WO2003012432A1

WO2003012432A1 - Erythropoietin and anti-tumor necrosis factor alpha combination therapy

Info

Publication number: WO2003012432A1
Application number: PCT/US2001/024384
Authority: WO
Inventors: Loretta Itri
Original assignee: Ortho-Mcneil Pharmaceutical, Inc.
Priority date: 2001-08-02
Filing date: 2001-08-02
Publication date: 2003-02-13
Also published as: EP1423693A1; CA2456177A1; EP1423693A4; JP2004537569A

Abstract

The present invention provides a method to treat anemic and non-anemic subjects having malignancies with a combination of EPO and an anti-Tumor Necrosis Factor compound such that there is a reduced need for transfusion and a greater hemoglobin level. The present invention provides a method to treat anemic and non-anemic subjects having malignancies with a combination of EPO and an anti-Tumor Necrosis Factor compound such that anemia may be successfully prevented or treated during the course of a chemotherapeutic regimen. The present invention provides a method to treat anemic and non-anemic subjects having malignancies with a combination of EPO and an anti-Tumor Necrosis Factor compound such that the patients show greater quality of life, show relief from fatigue symptoms, and show improvement in physical performance and well being.

Description

TITLE OF THE INVENTION

ERYTHROPOIETIN AND ANTI-TUMOR NECROSIS FACTOR ALPHA COMBINATION THERAPY

BACKGROUND OF THE INVENTION

Erythropoietin (EPO) 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) has an amino acid sequence identical to that of human urinary erythropoietin, and the two are indistinguishable in chemical, physical and immunological tests.

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).

In clinical trials to date, 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.

Other trials have evaluated 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.

Clinical experience has been collected over the past years to show that 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. Therefore 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). In a subsequent open-label dose titration study, doses up to 300 IU/kg, were sometimes required, demonstrating the relative resistance to the effect of Epoetin alpha in these patients. In three large community based studies, which enrolled over 7,000 patients with a wide range of non-myeloid malignancies, quality of life improvements correlated with the change in hemoglobin from baseline. (J. Glaspy, R. Bukowski, D. Steinberg, et al. /. Clin. Oncol. (1997) 15:1218-34; GD. Demetri, M. Kris, J. Wade, et al. J. Clin. Oncol. (1998) 16:3412-25; JL. Gabrilove, LH Einhorn, RB. Livingston, et al. American Society of Clinical Oncology Annual Meeting (1999) Abstract 2216). However, patients who did not experience an increase in hemoglobin over their baseline level did not show improvement in energy level, activity level, and overall quality of life. In each of the studies, approximately 35% of patients did not have an increase in their hemoglobin of 2 g/dl over baseline. Patients with progressive disease do not respond well to epoetin alfa, but the proportion (approximately 20%) of patients with progressive disease does not explain the overall rate of non-response of 35%. There is room to improve the overall response rate to erythropoietin in patients suffering from cancer.

Quality of life measures improve in association with increased hemoglobin levels in patients with cancer related anemia. Yet approximately one-third of patients fail to respond to erythropoietin treatment. Among the responders, quality of life measures improve significantly, but do not approach those seen in healthy subjects. TNF is implicated in many of the processes that complicate cancer therapy, including anemia, fatigue, and anorexia and cachexia. Cancer related fatigue has emerged as the most prevalent and bothersome symptom of cancer and its treatment. (RK. Portenoy, LM. Itri, The Oncologist (1999) 4:1-10). It is reported by 75%-100% of patients with cancer, depending on the patient's diagnosis, treatment and disease status. Cancer related fatigue is a multi-factorial problem. However, the treatment of cancer related anemia with erythropoietin has emerged as a safe and effective therapy to improve quality of life and relieve cancer related fatigue. Therefore, modulation of TNF simultaneously with EPO should increase the effectiveness of EPO for increasing hemoglobin levels, ameliorating anemia, and increasing the Quality of life measures in cancer patients.

Tumor necrosis factor (TNF) 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. Endrocrinol. Metab. (1997) 82:1313-6) TNF inhibition associated with the use of thalidomide has been exploited to treat the anorexia and cachexia of HIV disease (PAJ. Haslett. Semin. Oncol (1998) 25(6):53-7). The "procachetic" characteristics of some inflammatory cytokines, and TNF in particular, were recently reviewed (JM. Argiles, FJ. Lόpez- Soriano. Med Res Rev (1999) 19:223-48). The evidence of increased circulating TNF levels in cancer patients remains controversial; and, no single molecule has yet been identified as the mediator of cancer related cachexia. Still, TNF is an important candidate. An extensive review of asthenia echoes this sentiment. (DD. Von Hoff. Cancer Therapeutics (1998) 1:184-97).

