in Month 1 in the Extension Treatment Period (for patients who received comparator products in the Randomized Treatment Period), patients may self-administer or have CAM2029 administered by his/her partner at home. The patients will be given a diary for recording of the injections at home.
• a Product Quality Complaint is any written, electronic, or oral communication that alleges deficiencies related to device malfunctions or the identity, quality, stability, reliability, or safety of a product, including its labeling, delivery system, or packaging integrity.
• Any PQC discovered during the initial inventory of the IMP should follow the instructions provided on the receipt letter; no PQC should be filed for issues identified when opening or unpacking a shipment. Any PQC discovered after allocation of an IMP to a patient should be reported as a PQC. Subsequently, any observation of a PQC requires immediate notification within 24 hours after being made aware of the PQC, to the Sponsor via a completed and signed PQC form.
• Any IMP associated with a PQC should be quarantined and withheld until further direction is received from the Sponsor. Photographs or physical samples may be requested to support an investigation. The IMP must not be disposed.
• PQC information must be included on the Accountability Log or equivalent in the comments field. The monitor can assist in the event of questions relating to this process.
• PQC When enrolling patients into this trial it is the responsibility of the trial site to instruct patients not to use the IMP if they have a concern related to the IMP such as an issue with the labeling, IMP, or package integrity and to immediately report it using contact information provided on the patient ID card or on the ICF.
• the PQC is associated with an AE or an SAE, this should be indicated in the PQC form and the event recorded on the AE page of the eCRF. In case of an SAE, the event must be reported as described in Section [000551]
• the Sponsor will assess the PQC and use the information herein to monitor the patient’s safety and to improve the safety and performance of the product.
• the Sponsor is also responsible for notifying the relevant regulatory authorities and Market Authorization Holder of any PQC according to applicable legislation.
• the patient must notify the trial personnel about any new medications he/she takes after the start of the trial. All medications (other than the IMP and rescue medication) and significant non-drug therapies (including physical therapy, herbal/natural medications, and blood transfusions) administered during the trial must be listed on the concomitant medication page in the eCRF. The Investigator will determine if the concomitant medication(s) affects the patient’s eligibility to continue to participate in the trial.
• Supportive care agents and medications required to treat AEs or to manage cancer symptoms or concurrent diseases e.g. pain medications, pancreatic enzyme replacement, anti emetics, and anti-diarrheals are allowed.
• Octreotide IR may be used for symptom rescue at the Investigator’s discretion, see further information in Section [000372] Administration of octreotide IR must be avoided within 24 hours before each clinic visit.
• Dose adjustment of medicinal products such as beta blockers, calcium channel blockers, insulin and antidiabetic medicinal products, or agents to control fluid and electrolyte balance may be necessary during SSA administration.
• octreotide has been found to reduce the intestinal absorption of cyclosporin and to delay that of cimetidine (30).
• SSAs also increase the availability of bromocriptine (30, 34).
• SSAs might decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 (CYP) enzymes, which may be due to the suppression of growth hormone. Since it cannot be excluded that octreotide may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g. quinidine and terfenadine) should therefore be used with caution (30, 35).
• CYP3A4 cytochrome P450
• Palliative radiation is permitted if performed solely for bone pain relief but should not be delivered to a target lesion. If palliative radiotherapy is initiated after the start of IMP treatment, the reason for its use must be clearly documented and progression as per RECIST 1.1 must be ruled out.
• Anti -neoplastic therapy such as chemotherapy, targeted therapies (e.g. everolimus, sunitinib, and bevacizumab), PRRT, and interferon are not permitted until the End-of- treatment/End-of-extension-treatment Visit
• IMP treatment must be discontinued under the following circumstances:
• the patient is diagnosed with liver cirrhosis of Child-Pugh class C [000435] Re-challenge is not recommended when IMP treatment is discontinued due to the above criteria.
• hypokalemia ⁇ 3.5 mmol/L
• hypomagnesemia ⁇ 0.7 mmol/L
• clinically significant hypocalcemia confirmed by repeated testing that is either a new finding or accompanied by vomiting or diarrhea and not corrected by treatment
• a patient is free to withdraw his/her consent and discontinue participation in the trial at any time and for any reason.
• Patients who withdraw consent during a scheduled visit will be asked to complete that visit as the End-of-treatment/End-of-extension-treatment Visit. If they withdraw outside of a scheduled visit, they may be asked if they are willing to attend an End-of- treatment/End-of-extension-treatment Visit. The reason(s) for discontinuation will be appropriately documented.
• the Investigator will be trained about the importance of patient retention and steps to prevent missing data.
• the Investigator must maintain a record of all patients who discontinue from the trial before completion; the reason(s) for trial discontinuation will be documented. If a patient chooses to withdraw from the trial, the Investigator should make every effort to obtain and record the reason(s) for withdrawal, if possible, although the patient is not obligated to provide such a reason.
• visits or specific assessments may be conducted at a patient’s home or at a suitable alternative location by mobile qualified and delegated trial personnel. In such cases, the Investigator remains responsible for oversight and protocol procedure adherence. For this purpose, the terms “clinic visit” and “visit to the clinic” in this protocol may also refer to a remote visit.
