EP1423693A1 - Erythropoietine et traitement de combinaison alpha anti-facteur de necrose des tumeurs - Google Patents

Erythropoietine et traitement de combinaison alpha anti-facteur de necrose des tumeurs

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Publication number
EP1423693A1
EP1423693A1 EP01959479A EP01959479A EP1423693A1 EP 1423693 A1 EP1423693 A1 EP 1423693A1 EP 01959479 A EP01959479 A EP 01959479A EP 01959479 A EP01959479 A EP 01959479A EP 1423693 A1 EP1423693 A1 EP 1423693A1
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EP
European Patent Office
Prior art keywords
epo
tnfα
study
week
patients
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01959479A
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German (de)
English (en)
Other versions
EP1423693A4 (fr
Inventor
Loretta Itri
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Pharmaceuticals Inc
Original Assignee
Ortho McNeil Pharmaceutical Inc
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Publication date
Application filed by Ortho McNeil Pharmaceutical Inc filed Critical Ortho McNeil Pharmaceutical Inc
Publication of EP1423693A1 publication Critical patent/EP1423693A1/fr
Publication of EP1423693A4 publication Critical patent/EP1423693A4/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1793—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • 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
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1816—Erythropoietin [EPO]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Definitions

  • Erythropoietin is a glycoprotein hormone produced by the kidney in response to tissue hypoxia that stimulates red blood cell production in the bone marrow.
  • the gene for erythropoietin has been cloned and expressed in Chinese hamster ovary (CHO) cells as described in United States Patent No. 4,703,008.
  • Recombinant human erythropoietin r- HuEPO, Epoetin alfa
  • r- HuEPO Epoetin alfa
  • Recombinant human erythropoietin acts by increasing the number of cells capable of differentiating into mature erythrocytes, triggering their differentiation and augmenting hemoglobin synthesis in developing erythroblasts (SB. Krantz, Blood (1991) 77: 419-434; BS. Beckman, M. Mason-Garcia, The Faseb Journal (1991) 5: 2958-2964).
  • Epoetin alfa has been evaluated in normal subjects as well as in subjects with various ' anemic conditions. Epoetin alfa induces a brisk haematological response in normal human volunteers, provided that adequate supplies of iron are available to support increased hemoglobin synthesis. A majority of trials have investigated the safety and effectiveness of Epoetin alfa in the treatment of chronic renal failure and of anemia in cancer.
  • Epoetin alfa for the treatment of anemia associated with rheumatoid arthritis, prematurity, AIDS, bone marrow transplantation, myelofibrosis, sickle cell anemia, as a facilitator of presurgical autologous blood donation, and as a perisurgical adjuvant.
  • Epoetin alfa is approved for sale in many countries for the treatment of anemia in chronic renal failure (dialysis and predialysis), anemia in zidovudine treated HIN positive patients (US), anemia in cancer patients receiving platinum-based chemotherapy, as a facilitator of autologous blood predonation, and as a perisurgical adjuvant to reduce the likelihood of requiring allogeneic blood transfusions in patients undergoing orthopedic surgery.
  • Epoetin alfa can correct anemia in cancer patients, at doses several times higher than those shown to be effective in renal patients.
  • Anemia may result from the disease itself, the effect of concomitantly administered chemotherapeutic agents, or a combination of both.
  • the condition often takes on the characteristics of the anemia of chronic disease (ACD).
  • ACD is associated with erythroid hypoplasia of the bone marrow, a somewhat shortened circulating life of red cells and decreased bone marrow re-utilization of iron. If erythropoietin levels are measured, they are found to be within the normal range, but inappropriately low for the degree of anemia.
  • the patient has a blunted erythropoietin response.
  • About 50- 60% of anemic cancer patients receiving chemotherapy responded with a hemoglobin rise of at least 2 g/dL to Epoetin alfa therapy given three times weekly at a dose of 150 IU/kg over a period of 12 weeks (RI. Abels, KM. Larholt, KD. Krantz, and EC. Bryant, Proceedings of the Beijing Symposium, Alpha Medical Press, Dayton, Ohio, (1991) 121- 141).
  • doses up to 300 IU/kg were sometimes required, demonstrating the relative resistance to the effect of Epoetin alpha in these patients.
