JP2001288109A - Therapy for melanoma - Google Patents

Abstract

PROBLEM TO BE SOLVED: To satisfy the necessity for an improved therapy for treating a patient having melanoma within high patient compliance. SOLUTION: A PEG-derivatized interferon α is used for producing a medicine in order to treat the patient having the surgically enucleated melanoma, in which a therapeutically effective dose of the PEG-derivatized interferon α is administered to the patient for a period sufficient to increase the survival time without progress of the melanoma.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION The present invention relates to the treatment of melanoma after a clear surgical removal of a lesion by administering a therapeutically effective dose of PEGylated interferon alpha for a time sufficient to increase progression-free survival. Improved treatments for treating patients having.

[0002]

BACKGROUND OF THE INVENTION The incidence of melanoma is increasing at a rate that exceeds that of all other solid tumors. Patients with primary melanoma larger than 4 mm or metastatic melanoma with regional lymph nodes should
Has a risk of 90% mortality.

Recently, Eastern Cooperat
live Oncology Group ("ECO
G ") is the result of the use of interferon alpha-2b in patients with stage III cutaneous melanoma as adjuvant therapy after surgery for deep primary melanoma (T4) or focal metastatic melanoma (N1) (Kirk
wood, J.M. M. J. et al. Clin. Oncol. 1
4: (1996) 4-17). Interferon alpha-2b treatment used by ECOG is intravenous ("IV") with a daily increase in body surface area of 5 days a week for 4 weeks.
An induction phase of administering 20 million IU of interferon α-2b per square meter (m ² ) and then 48
Includes maintenance of treatment with 10 million IU / m ² of interferon alpha subcutaneously (“SC”) three times a week (“TIW”). Significant improvements in median disease-free survival and overall survival were noted in 50% of patients during IV induction therapy and 48% of patients in SC maintenance, despite reduced dosing or delayed toxicity. (Observation) was observed. Hematological, neurological, and systemic toxicities occurred among these patients, requiring dose reduction or withdrawal from interferon alpha treatment. Subject compliance with dosing and dosing regimens during both phases is considered important to achieve maximal clinical benefit.

[0004]

SUMMARY OF THE INVENTION Satisfying the need for improved therapies for treating patients with melanoma with higher patient compliance.

[0005]

SUMMARY OF THE INVENTION The present invention is directed to the use of PEGylated interferon alpha for the manufacture of a medicament for treating a patient having surgically removed melanoma, wherein the medicament comprises a therapeutic agent. An effective dose of PEGylated interferon alpha for a period sufficient to increase progression-free survival,
There is provided a use which is administered to such a patient.

In one embodiment, the PEGylated interferon is PEGylated interferon α-2.
a or PEGylated interferon α-2b.

[0007] In a preferred embodiment, the patient is an untreated patient.

In a further preferred embodiment, said untreated patient is a patient with a newly diagnosed melanoma.

[0009] In another embodiment, the patient is a treatment experienced patient.

[0010] In a preferred embodiment, the treatment-experienced patient is intolerant to or resistant to interferon-α.

In another embodiment, the period is at least about 24 months.

In yet another embodiment, the above-described PE
G-interferon alpha is administered after surgical resection of primary melanoma.

In yet another embodiment, the PEG described above
PEGylated interferon α
-2b and the effective amount is about 3.0 micrograms / kg to 9.0 micrograms / kg administered once a week.
kg range.

In another embodiment, the PEGylated interferon α is PEGylated α-2a and the effective amount is within the range of about 200 micrograms to 250 micrograms administered weekly. is there.

The present invention also relates to the use of PEGylated interferon alpha for the manufacture of a medicament for treating a patient having surgically removed cutaneous melanoma, the medicament comprising an effective amount of PEGylated melanoma. Providing interferon alpha is administered to the patient once a week for a period of time sufficient to increase progression-free survival.

[0016] In one embodiment, the PEGylated interferon α is PEGylated interferon α-
2b and the effective amount is about 3.0 micrograms / kg to 9.0 micrograms / kg administered once a week.
kg range.

For another embodiment, the PEGylated interferon-α is PEGylated α-2a and the effective amount is in the range of about 200 micrograms to 250 micrograms administered weekly. .

In another embodiment, the time period is at least about 100 weeks.