• Table 5 Schedule of trial procedures and assessments for the Open-label Randomized Treatment Period and the post-treatment and survival follow-up periods
• the administration on Day 15 of each month is only applicable for patients randomized to the CAM2029 treatment group.
• patients may self- or partner-administer CAM2029 at home on Day 15 of each month (except for M3D15, which is a mandatory PK sample visit). If the patients are not administering CAM2029 at home, they may have the injections performed by a trial personnel, and the assessments outlined in italics in the table will be performed
• the Safety follow-up may be performed as a visit to the clinic or as a telephone call
• the visits on Day 8 and Day 15 of Month 3 are mandatory PK sampling visits for patients who receive CAM2029 or octreotide LAR.
• the assessments outlined in italics will be performed for these patients. Patients who receive lanreotide ATG do not need to perform the visits on M3D8 and M3D 15
• Screening Visit assessments should occur within 28 days before randomization, except for assessments marked with , which should occur within 7 days before randomization
• CAM2029 may be self- or partner-administered or the administrations may be performed by the trial personnel. The injections will be given SC in the abdomen or thigh. Home administration of CAM2029 may be performed from the second injection (Day 15) in Month 2
• Octreotide IR may be self -injected for symptom rescue but must be avoided within 24 hours before each clinic visit
• Plasma samples for octreotide measurements are only applicable for patients treated with CAM2029 or octreotide LAR
• samples will be taken at 0.5, 2, 5, 24 and 168 h.
• samples For patients receiving octreotide LAR, only the sample at 24 h will be taken
• the patient exit interview will be performed approximately 1 week from the End-of-treatment Visit as a phone interview, regardless if the patients proceed to treatment with CAM2029 once weekly in the Extension Treatment Period or continue directly to the Safety follow-up
• AE adverse event
• ATG autogel
• BMI body mass index
• CT computed tomography
• D Day
• ECG electrocardiogram
• ECOG Eastern Cooperative Oncology Group
• EORTC QLQ- C30 European Organization for Research and Treatment of Cancer’s Core Quality of Life Questionnaire
• FDG fluorodeoxy glucose
• GEP-NET gastroenteropancreatic neuroendocrine tumors
• HIV human immunodeficiency vims
• IMP investigational medicinal product
• IR immediate release
• Ki-67 a nuclear antigen
• LAR long-acting release
• M Month
• MRI magnetic resonance imaging
• NIMP non-investigational medicinal product
• PET positron emission tomography
• PGI-S Patient Global Impression of Severity
• PRO patient reported outcome
• QLQ-GINET21 Quality of Life Questionnaire - Neuroendocrine Carcinoid Module
• Table 6 Schedule of trial procedures and assessments for patients participating in the optional Open-label Extension Treatment Period
• the Day 1 Visit of Month 1 in the Extension Treatment Period may be the same as the End-of -treatment Visit in the Randomized Treatment Period. If this is the case, assessments that were performed at the End-of-treatment Visit do not need to be repeated
• Patients may self- or partner-administer CAM2029 at home on Days 8, 15 and 22 of each month. If the patients are not self- or partner-administering CAM2029 at home, they may have the injections performed by a trial personnel and the assessments outlined in italics in the table will be performed
• the Safety follow-up may be performed as a visit to the clinic or as a telephone call
• the visits on Day 8 and Day 15 of Month 1 are mandatory visits for patients who received octreotide LAR or lanreotide ATG in the Randomized Treatment Period. These patients may self- or partner-administer CAM2029 or have the injections performed by a trial personnel.
• the first self- or partner-injection should preferably be made on Day 1 of Month 1
• CAM2029 may be self- or partner-administered or the administrations may be performed by trial personnel. The injections will be given SC in the abdomen or thigh. For patients who already self- or partner-administered CAM2029 in the Randomized Treatment Period, home administration of CAM2029 may be performed from the second injection (Day
• C AM2029 may be performed from the fourth injection (Day 22) in Month 1
• Octreotide IR may be self-injected for symptom rescue but must be avoided within 24 hours before each clinic visit Patients who have had a complete gallbladder removal do not need to undergo gallbladder ultrasounds
• AE adverse event
• ATG autogel
• BIRC Blinded Independent Review Committee
• E Extension
• ECG electrocardiogram
• ECOG Eastern Cooperative Oncology Group
• EORTC QLQ-C30 European Organization for Research and Treatment of Cancer’s Core Quality of Life Questionnaire
• FU follows-up; h: hour; HbAlc: hemoglobin Ale; IMP: investigational medicinal product; IR: immediate release; LAR: long-acting release; ME: Month in Extension Period; NIMP: non-investigational medicinal product; PD: progressive disease;
• PGI-S patient Global Impression of Severity; PRO: patient-reported outcome;
• QLQ-GINET21 Quality of Life Questionnaire - Neuroendocrine Carcinoid Module;
• QTcF QTc interval corrected by Fridericas’s formula
• SAE serious adverse event
• SC subcutaneously
• SF-36 Short Form-36
• TSQM Treatment Satisfaction Questionnaire for Medication
• Data on GEP-NET will include diagnosis and extent of cancer (including staging at trial entry), mitotic rate, and Ki-67 index.