  • Tumor necrosis factor is part of a group of inflammatory cytokines that has been implicated in the pathologic changes seen in a number of diseases. TNF has been implicated as a contributing cause of fatigue, asthenia, anorexia and cachexia in a number of disorders. Elevated levels of TNF were associated with post-dialysis fatigue in one study (AW. Dreisbach, T. Hendrickson, LA. Beezhold, et al, Int. J. Artif. Organs (1998) 21:83-6) and were seen in patients with disorders of excessive daytime sleepiness in another. (AN. Vgontzas, DA. Papanicolaou, EO. Bixler, et al., J. Clin.
  • TNF may act as a negative modulator of erythropoiesis.
  • murine models there are conflicting data regarding the ability to abrogate TNF mediated anemia.
  • human studies there is an association between circulating TNF levels and the need for increased doses of epoetin alfa in hemodialysis patients (M. Goiechea, J. Nartin, P.
  • the unmet need of enhanced EPO treatment for patients who suffer from cancer and fatigue has been met by the present invention that describes a method to treat patients with a combination of EPO and an anti- Tumor Necrosis Factor alpha agent.
  • the present invention provides a method for the treatment of a patient, comprising the steps, in any order or concurrently of administering a therapeutic amount of at least one anti-Tumor Necrosis Factor compound and a therapeutic amount of erythropoietin.
  • the present invention further provides a method for the treatment of a patient having malignancies, comprising the steps, in any order or concurrently of administering a therapeutic amount of at least one anti-Tumor Necrosis Factor compound, a therapeutic amount of erythropoietin, and a therapeutic amount of an anti-tumor agent.
  • the methods of the present invention result in a reduced need for transfusion and a greater hemoglobin level in the patient. Further, the present invention provides that anemia may be successfully prevented or treated during the course of a chemotherapeutic regimen using the method of the present invention. The methods of the present invention result in patients that show greater quality of life, show improvement in physical performance and well being.
  • EPO Erythropoietin
  • EPO molecules may include small organic or inorganic molecules, synthetic or natural arnino acid peptides, purified protein from recombinant or natural expression systems, or synthetic or natural nucleic acid sequences, or any chemical derivatives of the aforementioned.
  • the generally preferred, form of EPO is purified, recombinant EPO, distributed under the trademarks of EPREX® or ERYPO®.
  • Epoetin alfa is a sterile, clear, colourless, aqueous solution for injection, that is provided in prefilled, single-use syringes containing either 4,000 or 10,000 IU epoetin alfa (a recombinant human erythropoietin) and 2.5 mg/mL human serum albumin in 0.4 mL (4,000 IU syringe) or 1.0 mL (10,000 IU syringe) of phosphate buffer.
  • Erythropoietin shall include those proteins that have the biological activity of human erythropoietin, as well as erythropoietin analogs, erythropoietin isoforms, erythropoietin mimetics, erythropoietin fragments, hybrid erythropoietin proteins, erythropoietin receptor agonists, renal erythropoietin, brain erythropoietin, oligomers and multimers of the above, homologues of the above, and muteins of the above, regardless of the biological activity of same, and further regardless of the method of synthesis or manufacture thereof including but not limited to naturally occurring, recombinant, synthetic, transgenic, and gene activated methods.
  • anti-Tumor Necrosis Factor Compound refers to drug products that decrease the amount of circulating, active TNF ⁇ .
  • the compound may achieve this by decreasing the amount of cellular TNF ⁇ mRNA transcription, by decreasing mRNA translation into TNF ⁇ protein, or by decreasing cellular secretion of TNF ⁇ .
  • Roy A. Black et al, from Immunex Corp. have discovered a compound that inhibits the enzyme that releases TNF from cell surfaces ⁇ Nature, 370, 218(1994)). This compound, called TNF- ⁇ protease enzyme inhibitor, curbs production of soluble TNF.
  • Other suitable anti-TNF ⁇ compounds could work by increasing the rate of clearance or decreasing the amount of functional TNF ⁇ in circulation.
  • Preferred anti-TNF ⁇ compounds are Thalidomide, Pentoxifylline, Infliximab, glucocorticoids, and Etanercept.
  • the anti-TNF ⁇ compounds may be administered as combinations in order to maximize modulation of TNF since these agents acts as TNF ⁇ inhibitors at a different points in TNF synthesis and pharmacokinetic activity.
  • Pentoxifylline inhibits TNF- ⁇ gene transcription (Doherty et al, Surgery (St. Louis), 110:192, 1991), while thalidomide enhances TNF- ⁇ m-RNA degradation (Moreira et al., 1993) and glucocorticoids such as dexamethasone inhibit TNF- ⁇ m-RNA translation (Han et al., J. Exp. Med. (1990) 172:391).