A number of pre-clinical and clinical studies have demonstrated that TNF may act as a negative modulator of erythropoiesis. In murine models, there are conflicting data regarding the ability to abrogate TNF mediated anemia. (U. Clibon, L. Bonewald, J. Caro, et al. Exp Hematol. (1990) 18:458-41; CS. Johnson, CA. Cook, P. Furmanski, Exp Hematol. (1990) 18:109-13). In 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. de Sequera, et al, Kidney Int (1998) 54:1337-43) and between local production of TNF in the bone marrow of patients with the anemia of chronic disease secondary to rheumatoid arthritis. (M. Jongen-Lavrencic, HR. Peeters, A. Wognum, et al, / Rheumatol. (1997) 24:1504-9). TNF blockade with a monoclonal antibody lead to improvement in the anemia of rheumatoid arthritis patients in one study. (D. Davis, PJ. Chrles, A. Potter, et al. BrJ Rheumatol (1997) 36:950-6).

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.

SUMMARY OF THE INVENTION

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.

DETAILED DESCRIPTION OF THE INVENTION

The term Erythropoietin (EPO), as defined herein, refers to any molecule that specifically stimulates terminal differentiation of red blood cells from hematopoietic stem cells and stimulates production of hemoglobin. For example, but not to limit the scope of the current invention, 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 (EPREX^®, ERYPO^®) 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.

The term "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.

The term "anti-Tumor Necrosis Factor Compound" refers to drug products that decrease the amount of circulating, active TNFα. The compound may achieve this by decreasing the amount of cellular TNFα mRNA transcription, by decreasing mRNA translation into TNFα protein, or by decreasing cellular secretion of TNFα. 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-α protease enzyme inhibitor, curbs production of soluble TNF. Other suitable anti-TNFα compounds could work by increasing the rate of clearance or decreasing the amount of functional TNFα in circulation. Preferred anti-TNFα compounds are Thalidomide, Pentoxifylline, Infliximab, glucocorticoids, and Etanercept. The anti-TNFα compounds may be administered as combinations in order to maximize modulation of TNF since these agents acts as TNFα inhibitors at a different points in TNF synthesis and pharmacokinetic activity. Pentoxifylline inhibits TNF-α gene transcription (Doherty et al, Surgery (St. Louis), 110:192, 1991), while thalidomide enhances TNF-α m-RNA degradation (Moreira et al., 1993) and glucocorticoids such as dexamethasone inhibit TNF-α m-RNA translation (Han et al., J. Exp. Med. (1990) 172:391). Infliximab and etanercept act by reducing the amount of circulating, active TNFα.

Pentoxifylline (PENTOXIL™, Trental) decreases circulating TNFα at the Standard dose of 400 mg 3 times daily. Pentoxifylline inhibits TNF-α gene transcription (Doherty et al., Surgery (St. Louis), 110:192, 1991).

Glucocorticoids such as dexamethasone inhibit TNF-α 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 (N-phthalidoglutarimide) may act by enhancing TNF-α 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.

REMICADE™ (Infliximab) is a monoclonal antibody that blocks the biological activity of circulating TNFα. Infliximab does not neutralize TNFβ (lymphotoxin α), a related cytokine that utilizes the same receptors as TNFα. 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. Data from a study of single intravenous infusions of 1, 5, 10 or 20 mg/kg show a direct and linear relationship between the dose administered and the maximum serum concentration (C_max) and area under the concentration-time curve. The volume of distribution at steady state (V_d), clearance and mean residence time are independent of the administered dose. Infliximab has a prolonged terminal half-life and is predominantly distributed within the vascular compartment. A single infusion of the recommended dose of 5 mg/kg resulted in a median C_max of 118 μg/mL, a median Nd equal to 3.0 liters and a terminal half-life of 9.5 days.

EΝBREL™ (etanercept) is a dimeric fusion protein consisting of the extracellular ligand- binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TΝFR) linked to the Fc portion of human IgGl. The Fc component of etanercept contains the C_H domain, the C_R3 domain and hinge region, but not the C_HI 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. ENBREL™ 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 ENBREL™ is clear and colorless, with a pH of 7.4 ± 0.3. Each single-use vial of ENBREL™ contains 25 mg etanercept, 40 mg mannitol, 10 mg sucrose, and 1.2 mg tromethamine. ENBREL™ is administered as a single subcutaneous (SC) injection.