The present invention also relates to the use of PEGylated interferon alpha for the manufacture of a medicament for treating a patient having cutaneous melanoma, wherein the patient has between about 3.0 micrograms / kg and about 9 micrograms / kg. 2.0 microgram / kg PE
Provided is the use, wherein the G-interferon α-2b is administered once a week for a period sufficient to increase progression-free survival.

In one embodiment, the period is about 100 weeks.

In another embodiment, from about 4.5 to about 6.
5 microgram / kg PEGylated interferon alpha
-2b is administered once a week.

A method comprising the step of marketing a therapeutically effective dose of PEGylated interferon alpha for administration to a patient with melanoma within about 60 days after surgery in a protocol over a period of at least about 100 weeks. I do.

In one embodiment, the PEGylated interferon α is PEGylated interferon α-2.
b. and wherein said effective amount is administered once a week.
0 microgram / kg to about 9.0 microgram / k
g.

In another embodiment, the PEGylated interferon α is PEGylated α-2a and the effective amount is from about 200 micrograms administered weekly.
Within the range of 250 micrograms.

The present invention also provides a kit for treating a patient having surgically removed cutaneous melanoma, the kit comprising PEGylated interferon alpha and instructions wherein the medicament comprises a therapeutically effective amount of PEGylated interferon α
Is administered to the patient once a week for a period of time sufficient to increase progression-free survival.

In one embodiment, the PEGylated interferon α is PEGylated interferon α-2.
b, and said effective amount is about once a week.
0 microgram / kg to 9.0 microgram / kg
Within the range.

In another embodiment, the PEGylated interferon α is PEGylated interferon α-2.
a and the effective amount is in the range of about 200 micrograms to 250 micrograms administered weekly.

[0028] In yet another embodiment, the period is at least about 100 weeks.

The present invention also provides a kit comprising PEGylated interferon alpha and instructions for treating a patient having cutaneous melanoma, wherein the patient has about 3.0 micrograms / kg to about 9. There is provided a use wherein 0 microgram / kg of PEGylated interferon α-2b is administered once a week for a period sufficient to increase progression-free survival.

[0030] In one embodiment, the time period is about 100 weeks.

In another embodiment, about 4.5 to about 6.
5 microgram / kg PEGylated interferon alpha
-2b is administered once a week.

The present invention provides a method of treating a patient having a surgically removed melanoma, the method comprising providing such a patient with a therapeutic treatment for a period of time sufficient to increase progression-free survival. Administering an effective dose of PEGylated interferon alpha.

The present invention also provides a method of treating a patient having a surgically removed melanoma of the skin, comprising administering to said patient an effective amount of PEGylated interferon alpha.
Once a week, long enough to increase progression-free survival,
Administering.

The present invention further provides a method of treating a patient having a surgically removed cutaneous melanoma, the method comprising providing such a patient with a period of time sufficient to increase progression-free survival. 3.0 micrograms / kg to about 9.0 micrograms / kg of PEGylated interferon alpha-2
b) once a week. In a preferred embodiment, 6.0 micrograms per kilogram is administered to the patient weekly for 8 weeks and no more than 3.0 micrograms per kilogram is administered weekly to the patient for 5 years from the first dose minus 8 weeks. Is administered. If less than 3.0 micrograms per kilogram is to be administered to the patient, preferably, this dose reduction step is between 3.0-2.0-1.0 micrograms per kilogram.

The present invention further provides for a protocol over a period of at least about 100 weeks, wherein about 60
Providing a therapeutically effective dose of interferon alpha for administration to a patient having melanoma within a day.

[0036]

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to patients with melanoma, especially stage IIB (lesion> 4 mm but without positive nodules) melanoma, and stage III (lesion>
4 mm and nodule-positive) patients with primary cutaneous melanoma are preferably treated with their stage IIB or I
An improved method of treating stage II melanoma after surgery is provided. This improved method provides a safer, more effective, and more tolerable adjuvant therapeutic treatment for melanoma with the use of weekly PEGylated interferon injections. Melanoma patients that can be treated according to the improved method of the present invention include those newly diagnosed with the disease who have been free of the disease for 56 days after surgery but who have had systemic relapse of the disease. Includes patients at high risk. As used herein, the term "patients at high risk" refers to melanoma patients with foci of Breslow thickness of> 4 mm, as well as any Breslow thickness with concurrent primary or recurrent nodules Means a patient having the above-mentioned lesion. Also included is the intolerance or resistance of melanoma patients to interferon alpha treatment. Treatment with PEGylated interferon-alpha according to the present invention requires at least about 2 years (about 100-104 weeks) unless there is clinical evidence of disease progression, unacceptable toxicity, or the patient's requirement to discontinue this therapy. ) And last up to 5 years.