  • Infliximab and etanercept act by reducing the amount of circulating, active TNF ⁇ .
  • Pentoxifylline decreases circulating TNF ⁇ at the Standard dose of 400 mg 3 times daily. Pentoxifylline inhibits TNF- ⁇ gene transcription (Doherty et al., Surgery (St. Louis), 110:192, 1991).
  • Glucocorticoids such as dexamethasone inhibit TNF- ⁇ m-RNA translation.
  • Dexamethasone is administered orally, intramuscularly, or intravenously in the dose range of 8-40 mg (pediatric dose: 0.25-0.5 mg/kg). If given intravenously, dexamethasone should be given over 10-15 minutes, since rapid administration may cause sensations of generalized warmth, pharyngeal tingling or burning, or acute transient perianal and/or rectal pain.
  • Methylprednisolone is also administered orally, intramuscularly, or intravenously at doses and schedules that vary from 40-500 mg every 6-12 hours for up to 20 doses.
  • Thalidomide may act by enhancing TNF- ⁇ m-RNA degradation (Shannon et al. (1990) Amer. Society for Microbiology Ann. Mtg., Abs. U- 53). Thalidomide is given by oral administration in the range of about 30 mg to 1500 mg per 24 hours, preferably 200 to 500 mg per 24 hours for an adult human weighting 70 kg.
  • REMICADETM is a monoclonal antibody that blocks the biological activity of circulating TNF ⁇ . Infliximab does not neutralize TNF ⁇ (lymphotoxin ⁇ ), a related cytokine that utilizes the same receptors as TNF ⁇ . Remicade is supplied as a sterile, white, lyophilized powder for intravenous infusion. Following reconstitution with 10 mL of Sterile Water for Injection, USP, the resulting pH is approximately 7.2. Each single- use vial contains 100 mg Infliximab, 500 mg sucrose, 0.5 mg polysorbate 80, 2.2 mg monobasic sodium phosphate and 6.1 mg dibasic sodium phosphate. No preservatives are present.
  • E ⁇ BRELTM (etanercept) is a dimeric fusion protein consisting of the extracellular ligand- binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (T ⁇ FR) linked to the Fc portion of human IgGl.
  • the Fc component of etanercept contains the C H domain, the C R 3 domain and hinge region, but not the C H I domain of IgGl.
  • Etanercept is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell expression system. It consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons.
  • ENBRELTM is supplied as a sterile, white, preservative-free, lyophilized powder for parenteral administration after reconstitution with 1 mL of the supplied Sterile Bacteriostatic Water for Injection, USP (containing 0.9% benzyl alcohol). Following reconstitution, the solution of ENBRELTM is clear and colorless, with a pH of 7.4 ⁇ 0.3. Each single-use vial of ENBRELTM contains 25 mg etanercept, 40 mg mannitol, 10 mg sucrose, and 1.2 mg tromethamine. ENBRELTM is administered as a single subcutaneous (SC) injection.
  • SC subcutaneous
  • Such tumor types include, but are not limited to, solid tumors, hematological tumors, sarcomas, carcinomas, neoplasms, as well as tumors of the breast, Non-Hodgkin's Lymphoma, myeloma, Hodgkin's lymphoma, leukemia, colon, rectal, colo-rectal, stomach, gastrointestinal, ovarian, lung, pancreas, and prostate.
  • Platinum containing anti-tumor agents include, but are not limited to, cisplatin, and cis-dichlorodiammineplatinum.
  • Non-platinum containing anti-tumor agents include, but are not limited to, cyclophosphamide, fluorouracil, epirubicin, methotrexate, vincristine, doxorubicin, bleomycin, and etoposide.
  • Quality of life is usually affected by malignancy, e.g., due to the underlying disease, effects of therapy and the psychological burden of coping with cancer.
  • Fatigue is the most frequently reported symptom in cancer patients and impairs significantly their quality of life (ML. Winningham, LM. Nail, M. Barton Burke, et al., Oncol Nursing Forum (1994) 21: 23-34)
  • Anemia contributes to fatigue and to the reduction in quality of life.
  • the effects on fatigue (FACT An) and quality of life (ECOG performance score, Cancer Linear Analogue Scale, SF36) of early intervention and/or treatment of anemia with the combination therapy of EPO + anti-TNF ⁇ can be alleviated with concurrent use of EPO + anti-TNF ⁇ during chemotherapy.
  • Randomization will be used to avoid bias in the assignment of patients to treatment, to increase the likelihood that subject attributes are evenly balanced across groups, and to enhance the validity of comparisons across treatment groups.
  • Investigators and patients will be blinded to the identity of etanercept and placebo to enhance the validity of comparisons that are subject to observer bias or the placebo effect (e.g. - QoL end points).