It is readily apparent to those skilled in the art that a wide variety of malignancies are treatable according to the methods of the present invention.

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.

It is readily apparent to those skilled in the art that a wide variety of non-platinum and platinum containing anti-tumor agents are suitable for use in the methods of the present invention. 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-TNFα can be alleviated with concurrent use of EPO + anti-TNFα during chemotherapy.

The following examples illustrate the present invention without, however, limiting the same thereto.

EXAMPLE 1

A Randomized, Controlled Trial of Epoetin Alfa and Etanercept

OVERVIEW OF STUDY DESIGN

The study will be a double-blind, randomized, placebo controlled trial. After initial evaluation for eligibility, cancer patients with treatment related anemia will be assigned in a 1:1 randomization to receive either epoetin alfa plus placebo (Regimen A) or epoetin alfa plus etanercept (Regimen B). Patients who do not achieve an increase in hemoglobin of 1 g/dl without transfusion after four weeks of treatment will receive an increased dose epoetin alfa during weeks 5-8. Patients on Regimen A (epoetin alfa + placebo) who do not achieve an increase in hemoglobin of 2 g/dl over baseline by week 9 will be crossed over to Regimen B in an 8 week open label extension phase. Patients on Regimen B who do not achieve a 2 g/dl increase in hemoglobin over baseline by week 9 will be taken off study. Responding patients will continue on their assigned treatment and blinding will be maintained for 16 weeks. All patients must have received at least one course of chemotherapy and be scheduled to receive a minimum of 8 weeks of additional chemotherapy after study enrollment. Measures of Quality of Life (QoL), executive function, and weight will be obtained at study entry and at weeks 9 and 17 or at the time of withdrawal from the study. Hematologic parameters will be measured bi-weekly. All measurements should be made within 3 days prior to a subsequent course of chemotherapy. Assessments of tumor response will be made at enrollment, with subsequent assessments at weeks 9 and 17 or at the time of withdrawal from the study.

STUDY POPULATION

General Considerations

The specific inclusion and exclusion criteria for enrolling subjects in this study are described in the following sections. Exceptions to these inclusion/exclusion criteria should occur infrequently and should be discussed in advance with the Ortho Biotech medical monitor. If an exception is agreed upon and a subject is allowed to participate, the medical monitor will send confirmation to the site acknowledging the exception. This confirmation form or letter is to be kept with the case report forms (CRFs) both at the site and at the sponsor.

Inclusion Criteria

Subjects must satisfy the following criteria before entering the study:

• Histologically proven breast or lung cancer

• Prior chemotherapy < 1 course

• No evidence of progressive disease at study entry

• Treatment related anemia (must have started chemotherapy prior to study entry) with hemoglobin > 8 g/dl and < 12 g/dl

• Age > 18 years • Iron replete (transferrin saturation of > 20% and serum ferritin > 100 ng/ml)

• ECOG Performance status of 0-1 (see Appendix X) as determined by the investigator of designee,

• Life expectancy of at least 6 months

• Scheduled to receive at least an 8 weeks of chemotherapy

• Understands and signs informed consent

Exclusion Criteria

Subjects who meet any of the following criteria will be excluded from participating in the study:

• Prior chemotherapy > 1 course

• Use of biological response modifiers or cytokines within 30 days of study entry

• Diagnosis of rheumatoid arthritis, inflammatory bowel disease, or any disease for which etanercept may be primary therapy

• Chronic infection within 30 days of study entry

• Active infection at study entry

• Acute infection within 7 days of study entry

• Brain metastases

• Uncontrolled seizures

• Uncontrolled hypertension

• Transfusion within 2 months of study entry

• Iron deficiency or other nutritional anemia • Active hemolytic anemia

• Bleeding

• Known hypersensitivity to mammalian cell-derived products

• Known hypersensitivity to human albumin

• Prior treatment with epoetin alfa or any investigational erythropoietin within 8 weeks of study entry

• Significant medical disease other than cancer

• Second malignancy, other than basal cell carcinoma of the skin, within 5 years of study entry

• Use of corticosteroids other than for occasional use for anti-emesis or pre-treatment for a medication

• Advanced or poorly controlled diabetes mellitus

• Pregnant or lactating woman

RANDOMIZATION AND BLINDING

Overview

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. PROCEDURES

Pre-Randomization Phase (Baseline)

The following evaluations and procedures are to be performed within 14 days prior to randomization unless otherwise specified. All laboratory tests and QoL and cognitive measures must be performed prior to the start of the first chemotherapy course after randomization.