Administered PEGylated Interferon α
Is a PEGylated interferon α-2b, the administered therapeutically effective amount of the PEGylated interferon α-2b
2b ranges from about 3.0 to about 9.0 micrograms per kilogram of PEGylated interferon alpha-2b administered once weekly (QW), preferably PEG.
About 4.5 to about 6.5 micrograms per kilogram of activated interferon α-2b (QW);
More preferably, PEGylated interferon α-2b (Q
W) in the range of about 5.5 to about 6.5 micrograms per kilogram, and most preferably in the range of about 6.0 micrograms per kilogram of PEGylated interferon alpha-2b administered in QW. is there.

In a preferred embodiment, 6.0 micrograms per kilogram is administered weekly to the patient for 8 weeks, and 3.0 micrograms per kilogram is less than 3.0 micrograms per kilogram for a period of five to eight weeks less than the first dose. Administered weekly. If less than 3.0 micrograms per kilogram is to be administered to this patient, preferably the dose escalation phase will be 3.0-2.0-kg per kilogram.
1.0 microgram.

When the administered PEGylated interferon α is PEGylated interferon α-2a, a therapeutically effective amount of the administered PEGylated interferon α-2a is administered.
Once a week ("QW") is in the range of about 50 micrograms to about 500 micrograms, preferably about 200 micrograms to about 250 micrograms QW.

As used herein, the term "PEGylated interferon alpha" refers to a conjugate of interferon alpha with polyethylene glycol, preferably interferon alpha-2a and 2b. A preferred polyethylene glycol interferon α-2b conjugate is PE
G ₁₂₀₀₀ -interferon α2b. As used herein, the phrases “12,000 molecular weight polyethylene glycol conjugated interferon α” and “PEG ₁₂₀₀₀ −
IFNα ”is prepared according to the method of International Application WO 95/13090 and comprises interferon α-2
A conjugate containing a urethane bond between the amino group a or -2b and polyethylene glycol having an average molecular weight of 12,000 is meant.

A preferred PEG ₁₂₀₀₀ -interferon α-2b is prepared by attaching a PEG polymer to the ε-amino group of a lysine residue in the IFN α-2b molecule. A single PEG ₁₂₀₀₀ molecule is attached via a urethane linkage to a free amino group on the IFNα-2b molecule. This conjugate is characterized by the molecular weight of the PEG ₁₂₀₀₀ attached. The PEG ₁₂₀₀₀ -IFNα-2b conjugate is formulated as a lyophilized powder for injection. IFN
The purpose of conjugation of α to PEG is to improve protein delivery by significantly extending its plasma half-life, thereby providing prolonged activity of IFNα.

As used herein, the term "interferon alpha" inhibits viral replication and cell growth,
And a family of highly homologous species-specific proteins that modulate the immune response. Representative suitable interferons alpha include, but are not limited to, Schering Corporation,
Kenilworth, N.M. J. Int available from
recombinant interferon α-2b, such as ron-A interferon, Hoffmann-LaRoch
e, Nutley, N .; J. Rofer available from
recombinant interferon α-2a, such as on interferon, Boehringer Ingelhei
m Pharmaceutical, Inc. , Rid
gefield, CT. Berfor available from
Recombinant interferon α-2C such as α2 interferon, Sumiferon or Glaxo-Wellc available from Sumitomo, Japan
ome Ltd. , London, Great Bri
Interferon α-n, a purified blend of natural α-interferons such as Wellferon interferon α-n1 (INS) available from Tyne
1, or consensus alpha interferon as described in U.S. Patent Nos. 4,897,471 and 4,695,623 (especially Examples 7, 8 or 9 thereof), and Amgen, Inc. , Newbury
Specific products available from Park, CA, or In
Made by terferon sciences,
And P under Alferon Tradename
flude Frederick Co. Norwal
k, CT. Interferon α-n3, which is a mixture of natural α-interferons available from E.I. The use of interferon α-2a or α-2b is preferred. Among all interferons, interferon α
-2b is most preferred because it has the broadest certification worldwide to treat chronic hepatitis C infection. The production of interferon α-2b is described in US Pat. No. 4,530,90.
No. 1.