  • EPO will be given to all patients in an open label manner. Patients will be assigned randomly to each treatment regimen.
  • Serum TNF ⁇ and anti-TNF ⁇ levels • FACT- An, Linear Analog Scale Assessment (LAS A), CLOX and EXIT 25 within 3 days prior to the administration of chemotherapy
  • Subjects will be assigned to treatment groups based on a computer- generated randomization schedule. The randomization will be balanced by using permuted blocks and will be stratified by center and type of cancer. Based on this randomization code, the study drug will be packaged and labeled for each subject. [Subject numbers] [Medication code numbers] will be preprinted on the study drug labels and assigned sequentially as subjects qualify for the study and are randomized to treatment.
  • the etanercept or placebo drug container will have a two-part, tear-off label with directions for use and other information on each part.
  • the tear-off section of the label will contain a concealed area identifying the study drug (e.g., active or placebo) and will be removed and attached to the subject's CRF when the drug is dispensed.
  • the second part of the label will remain affixed to the study drug container and will contain all identifying information except for the identity of the drug contained.
  • the study drugs will be identical in appearance and will be packaged in identical containers.
  • the blind should not be broken.
  • the blind should be broken only if specific emergency treatment would be dictated by knowing the treatment status of the subject. In such cases, the investigator must contact the sponsor. If the investigator is unable to contact the sponsor, the investigator may in an emergency determine the identity of the treatment by exposing the concealed area of the label attached to the subject's CRF. Individual code breaks by the investigator will normally result in withdrawal of the subject from the trial. The date, time, and reason for the unblinding must be documented on the appropriate page of the CRF (Study Completion Information) and the sponsor must be informed as soon as possible.
  • the randomization schedule will not be revealed to study subjects, parents or guardians, investigators and clinical staff, or site managers until all subjects have completed the double-blind phase of the trial.
  • patients should remain blinded to study-related test results prior to the completion of each set of QoL and cognitive measures.
  • the treating physician may provide laboratory results as soon as the forms are completed for that visit.
  • evaluations For patients receiving every three week chemotherapy, evaluations should be completed at least 3 days following the end of the last dose of chemotherapy. For patients receiving every four week chemotherapy, evaluations should be completed within 3 days prior to the scheduled chemotherapy course.
  • EPO will be started at a dose of 40,000 U per week given SC, without regard to the timing of chemotherapy. If at the evaluation prior to the week 5 dose the hemoglobin has not increased by at least 1 g/dl over the baseline value, the dose of EPO will be increased to 60,000 U per week for weeks 5-8. If the hemoglobin increases by at least 2 g/dl over baseline at the time of the week 9 evaluation, the patient will be considered a responder. Responders will continue to receive the dose of EPO given during weeks 5-8 until week 16. Non-responders will be offered the opportunity to receive EPO + ETAN in an 8 week open label extension.
  • Placebo injections will be given at a dose of 1 ml SC, at a site separate from the EPO site, on days 1 and 4 of each week (day 1 is counted as the day the EPO and placebo are given together).
  • the patient should receive two doses of placebo during week 8, prior to the week 9 evaluation.
  • Responders will continue to receive placebo in a blinded manner through week 16.
  • Two placebo injections should be given in week 16, prior to the off study evaluation.
  • Non-responders will be offered the opportunity to receive EPO + ETAN in an 8 week open label extension.
  • EPO will be started at a dose of 40,000 U per week given SC, without regard to the timing of chemotherapy. If at the evaluation prior to the week 5 dose the hemoglobin has not increased by at least 1 g/dl over the baseline value, the dose of EPO will be increased to 60,000 U per week for weeks 5-8. If the hemoglobin increases by at least 2 g/dl over baseline at the time of the week 9 evaluation, the patient will be considered a responder. Responders will continue to receive the dose of EPO given during weeks 5-8 until week 16. Non-responders will proceed to the Off Study Evaluation at week 9.