• Patient demographics

• ECOG Performance Status as rated by the investigator or designee

• Tumor assessment using the NCI RECIST Criteria within 14 days prior to randomization

• Chemotherapy, radiation and surgery history

• Weight measured fully dressed except for shoes on the same scale to be used throughout the study

• Clinical laboratory tests

• Hemoglobin, hematocrit, MCV, absolute reticulocyte count, white blood cell count with differential and platelet count within 3 days prior to randomization

• Iron studies: ferritin, total iron binding capacity (TIBC), transferrin saturation, serum iron, transferrin receptor levels

• RBC ate and vitamin B 12 levels

• BUN, creatinine

• AST, ALT, total bilirubin

• Serum TNFα and anti-TNFα levels • FACT- An, Linear Analog Scale Assessment (LAS A), CLOX and EXIT 25 within 3 days prior to the administration of chemotherapy

• Transfusion history

• Signed informed consent

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.

To maintain the blind, 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.

Under normal circumstances, 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.

To allow for the cross-over of non-responding patients randomized to EPO alone, the investigator will call the study sponsor with the week 9 hemoglobin results. If a patient is a non-responder, the study sponsor will inform the investigator of the patient's treatment assignment. Patients who do not respond to EPO + ETAN (Regimen B) will proceed to Off Study Evaluation procedures. Non-responding patients treated on EPO + placebo (Regimen A) will be treated with EPO + ETAN for an additional 8 weeks in an open label extension phase. Non- responding patients treated with EPO+ETAN who subsequently respond indicate synergistic action of the anti-tumor necrosis factor agent with EPO Comparison of the response of patients treated with EPO or with EPO+ETAN will further indicate synergistic action of the combination therapy.

DOUBLE-BLIND TREATMENT PHASE

During this phase 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.

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.

Week 3

• ECOG Performance Status as rated by the investigator or designee

Weight measured fully dressed except for shoes on the same scale to be used throughout the study

Clinical laboratory tests

• Hemoglobin, hematocrit, MCV, absolute reticulocyte count, white blood cell count with differential and platelet count

• Serum TNFα and anti-TNFα levels

Transfusion history

Week 5

• ECOG Performance Status as rated by the investigator or designee

• Chemotherapy, radiation and surgery history

Clinical laboratory tests • Hemoglobin, hematocrit, MCV, absolute reticulocyte count, white blood cell count with differential and platelet count Iron studies: ferritin, total iron binding capacity (TIBC), transferrin saturation, serum iron, transferrin receptor levels

• Serum TNFα and anti-TNFα levels

• Transfusion history

Week 9 This evaluation will serve as the Off Study Evaluation for Non-responders on Regimen B

• ECOG Performance Status as rated by the investigator or designee

Tumor assessment using the NCI RECIST Criteria (see Appendix X) within 14 days

Chemotherapy, radiation and surgery history

Clinical laboratory tests

• RBC Mate and vitamin B 12 levels

• BUN, creatinine

• AST, ALT, total bilirubin • Serum TNFα and anti-TNFα levels

• FACT-An, Linear Analog Scale Assessment (LASA), CLOX and EXIT 25 within 3 days prior to the administration of chemotherapy

• Transfusion history

Responding patients on both regimes will continue on their assigned treatment and be evaluated through week 17 as follows.

Week 13

ECOG Performance Status as rated by the investigator or designee

Clinical laboratory tests

• Serum TNFα and anti-TNFα levels

Transfusion history

Determination of response: non-responders already on 60,000 U/week proceed to Off Study Evaluation

Week 17

Proceed to Off Study Evaluation OPEN LABEL EXTENSION PHASE FOR NON-RESPONDERS IN REGIMEN A

Week 13

• ECOG Performance Status as rated by the investigator or designee

• Clinical laboratory tests

• Serum TNFα and anti-TNFα levels

• Transfusion history

Week 17

• Proceed to Off Study Evaluation

OFF STUDY EVALUATION

• ECOG Performance Status as rated by the investigator or designee

• Tumor assessment using the NCI RECIST Criteria within 14 days

• Chemotherapy, radiation and surgery history

• Clinical laboratory tests • Hemoglobin, hematocrit, MCV, absolute reticulocyte count, white blood cell count with differential and platelet count

• Iron studies: ferritin, total iron binding capacity (TIBC), transferrin saturation, serum iron

• BUN, creatinine

• AST, ALT, total bilirubin

• Serum TNF and anti-TNF levels

• Transfusion history

DOSAGE AND ADMINISTRATION

Regimen A (EPO + Placebo)

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.