Other interferon-α conjugates can be prepared by coupling interferon-α with a water-soluble polymer. A non-limiting list of such polymers includes other polyalkylene oxide homopolymers such as polypropylene glycols, polyoxyethylenated polyols, their copolymers, and their block copolymers. As an alternative to polyalkylene oxide based polymers, dextran,
Virtually non-antigenic substances such as polyvinylpyrrolidone, polyacrylamide, polyvinyl alcohol, and carbohydrate-based polymers can be used. Such interferon alpha polymer conjugates are disclosed in U.S. Pat.
No. 66,106, U.S. Pat. No. 4,917,888, European Patent Application No. 0,236,987, European Patent Application Nos. 0,510,356, 0,593,868 and 0,086. No. 809,996 (PEGylated interferon α-2a) and International Publication No. WO 95/130.
No. 90.

Pharmaceutical compositions of PEGylated interferon α suitable for parenteral administration can be prepared in a suitable buffer (eg, Tr
is-HCl, acetate, or dibasic sodium phosphate /
Phosphate buffers such as sodium monophosphate), as well as pharmaceutically acceptable excipients (eg, sucrose), carriers (eg, human serum albumin) in sterile water for injection, tonicity It may be formulated with a drug (eg, NaCl), a preservative (eg, thimerosal, cresol, or phenyl alcohol (or benzyl alcohol)), and a surfactant (eg, tween or polysorbate). PEGylated interferon α is
It can be stored as a lyophilized powder under refrigeration at 2-8 ° C. The reconstituted aqueous solution is stable when stored between 2-8 ° C and is used within 24 hours of reconstitution. See, for example, U.S. Patent Nos. 4,492,537; 5,762,923 and 5,766,582. The reconstituted aqueous solution may also be stored in a pre-filled multi-dose syringe, such as a syringe useful for delivering drugs such as insulin. Exemplary suitable syringes include pre-filled vials that attach to pen-type syringes such as NOVOLET Novo Pen available from Novo Nordisk, as well as pre-filled pen shapes that allow the user to easily inject themselves. A system comprising the syringe of the present invention. Other syringe systems include diluent and lyophilized P
Included is a pen-type syringe with a glass cartridge containing EGylated interferon alpha powder in a separate compartment.

As used herein, the term "patient with melanoma" means any patient with melanoma, and is untreated, as well as patients who have undergone treatment, and stage IIB or III Includes patients with early stage cutaneous melanoma. All patients with melanoma are preferably treated by extensive excision of the primary melanoma lesion before commencement of the improved therapy of the present invention.

As used herein, the term “na 処置 ve patient” refers to a patient with melanoma and can be any chemotherapeutic drug (eg, dacarbazine (“DTIC”)) or immunotherapy (eg, Includes newly diagnosed melanoma patients who have never been treated with IL-2 and any interferons, including but not limited to interferon alpha or PEGylated interferon alpha. All untreated patients with melanoma are preferably
It is treated by extensive resection of the primary melanoma lesion before the start of the improved treatment of the present invention.

As used herein, the term “treatment experienced patient” refers to any form of chemotherapeutic drug (eg, DTI
C) or immunotherapy (interferon alpha, IL-2,
And GMCSF (including but not limited to). All treatment-experienced patients with melanoma are preferably treated by extensive excision of the primary melanoma lesion before commencement of the improved therapy of the present invention.

As used herein, the term “primary cutaneous melanoma” refers to the current (1992) American J
oint Committee on Cancer
Staging Criteria ("AJCC"):
the AJCC Manual for Strat
egy of Cancer (4th edition) Philade
lphia PA Lippincott Publi
Mean histologically demonstrated primary cutaneous melanoma as defined by shers 1992 and includes: (a) Nodule negative IIB with deep primary melanoma with Breslow depth greater than 4 mm Stage disease, and (b) nodule-positive stage III disease defined as follows: (1) primary melanoma with deep Breslow depth greater than 4 mm (designated CS1 PS1: T4N0M0);
(2) Primary melanoma of any tumor stage in the presence of N1 regional lymph node metastases (CS1), where clinically occult local lymph node metastases were detected at selected lymph node resection sites
PS2: Named any TpN1M0); (3) T1-4
Clinically overt N1 regional lymph node involvement synchronous with primary melanoma (CS2 PS2: named any TcN1M0); and (4) after appropriate surgery for any depth of primary melanoma Recurrence of regional lymph nodes at any interval (named CS2R: TxrN1M0 recurrence). Groups 1-3 patients were required to enter this study within 56 days of the first primary melanoma biopsy. Four groups of patients with local nodular recurrence were required to enter this study within 42 days of lymphadenectomy.