• GEP-NET A complete treatment history for GEP-NET will be recorded, including prior anti neoplastic therapies as treatment for cancer and prior embolization or ablative interventions.
• a physical examination including all major body systems will be performed at screening and at the time points indicated in Table 5 and Table 6.
• Clinically significant findings that were present before screening must be included on the Medical History eCRF page.
• Clinically significant findings that begin or worsen after screening must be recorded on the AE page of the eCRF.
• Weight, weight, and BMI will be measured/calculated at screening. Weight will also be measured at the time points indicated in Table 5 and Table 6.
• Somatostatin-receptor imaging will be performed in conjunction with the screening using any imaging modality available, e.g. octreotide scintigraphy or [ 68 Ga]-DOTATATE PET/CT. Any preexisting assessment done as part of standard of care within 3 months prior to randomization can be used. The date of assessment and information on somatostatin-receptor expression will be collected in the eCRF.
• imaging modality e.g. octreotide scintigraphy or [ 68 Ga]-DOTATATE PET/CT.
• Any preexisting assessment done as part of standard of care within 3 months prior to randomization can be used. The date of assessment and information on somatostatin-receptor expression will be collected in the eCRF.
• Women are considered post-menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e. appropriate age, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), or tubal ligation at least 6 weeks before screening.
• oophorectomy alone, the woman is considered not to be of childbearing potential only when her reproductive status has been confirmed by follow-up hormone level assessment.
• Tumor imaging assessments should comprise CT (strongly preferred) or MRI of the chest, abdomen, and pelvis. MRI should primarily be used when CT is contraindicated. Chest X- ray may be used for assessment of lung metastases in exceptional cases and only after the Sponsor’s confirmation. The same imaging technique regarding modality and contrast should be used for a patient throughout the trial. If somatostatin-receptor imaging is performed using scintigraphy, a whole-body bone scan (alternatively, a whole-body MRI) must be acquired at screening to assess bone metastases. Patients with bone metastases at baseline will undergo further assessments of bone lesions performed at protocol-scheduled time points for tumor assessments and as per institutional practice.
• the first tumor imaging assessment will be performed during the screening period. Any CT, MRI or whole-body bone scan assessments already completed during the regular work-up of the patient within 28 days prior to randomization, including before signing the ICF at screening, can be considered as the baseline images for this trial, if they fulfil the imaging requirements.
• CT computed tomography
• FDG fluorodeox glucose
• ICF informed consent form
• IMP investigational medicinal product
• MRI magnetic resonance imaging
• NET neuroendocrine tumors
• PD progressive disease
• PET positron emission tomography
• Tumor evaluation is also required for patients whose previous tumor assessment did not demonstrate PD and was done more than 21 days before the End-of-treatment End-of-extension-treatment Visit b
• PFS is defined as the time from the date of randomization to the date of the first documented disease progression as per RECIST 1.1 or death due to any cause, whichever occurs first, as assessed by the BIRC.
• the BIRC at the central imaging core laboratory will verify the PD.
• the imaging core laboratory will expedite verification of radiologic PD to the trial site and to the Sponsor. Further details on the central confirmation of PD will be provided in an imaging review charter.
• the Investigator While the Investigator is waiting for the results of the BIRC review, the patient must continue to receive IMP treatment unless the Investigator believes that continuation would be detrimental to the patient’s well-being.
• PFS2 is defined as the time from date of randomization to the date of documented progression on next-line therapy (not including treatment with CAM2029 in the Extension Treatment Period) as per RESIST 1.1 or death from any cause, whichever comes first.
• the disease progression will be determined based on Investigator assessment of progression.
• subsequent anti -neoplastic therapies including start/end date, reason for discontinuation and date of disease progression will be captured in the eCRF.
• PFS-ext is the time from date of randomization to the date of documented progression on CAM2029 20 mg once weekly as per RECIST 1.1 or death from any cause, whichever comes first, in the Extension Treatment Period.
• PFS-ext the disease progression will be determined based on BIRC assessment of progression.
• the PROs should be administered in the patient’ s local language. Only PROs validated in the local language and provided by the Sponsor will be used in this trial.
• the PROs should preferably be administered at the beginning of the trial visit before any tests or treatments are performed and before the patient receives results from any tests to avoid biasing the patient’s perspective.
• Patients should be given enough space and time to complete all trial questionnaires and all questionnaires should be reviewed for completeness. If missing responses are noted, patients should be encouraged to complete any missing responses.
• Investigators should not encourage the patient to change responses reported in the questionnaires. If a patient refuses to complete a questionnaire, this should be documented in the source records. A patient’s refusal to complete trial questionnaires is not a protocol deviation.
• EORTC QLQ-C30 The European Organization for Research and Treatment of Cancer’s Core Quality of Life Questionnaire (EORTC QLQ-C30, version 3.0) is recognized as a reliable and valid measure that is used to assess generic quality of life for cancer patients.
• the EORTC QLQ-C30 contains 30 items and comprises both multi-item scales and single-item measures. These include 5 functional scales (physical, role, emotional, cognitive, and social functioning), 3 symptom scales (fatigue, nausea/vomiting, and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial impact), and a global health status/quality of life scale (37).