Regimen B (EPO + ETAN)

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.

Open label phase for non-responders on Regimen A

To assess the effectiveness of ETAN in overcoming resistance to EPO, 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. 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 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.

(2) Patients on an EPO dose of 40.000 U/week at week 8 will continue that dose through 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). 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. The patient then will proceed to the Off Study Evaluation. If the patient is a non-responder at week 13, then the EPO dose will be increased to 60,000 U/week and the patient will continue on study through week 16. ETAN should continue until 2 doses are given during week 16 EPO. The patient then will proceed to the Off Study Evaluation.

Dose adjustment of EPO

If the hemoglobin is > 13 g/dl on 2 consecutive evaluations, 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.

Patients who develop sepsis

All study medication should be discontinued in patients who develop sepsis while on study. The Study Completion/Early Withdrawal form should be completed and the study sponsor informed immediately.

Administration of EPO

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.

Administration of ETAN

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.

CONCOMITANT THERAPY

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.

All concomitant therapy administered during the study will be recorded on the case report form. The use of androgens or hematinic agents (folate, B12) other than iron is prohibited during the study. The use of corticosteroids, other than occasional use as a pre-medication or an anti-emetic is prohibited during the study.

The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in which prohibited therapies are administered.

EFFICACY EVALUATIONS

The primary endpoints to be evaluated in this study are as follows:

1. a comparison of the proportion of patients in each regimen who achieve a response by week 9

2. a comparison of the change in scores on QoL measures in each regimen between Baseline, week 9 and Off Study in responders, and using an intent to treat analysis of all patients 3. the proportion of non-responders in Regimen A who show a response at week 13 and week 17 when crossed over to the EPO + ETAN arm (Regimen B)

4. a comparison of the proportion of patients in each regimen who experience significant weight loss.

EFFICACY AND DISEASE STATUS EVALUATION CRITERIA

♦ 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.

The following measurement tools will be used in this study:

• Linear Analog Scale Assessment

• Fact-An

• CLOX: An Executive Clock Drawing Task

• EXIT 25: The Executive Interview.

Claims

WHAT IS CLAIMED IS:

1. A method for treating a patient, comprising the steps, in any order or concurrently: a) administering a therapeutic amount of at least one anti-TNF alpha compound; and b) administering a therapeutic amount of erythropoietin.

2. The method of claim 1 wherein the patient has at least one malignancy.

3. The method of claim 1 wherein only one anti-TNF alpha compound is administered.

4. The method of claim 1 wherein two or more anti-TNF alpha compounds are administered.

5. The method of claim 1 wherein the anti-Tumor Necrosis Factor compound decreases circulating, active TNFα by a mechanism selected from a group consisting of decreasing TNFα mRNA transcription, increasing TNFα mRNA degradation, inhibiting TNFα mRNA translation, decreasing cellular secretion of TNFα protein, and reducing circulating TNFα protein.

6. The method of claim 1 wherein the anti-Tumor Necrosis Factor compound is selected from the group consisting of Thalidomide, Pentoxifylline, Infliximab, Glucocorticoids, and Etanercept.

7. A method for treating a patient having a malignancy, comprising the steps, in any order or concurrently: a) administering a therapeutic amount of at least one anti-TNF alpha compound; b) administering a therapeutic amount of erythropoietin; and c) administering a therapeutic amount of an anti-tumor agent.

8. The method of claim 7 wherein only one anti-TNF alpha compound is administered.

9. The method of claim 7 wherein two or more anti-TNF alpha compounds are administered.

10. The method of claim 7 wherein the anti-Tumor Necrosis Factor compound decreases circulating, active TNFα by a mechanism selected from a group consisting of decreasing TNFα mRNA transcription, increasing TNFα mRNA degradation, inhibiting TNFα mRNA translation, decreasing cellular secretion of TNFα protein, and reducing circulating TNFα protein.

11. The method of claim 7 wherein the anti-Tumor Necrosis Factor compound is selected from a group consisting of Thalidomide, Pentoxifylline, Infliximab, Glucocorticoids, and Etanercept.