  • ETAN injections will be given at a dose of 25 mg (1 ml) SC, at a site separate from the EPO site, on days 1 and 4 of each week (day 1 is counted as the day the EPO and ETAN are given together).
  • the patient should receive two doses of ETAN during week 8, prior to the week 9 evaluation. Responders will continue in ETAN through week 16. Two ETAN injections should be given during week 16 and prior to the off study evaluation. Non-responders will proceed to the off study evaluation at week 9.
  • ETAN ETAN
  • Week 9 placebo will be replaced with ETAN at week 9 for patients who are non-responders in Regimen A.
  • the following doses of EPO and ETAN will be given during weeks 9-16 in these patients: (1) Patients on an EPO dose of 60,000 U/week at week 8 will continue on that dose for weeks 9-12.
  • ETAN will be given at a dose of 25 mg SC, at a site separate from the EPO site, on days 1 and 4 of each week (day 1 is counted as the day the EPO and placebo are given together).
  • ETAN will be started on the day of the week 9 EPO dose and continue until 2 doses are given during week 12.
  • the patient will be considered a responder and continue on study through week 16. ETAN should continue until 2 doses are given in week 16. The patient then will proceed to the Off Study Evaluation. If the patient is a non-responder at week 13, then the patient will proceed to the Off Study Evaluation.
  • ETAN ETAN will be given at a dose of 25 mg SC, at a site separate from the EPO site, on days 1 and 4 of each week (day 1 is counted as the day the EPO and placebo are given together).
  • the first dose of ETAN will be given on the day of the week 9 EPO dose and continue until 2 doses are given during week 12. If the evaluation at week 13 indicates at least a 1 g/dl increase in hemoglobin over the week 9 value, or a 2 g/dl increase over the baseline value, then the patient will continue on study through week 16 at the same dose of EPO. ETAN should continue until 2 doses are given during week 16 EPO.
  • EPO should be withheld until the hemoglobin drops to 12 g/dl. EPO should then be resumed at 75% of the last dose given before discontinuation. If the hemoglobin increases by > 1.3 g/dl in a 2 week period, EPO should be continued at 75% of the previous dose.
  • Epoetin alfa 40,000 U/ml should be brought to room temperature and drawn up into a plastic syringe immediately prior to administration by SC injection according to standard techniques.
  • the EPO and ETAN/placebo may be given at the same time on day 1 of each week, but should be administered at separate sites.
  • Each vial of EPO should be used only once.
  • the maximum injection volume per site is 2 ml.
  • Study medication (ETAN/placebo) should be reconstituted with 1 ml of the supplied sterile bacteriostatic water for injection, USP (0.9% benzyl alcohol). The diluent should be slowly injected into the vial. Some foaming may occur. To avoid excessive foaming, do not shake or agitate vigorously. Swirl gently until dissolution occurs, usually over less than 5 minutes. The solution should be clear and colorless. The medication should then be drawn up into a plastic syringe and administered SC as soon as possible after reconstitution. New injections should be given at least 1 inch from an old site and never into areas where the skin is tender, bruised, hard or red. Prior to injection of the study medication, Part 2 of the two-part vial label is to be attached to the subject's case report form after entry of the subject's initials and number, and the date of study medication administration. Each vial of study medication should be used only once. Iron
  • Iron deficiency may develop during the use of EPO and may limit the efficacy of EPO if left untreated. If laboratory evidence of iron deficiency develops during the study, the patient should be given 150-200 mg of elemental iron per day. The appropriate formulation of the iron supplement is left to the discretion of the treating physician.
  • Patients may be transfused with packed red blood cells when judged to be necessary by the physician of record.
  • a hemoglobin level should be obtained at the time the type and cross-match specimen is drawn.
  • the pre-transfusion hemoglobin value, along with the number of units used and the total volume transfused, should be recorded in the case report form.
  • the sponsor must be notified in advance (or as soon as possible thereafter) of any instances in which prohibited therapies are administered.
  • ⁇ Response is defined as a 2g/dl or greater increase in the hemoglobin when compared to the Baseline value.
  • ⁇ Significant weight loss will be defined as Off Study Weight divided by Baseline Weight less than 0.90.
  • ⁇ Disease status will be defined according the current version of the RECIST Criteria issued by the National Cancer Institute.