• the scores of all scales and single-item measures range from 0 to 100.
• a high scale score represents a higher response level.
• a high score for a functional scale represents a high/healthy level of functioning
• a high score for the global health status/quality of life represents a high quality of life
• a high score for a symptom scale/item represents a high level of symptomatology/problems. All scoring will follow the scoring procedures defined by the EORTC Scoring Manual (38).
• the EORTC Quality of Life Questionnaire - Neuroendocrine Carcinoid Module (QLQ-GINET21) is a disease-specific module that may be used with the EORTC QLQ-C30 and that has been developed for use in patients with Gl-related NET, whose disease stages and treatments vary. This module comprises 21 questions assessing disease symptoms, side effects of treatment, body image, disease-related worries, social functioning, communication, and sexuality. This module has been developed according to the EORTC guidelines and has been shown to be a valid and responsive disease specific tool for assessing quality of life in NET of the gut, pancreas, and liver (39).
• the Short Form-36 (SF-36) is a widely used standardized instrument with strong psychometric properties (40).
• the SF-36 will be used to assess self-perceptions of general health functioning across multiple dimensions (including general, physical, and emotional/psychiatric functioning). Higher scores indicate better quality of life.
• the SF-36 can be used in clinical practice and research, health policy evaluations, and general population surveys. It comprises a physical component summary and a mental component summary, both for which a higher score indicates better health status.
• the Patient Global Impression of Severity (PGI-S) assessment tool is included to assess the patients’ overall perception of their condition.
• the PGI-S is a 1-item questionnaire using a balanced Likert scale that asks the patient to rate the severity of a specific condition on a single state, 5-point, categorical scale.
• the PGI scales were modelled on the Clinical Global Impression scales developed in the 1970s (41). They are simple, direct and easy to use and can be tailored to specific conditions and disease parameters.
• TQM Treatment Satisfaction Questionnaire for Medication
• the TSQM Version 1.4 will be used to compare the patients’ satisfaction with CAM2029 or the comparator treatment during the trial.
• the questionnaire has 4 domains (effectiveness, side effects, convenience, and global satisfaction), each comprising 3 to 4 items. Responses are evaluated on a 5- to 7-point scale for each item. The calculation of domain scores will be done according to the instrument manual. All domain scores range from 0 to 100. Higher scores indicate a better outcome from the patient’s perspective.
• the TSQM questionnaire and instrument manual will be included in the Manual of Procedures.
• the TSQM questionnaire will be completed at the beginning of the scheduled trial visits according to Table 5 and Table 6, before the Investigator conducts any clinical assessment.
• the interview will be conducted via phone by an external designated qualitative trial interviewer from a designated vendor and will last for up to 60 minutes.
• the trial personnel will collect contact information for the patient and notify the interviewer to schedule the interview. Any contact information will be stored in an encrypted database accessible only to relevant trial personnel and the external interviewers.
• All blood samples for analyses of octreotide will be taken by either direct venipuncture or indwelling cannula inserted in a forearm vein. Blood samples (2.5 mL) will be collected to yield 1 mL plasma for analysis of octreotide plasma concentration.
• Plasma concentrations of octreotide will be measured using a validated liquid chromatography-tandem mass spectrometry assay with a lower limit of quantification of approximately 0.0286 ng/mL.
• An AE (synonym: adverse experience) is defined as any untoward medical occurrence associated with the use of a drug in humans, in a patient or clinical trial subject administered a trial treatment and which does not necessarily have a causal relationship with this treatment (i.e. whether or not considered drug-related).
• An AE can, therefore, be any unfavorable and unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally associated with the use of a trial treatment, whether or not considered related to the trial treatment. Patients will be instructed to contact the Investigator at any time after enrollment if any symptoms develop.
• An ADR is any untoward and unintended response to a trial treatment assessed as related to any dose administered. AEs or SAEs assigned a causality assessment by the Investigator of “probably related” or “possibly related” will be considered by the Sponsor to be related for the purpose of defining ADRs and thereby also expedited reporting.
• An AE is considered “unexpected” if the nature, severity, or outcome is not consistent with the reference safety information.
• An SAE is any untoward medical occurrence that at any dose: • Results in death
• the Investigator is responsible for ensuring that all AEs and SAEs are recorded on the AE page of the eCRF and reported to the Sponsor. AEs will be assessed from the time of signing the ICF until the Safety Follow-up Visit. If there is any doubt as to whether a clinical observation is an AE, the event should be reported.
• Abnormal laboratory values shall be recorded as AEs if assessed as clinically significant by the Investigator.
• Laboratory abnormalities that are associated with an already reported medical condition will not be reported as separate AEs but will be used to assess the associated medical condition (e.g. increased neutrophil levels in case of reported infection or increased glucose in a patient with diabetes).
• Information to be collected includes trial treatment, type of event, time of onset, dosage, Investigator-specified assessment of seriousness, severity, and relationship to trial treatment, and time of event resolution, as well as any required treatment or evaluations, and outcome.
• AEs resulting from concurrent illnesses, reactions to concurrent illnesses or reactions to concurrent medications must also be reported. All AEs should be followed until they have reached a final outcome or to the Safety Follow-up Visit, whichever comes first (see further details in Section [000562]).
• the Medical Dictionary for Regulatory Activities (MedDRA) will be used to code all AEs.
• Any medical condition that is present at the time that the patient is screened but does not deteriorate thereafter should not be reported as an AE. However, if it deteriorates at any time during the trial, it should be recorded as an AE. Disease progression (including fatal outcomes), if documented by use of appropriate method (RECIST 1.1), should not be reported as an AE/SAE.
• the Sponsor is responsible for notifying the relevant regulatory authorities of any SAEs according to applicable legislation.
• the Investigator is responsible for notifying the Independent Ethics Committee (IEC)/Institutional Review Board (IRB) directly, as per IEC/IRB requirements.
• Severity is defined as a measure of the intensity of an AE or SAE and will be assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). If CTCAE grading does not exist for an AE, the severities of mild, moderate and severe, corresponding to Grades 1 to 3, will be used.
• the outcome “recovering” can be used as the final outcome for events that are stabilized (i.e. no further worsening is expected) and that the Investigator expects to resolve over time.
• the outcome “not recovered” can be used as the final outcome for events that are not expected to resolve over time (e.g. cancer).
• ADRs reported during octreotide therapy include GI disorders, nervous system disorders, hepatobiliary disorders, and metabolism and nutritional disorders.
• the most commonly reported ADRs in clinical trials with octreotide administration were diarrhea, abdominal pain, constipation, nausea, flatulence, headache, cholelithiasis, hyperglycemia and injection-site reactions.
• Other commonly reported ADRs were dizziness, biliary sludge, thyroid dysfunction (e.g., decreased thyroid stimulating hormone, decreased total T4, and decreased free T4), loose stools, impaired glucose tolerance, vomiting, asthenia, and hypoglycemia (30).
• Bradycardia has been reported in patients treated with octreotide with frequency ranging between 1% and 10% (30). Therefore, dose adjustment of medicinal products such as beta blockers, calcium channel blockers, or agents to control fluid and electrolyte balance may be necessary during octreotide administration.
• octreotide may affect glucose regulation. Post-prandial glucose tolerance may be impaired. In some instances, persistent hyperglycemia may be induced as a result of chronic administration. Hypoglycemia has also been reported (30).
• octreotide can affect glucose regulation, and insulin requirements may be reduced.
• Sandostatin IR administration resulted in increases in post-prandial glycemia in some subjects.
• a central laboratory will be used to analyze all laboratory evaluations. Details on the collections, shipment of samples, and reporting of results by the central laboratory will be provided separately. The results of the clinical safety laboratory assessments at screening must be reviewed before enrollment to assess the patient’s eligibility for the trial.
• ALP alkaline phosphatase
• ALT alanine aminotransferase
• AST aspartate aminotransferase
• GGT gamma glutamyl transferase
• HbAlc hemoglobin Ale
• HBsAg hepatitis B surface antigen
• HCV hepatitis C vims
• HIV human immunodeficiency vims
• INR international normalized ratio
• PCR polymerase chain reaction
• TSH thyroid stimulating hormone
• ULN upper limit of normal
• WBC white blood cells
• Blood samples for immunogenicity assessment of anti-drug antibodies for octreotide will be collected from patients treated with CAM2029 or octreotide LAR according to Table 5 and Table 6. The blood samples will be sent to a central laboratory. Detailed method descriptions of the immunogenicity assays will be provided separately.
• Women of childbearing potential will have a serum beta-human chorionic gonadotropin pregnancy test at screening. This will be performed by a central laboratory. The results of the pregnancy test at screening must be reviewed and confirmed to be negative before enrollment to assess the patient’s eligibility for the trial. Moreover, urine pregnancy test will be performed at the other visits, as indicated in Table 5 and Table 6. Urine pregnancy tests will be performed by dipstick locally. A positive pregnancy test requires immediate interruption of IMP treatment until the pregnancy is confirmed via a serum pregnancy test performed by a central laboratory. If confirmed positive, the patient must be discontinued from the trial.
• Vital signs consist of body temperature, blood pressure (systolic and diastolic, mmHg), pulse rate (beats per minute), and respiratory rate (breaths/min) and will be collected at the time points outlined in Table 5 and Table 6, following a resting period of at least 3 minutes. More frequent examinations may be performed at the Investigator’s discretion, if medically indicated. Vital signs will be measured before performing ECG and collecting blood samples.
• ECGs will be recorded and readings will be transmitted to a selected ECG central laboratory for analysis.
• Triplicate 12-lead ECG (3 ECG recordings at approximately 2-minute intervals) will be performed at each scheduled time point.
• the combined QTcF values from triplicate ECGs will be averaged to provide a single value for each patient.
• ECGs will be recorded at screening and at the time points outlined in Table 5 and Table 6.
• ECGs will be recorded after the patient has been resting in a supine position for at least 10 minutes. All ECGs should be recorded with the patient in the same physical position. ECGs will be recorded after vital signs and before blood samples for PK and clinical safety laboratory assessments.