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Abstract

L'invention concerne un procédé permettant de traiter des sujets anémiques et non anémiques présentant des tumeurs malignes par une combinaison d'érythropoïétine (EPO) et d'un composé anti-facteur de nécrose des tumeurs, de sorte à réduire le besoin de transfusion et à augmenter le taux d'hémoglobine. L'invention concerne également un procédé permettant de traiter des sujets anémiques et non anémiques présentant des tumeurs malignes par une combinaison d'EPO et d'un composé anti-facteur de nécrose des tumeurs, de sorte à empêcher ou à traiter l'anémie de manière efficace pendant un régime chimiothérapique. L'invention concerne encore un procédé permettant de traiter des sujets anémiques ou non anémiques présentant des tumeurs malignes par une combinaison d'EPO et d'un composé anti-facteur de nécrose des tumeurs, de sorte que les patients ont une meilleure qualité de vie, que leurs symptômes de fatigue sont atténués et que leurs performances physiques et leur bien-être sont améliorés.
EP01959479A 2001-08-02 2001-08-02 Erythropoietine et traitement de combinaison alpha anti-facteur de necrose des tumeurs Withdrawn EP1423693A4 (fr)

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PCT/US2001/024384 WO2003012432A1 (fr) 2001-08-02 2001-08-02 Erythropoietine et traitement de combinaison alpha anti-facteur de necrose des tumeurs

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AU2004296765B2 (en) * 2003-12-02 2011-03-24 Celgene Corporation Methods and compositions for the treatment and management of hemoglobinopathy and anemia
WO2007139150A1 (fr) * 2006-05-30 2007-12-06 The University Of Tokushima AGENT ANTI-VIRUS DE LA GRIPPE COMPRENANT L'INHIBITEUR DU TNF-α
GR1005808B (el) * 2006-11-27 2008-02-06 Bionature E.A. Limited Επιταση της δρασεως της ερυθροποιητινης με αγωνιστες των μεμβρανικων στεροειδων υποδοχεων

Citations (2)

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WO2002010743A1 (fr) * 2000-08-02 2002-02-07 Ortho-Mcneil Pharmaceutical, Inc. Chimiotherapie antivirale et anticancereuse amelioree faisant appel a l'administration d'erythropoietine (epo)
WO2002036152A1 (fr) * 2000-10-31 2002-05-10 Amgen Inc. Utilisation d'inhibiteurs il-1 et d'antagonistes tnf, en partie en combinaison avec des erythropoietines de recombinaison, pour traiter l'anemie

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Publication number Priority date Publication date Assignee Title
WO2002010743A1 (fr) * 2000-08-02 2002-02-07 Ortho-Mcneil Pharmaceutical, Inc. Chimiotherapie antivirale et anticancereuse amelioree faisant appel a l'administration d'erythropoietine (epo)
WO2002036152A1 (fr) * 2000-10-31 2002-05-10 Amgen Inc. Utilisation d'inhibiteurs il-1 et d'antagonistes tnf, en partie en combinaison avec des erythropoietines de recombinaison, pour traiter l'anemie

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Title
DEMETRI G D ET AL: "QUALITY-OF-LIFE BENEFIT IN CHEMOTHERAPY PATIENTS TREATED WITH EPOETIN ALFA IS INDEPENDENT OF DISEASE RESPONSE OR TUMOR TYPE: RESULTS FROM A PROSPECTIVE COMMUNITY ONCOLOGY STUDY" JOURNAL OF CLINICAL ONCOLOGY, GRUNE AND STRATTON, NEW YORK, NY, US, vol. 16, no. 10, October 1998 (1998-10), pages 3412-3425, XP009031711 ISSN: 0732-183X *
See also references of WO03012432A1 *
WOLCHOK J D ET AL: "PROPHYLACTIC RECOMBINANT EPOETIN ALFA MARKEDLY REDUCES THE NEED FOR BLOOD TRANSFUSION IN PATIENTS WITH METASTATIC MELANOMA TREATED WITH BIOCHEMOTHERAPY" CYTOKINES, CELLULAR AND MOLECULAR THERAPY, MARTIN DUNITZ PUBLISHERS, LONDON, GB, vol. 5, no. 4, December 1999 (1999-12), pages 205-206, XP009031732 ISSN: 1368-4736 *

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WO2003012432A1 (fr) 2003-02-13
JP2004537569A (ja) 2004-12-16
CA2456177A1 (fr) 2003-02-13
EP1423693A4 (fr) 2006-06-07

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