• ECG assessments pre-dose and at the 24-hour time point have been selected to coincide with trough concentrations and near Cmax of octreotide for CAM2029, based on PK results from trial HS-11-411. If at any visit QTcF >481 msec is observed, the procedures for QT- prolongation management described in Section [000760], Appendix 1 must be considered. [000598] All ECG assessments will initially be assessed by the Investigator/qualified physician for any findings that require immediate medical attention. All ECGs will also be read by an ECG central reader. The clinical significance of any ECG findings will be determined by the Investigator, including after the central reading result is available. However, only ECG results provided by the central reader will be recorded in the clinical database.
• Clinically significant abnormalities present at screening should be reported on the Medical History eCRF page. Clinically significant findings must be discussed with the Sponsor before enrolling the patient in the trial. New or worsened clinically significant findings occurring after screening must be recorded on the AE page of the eCRF.
• Gallbladder ultrasounds will be performed locally at visits indicated in Table 5 and Table 6. Patients with symptomatic cholelithiasis at screening will be excluded from participating in the trial (refer to Section [000334]). Information on the presence and location of gallstones, gallbladder sludge, and biliary dilatation will be recorded in the appropriate eCRF page.
• Historical gallbladder ultrasound performed within 3 months before screening may be used as baseline measurement. If such a gallbladder ultrasound is available, the screening gallbladder ultrasound does not need to be performed.
• the patients and their partners will have the possibility to administer CAM2029 by themselves (after appropriate training and the option of simulated injection).
• the first self- or partner-administration should preferably be performed at the first injection. Qualified trial personnel will supervise the first 3 administrations and assess the patient’s/partner’s ability to successfully administer CAM2029 using a checklist based on assessments used in previous studies on SSAs (44, 45), see the Manual of Procedures.
• the qualified trial personnel will train the patient or their partner, and the training is successful, a supervised self- or partner-administration according to the provided checklist can be performed.
• the patient or their partner may receive training in administration of CAM2029 for a maximum of 3 times (3 visits).
• the training attempts and outcomes will be collected as “successful” or “unsuccessful” on the appropriate eCRF page.
• the trial personnel will continue the administration at the scheduled time points indicated in Table 5 and Table 6. If a patient or a partner is declared competent by the qualified trial personnel to successfully self-or partner-administer CAM2029, then he/she will have the possibility to continue to self- or partner-administer CAM2029 throughout the trial.
• a DMC will be established for this trial.
• the DMC will include a minimum of 2 physicians with appropriate disease area qualifications and 1 statistician.
• the DMC will conduct periodic reviews of safety data from the trial and will continuously review Grade 3 ADRs and serious ADRs.
• the DMC will recommend actions to the Sponsor, as appropriate.
• the DMC will be informed to what extent the data and analyses provided to them have been quality controlled. Members of the DMC will not be involved in other trial-related tasks.
• the DMC procedures are described in the DMC Charter.
• SAP statistical analysis plan
• a one-sided log rank test with an overall sample size of 280 patients (140 in the CAM2029 treatment group and 140 in the comparator treatment group) will achieve at least 85% power at a 0.025 (one-sided) significance level to detect a hazard ratio of 0.65 when the comparator group median time to progression or death is 18 months. Under the same assumptions, an observed hazard ratio of 0.755 or less should give a p-value ⁇ 0.025 (one-sided).
• the Randomized Treatment Period of the trial is planned to run for 48 months, of which patient accrual (entry) occurs in the first 18 months. The accrual pattern across time periods is assumed to be uniform. Given the assumptions, 194.3 events are needed. The event rate will be monitored during the trial. These calculations are neither adjusted for potential loss to follow up, nor for cross-over between treatments.
• the trial will also evaluate the treatment effect on overall survival. Assuming a median time of 80 months to death in the comparator group, the expected number of events at 48 (72) months is approximately 77 (114). With a true hazard ratio of 0.75 favoring treatment with CAM2029, the power is approximately 24% (33%) using a significance level of 0.025% one-sided. To control the overall significance level for the analysis of overall survival, a group sequential approach will be used where the treatment difference in overall survival will be tested with a stratified log rank test at 48 months, using a one-sided significance level of 0.72% and at 72 months, using a one-sided significance level of 2.26%.
• the primary efficacy analysis will be based on the Randomized Treatment Period of the trial and will compare patients randomized to receive CAM2029 against participants randomized to receive the comparator product.
• the primary estimand will be used for the analysis of the primary efficacy endpoint, PFS. It will be based on patients in the intent-to-treat (IIT), which is defined as all randomized patients who received at least 1 dose of IMP, analyzed according to their randomized treatment.
• IIT intent-to-treat
• the set of intercurrent events for this estimand consists of patients who withdraw from the trial prior to having met the primary efficacy endpoint. The intercurrent events will be handled using the treatment policy strategy and the potential absence of data following these patients’ withdrawal will be treated as missing (i.e. counted as not having met the criteria of PFS).
• Survival endpoints will be summarized by presenting the quartiles of the survival distribution and the survival rate at 12, 24, and 36 months in each treatment group, as well as the hazard ratio and 95% Cl for the comparison between the treatment groups.
• the IIT analysis set comprises all patients who have been randomized to a treatment group. Analyses based on this population will group patients according to the treatment they were randomized to receive, regardless of actual treatment received.
• the full analysis set comprises all randomized patients in the IIT analysis set who received at least 1 dose of the randomized IMP.
• the per protocol analysis set is defined as all patients in the IIT analysis set with no major protocol deviations that would impact the efficacy assessment. Detailed criteria defining this analysis set will be documented in the SAP.
• the PK analysis set will include all enrolled patients who were administered CAM2029 or octreotide LAR and for whom at least 1 post-dose plasma octreotide concentration result is available after the IMP administration.
• the PK analysis set will be used for analysis of PK data.
• the safety analysis set comprises all patients who were administered at least 1 dose of IMP. Analyses based on this population will group patients according to the actual treatment the patients received.
• ATC Anatomical Therapeutic Chemical
• the primary efficacy endpoint of the trial is PFS, which is defined as the time from the date of randomization to the date of the first documented disease progression as per RECIST 1.1 or death due to any cause, whichever occurs first, as assessed by the BIRC.
• PFS The primary efficacy endpoint, PFS, will be analyzed based on the data from the ITT analysis set in the Randomized Treatment Period, according to treatment group.
• the items that define the primary estimand are the following: a) Population of interest: Patients with GEP-NET as defined by the inclusion/exclusion criteria in the trial b) Variable (or endpoint) of interest: PFS, where the time point of progression or death will be used as a composite variable. Patients without progression and who are still alive will be censored at the end of the trial in the analysis c) Specification of how intercurrent events are reflected in the scientific question of interest:
• the proposed primary estimand is the entity defined to address the effect of treatment with CAM2029 or comparator product on reducing the risk of disease progression or death in patients with a diagnosis as defined by the inclusion and exclusion criteria.
• a stratified Cox regression model will be used to estimate the hazard ratio of PFS, along with the associated 95% Cl.
• the stratification will be based on the randomization stratification factors and the censoring will be calculated as for the log rank test. If the number of patients in a stratification group is small, this stratification factor will not be used in the log rank test.
• Overall survival is defined as the time from date of randomization to date of death due to any cause. If a patient is not known to have died, then overall survival will be censored at the last date the patient is known to be alive.
• An O’Brien Fleming stopping boundary (as implemented in PASS16) will be used for the analysis of overall survival. At the first analysis at the end of the Randomized Treatment Period, the observed p-value must be less than 0.0072 in order to conclude superior efficacy. If the trial continues to the final analysis approximately 72 months after the first randomization of a patient, the p-value that will be used to declare statistical significance at the final analysis will be 0.0226 (one-sided). By utilizing an O’Brien Fleming stopping boundary for efficacy, treatment with CAM2029 will be declared effective at interim only if overwhelming efficacy is demonstrated.
• ORR is defined as the proportion of patients with best overall response of complete response (CR) or partial response (PR), as per BIRC according to RECIST 1.1.
• the ORR will be analyzed with Cochran-Mantel- Haenszel test stratified by the randomized stratification factors.
• DCR is defined as the proportion of patients with a best overall response of CR, PR, or SD as per BIRC according to RECIST 1.1. DCR will be analyzed using similar model as for ORR.
• Time to tumor response is defined as the time from the date of randomization to the first documented response of either CR or PR as per BIRC according to RECIST 1.1 and will be analyzed in a similar model as for PFS.
• Duration of response only applies to patients whose best overall response is CR or PR according to RECIST 1.1 based on tumor-response data per BIRC review.
• the start date is the date of first documented response of CR or PR (i.e. the start date of response, not the date when response was confirmed), and the end date is defined as the date of the first documented progression or death due to underlying cancer. Patients continuing without progression or death due to underlying cancer will be censored at the date of their last adequate tumor assessment. Duration of response will be summarized by descriptive statistics for all patients in the IIT analysis set with confirmed best overall response of CR or PR.
• TSQM scores over time using all 4 domains of TSQM will be analyzed in an MMRM with factors for treatment, visit, and their interaction.
• PK/efficacy analyses The relationship between octreotide exposure and PFS will be explored. Other relevant endpoints (such as tumor response) may also be considered.
• PK/safety analyses The relationship between octreotide exposure and QTcF change from baseline will be explored using a linear mixed effect model, including octreotide concentration as a fixed effect and patient as a random effect. Other safety endpoints may also be considered.
• Plasma concentration data generated from this trial will be used together with data from other clinical trials in a population PK assessment.
• Patient demographics and baseline data e.g. age, sex, race, ethnicity, body weight, BMI
• relevant laboratory assessments will be explored as covariates, if appropriate.
• the broad principles outlined in the FDA “Guidance for Industry: Population Pharmacokinetics” (48) will be followed during the population PK analysis along with any applicable internal Guidance and Standard Operating Procedures. The results from the population PK analysis will be presented in a separate report.
• Pre-treatment period from the day of the patient’ s informed consent to the day before first dose of IMP
• Randomized Treatment period from day of first dose of IMP to Day 56 after last dose of IMP (i.e. Safety Follow-up) or to start of the Extension Treatment Period (if the patient proceeds to that period)
• Post-treatment period starting on Day 57 after last dose of IMP
• TEAEs treatment-emergent AEs
• An overview of all TEAEs including severity, relationship to the IMP, injection site AEs, SAEs, and AEs leading to withdrawal or death will be presented by treatment group, treatment, and overall.
• TEAEs will be summarized by MedDRA system organ class and preferred term, displaying number of patients in the group, number, and percentage of patients having the AE, as well as the number of AEs. Furthermore, AEs will be summarized according to severity, relationship, outcome, and seriousness.
• summary tables will be prepared for TEAEs with an incidence of at least 5% or lower threshold as applicable for reporting.
• CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher.
• results will be categorized as low/normal/high based on laboratory normal ranges.
• PFS-ext is defined as the time from date of randomization to the date of documented disease progression as per RECIST 1.1 or death from any cause, whichever comes first, in the Extension Treatment Period.
• disease progression will be determined based on BIRC assessment of progression.
• PFS-ext will be analyzed using a log rank test and a stratified Cox model, with the same conventions as those of the primary efficacy analysis of PFS.
• the treatment effect will be summarized by the hazard ratio with its 95% Cl.
• PFS2 is the time from date of randomization to the date of documented progression on next-line therapy as per RECIST 1.1 or death from any cause.
• the documented progression on next-line therapy will be based on local Investigator assessment of PD.
• PFS2 will be analyzed using a log rank test and a stratified Cox model, with the same conventions as those of the primary efficacy analysis of PFS (see Section [000659]).
• the treatment effect will be summarized by the hazard ratio with its 95% Cl.
• Patient interview data will be analyzed by trained qualitative researchers. These analyses involve reviewing field notes, transcripts, and data-collection forms to identify patterns found in the interview data to and facilitate description of the themes and relative importance of concepts based on participants’ experiences.
• Quantitative data such as responses to close-ended questions or ranking exercises, are usually descriptive. Meaningful change will be established using concept elicitation and cognitive debriefing techniques.
• Time to definitive deterioration in ECOG performance status is defined as the time from the date of randomization to the date when ECOG performance status has definitively deteriorated by at least 1 category compared with baseline. Deterioration is considered definitive if there is no subsequent improvement in ECOG performance status back to the baseline category or above. Patients will be censored if no definitive deterioration in ECOG performance status is observed before the first to occur between: (i) the analysis cut-off date, and (ii) the date when a next-line therapy is started. The censoring date will be the date of the last performance status assessment prior to cut-off/start of next-line therapy.
• Time to definitive deterioration in ECOG performance status will be analyzed for the IIT analysis set according to the randomized treatment group and strata assigned at randomization. Kaplan-Meier curves, medians, and 95% CIs of the medians will be presented for each treatment group. The hazard ratio for the time to definitive deterioration in ECOG performance status will be calculated along with its 95% Cl using a stratified Cox model.
• Exposure and compliance will be calculated per patient and summarized descriptively.
• the duration of exposure in weeks will be summarized by means of descriptive statistics using the safety analysis set.
• the number of injections received may also be summarized.
• [000752] The number of patients with dose delays or permanent discontinuation of IMP and the reasons will be summarized by treatment group and all dosing data will be listed.
• Gastrointestinal neuroendocrine tumors treated with high dose octreotide-LAR a systematic literature review. World J Gastroenterol. 2015;21(6): 1945-55. Eriksson B, Renstrup J, Imam H, Oberg K. High-dose treatment with lanreotide of patients with advanced neuroendocrine gastrointestinal tumors: clinical and biological effects. Ann Oncol. 1997;8(10): 1041-4. Faiss S, Rath U, Mansmann U, Caird D, Clemens N, Riecken EO, et al. Ultra-high-dose lanreotide treatment in patients with metastatic neuroendocrine gastroenteropancreatic tumors. Digestion. 1999;60(5):469-76.
• ICH Harmonised Tripartite Guideline E6 (R2): Guideline for Good Clinical Practice [Available from: [Internet] ema.europa.eu/en/documents/scientific-guideline/ich-e-6-r2- guideline-good-clinical-practice-step-5_en.pdf].
• ADR adverse drag reaction
• CTCAE Common Terminology Criteria for Adverse Events
• IMP investigational medicinal product
• Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma glutamyl transferase, prothrombin time/international normalized ratio and alkaline phosphatase
• liver imaging e.g. biliary tract potential metastases
• hepatotropic viral infection cytomegalovirus, Epstein-Barr virus, herpes simplex virus
• autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after consultation with specialist/hepatologist
• ECG electrocardiogram
• IMP investigational medicinal product
• PK pharmacokinetic
• QTcF QTc interval corrected by Fridericia’s formula
• PK parameters maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC) and average concentration during a dosage interval at steady state (C avg ) used herein are based on the population PK model.
• the plasma exposure in subject used for the PK model and used in the clinical studies were obtained as described by Karnes et al, Journal of Chromatography B, 879 (2011), 2081-2088.
• the model resulted in the predicted doses disclosed in Figure 2, and lead to the dosing regime disclosed herein.

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