All patients with stage III melanoma
It should be treated by extensive resection of the primary melanoma lesion.

Patients with clinically positive nodules in the inguinal, axillary, or cervical regions should undergo a complete lymphadenectomy to surgically remove these sites.

All surgeries should be completed within 56 days prior to randomization to this clinical study.

As used herein, the term “progression-free survival” (“PFST”) refers to the progression or recurrence of disease by histological or cytological evidence from the start of melanoma treatment according to the present invention. It means the period until it is recorded.

The expected progression-free survival for a melanoma patient treated according to the method of the present invention is at least about 4 years from the start of the melanoma treatment of the present invention; preferably, the PFST is a melanoma of the present invention. About 30 from the start of treatment
~ 43 months.

The expected increase in progression-free survival for melanoma patients treated according to the methods of the present invention is greater than about 1.0 years to about 1.5 years as compared to controls (observations).

The following criteria for failure to treat constitute only acceptable evidence of disease recurrence or progression: Lung / liver: positive cytology or biopsy in the presence of a single new lesion, or Appearance of multiple lesions consistent with metastatic disease Central nervous system: positive brain CT or MRI scan or cerebrospinal fluid (CSF) cytology Skin, subcutaneous, and lymph node recurrence: positive cytology or biopsy Other organs: positive cytology or biopsy in the presence of a single new lesion, or the appearance of multiple lesions consistent with metastatic disease identified by two different radiological studies (ie, positive gallium Scan and Contrast GI Series, or Abdominal Ultrasound, X-Ray, or CT for Abdominal Disease).

The term “prohibited medication” as used herein
Include: a) other chemotherapy, hormonal therapy, immunotherapy, biological therapy, or radiation therapy b) colony stimulating factor including erythropoietin and G-CSF c) other research drugs d) chronic systemic Sexual corticosteroid therapy.

A melanoma patient treated according to the method of the present invention should not receive any of the above-listed prohibited medications during this treatment period.

The preferred method of administering PEGylated interferon-α is parenteral, as the PEGylated interferon-α formulation is not effective when administered orally, and is preferably subcutaneous, IV, or IM injection. by. Of course, the administration of other forms of both medicaments (eg, by nasal spray, transdermal, suppository, sustained release dosage form, and pulmonary inhalation) is contemplated where they become available. Any form of administration can be used so long as the proper dosage is delivered without destroying the active ingredient.

The following clinical study design can be used to treat melanoma patients according to the methods of the present invention. Many modifications of this clinical study design protocol will be apparent to the skilled clinician, and the following study design is intended to limit the scope of the method of the present invention as defined by the claims appended hereto. Should not be interpreted.

[0060]

EXAMPLE (Clinical Study Design) This is a resected II
PEG Intro when given as adjuvant therapy in patients with stage I nodule positive cutaneous melanoma
n (PEGylated interferon α2b, ie, PEG
₁₂₀₀₀ -Interferon α2b) and INTRON
® A (interferon α2b) (each of which is available from Schering Corporation,
Available from Kenilworth, NJ), safety, efficacy, and impact on quality of life;
Phase II / III randomized, controlled, multicenter, open-label study designed to evaluate population pharmacokinetics of the EG intron. It is expected that approximately 450 subjects will be enrolled and 225 subjects will be randomized to each treatment group.

Subjects will enter this study within 56 days of their final stage III melanoma surgery and will be randomized into one of the two treatment groups shown below. Final surgery involves extensive surgical resection of the primary melanoma,
And lymphadenectomy of all clinically positive nodules in the groin, axilla, or neck. All surgeries should be completed at least 56 days before randomization.

(Group A: INTRON (registered trademark) A) 2
0 MIU / m ² / day IV 5 days / week x 4 weeks, then 10
MIU / m ² SC TIW × 48 weeks.

(Induction therapy: 20 MIU / m ² / day IV week, 5 days for 4 weeks) All subjects randomized to treatment group A were intravenous INTRON® A, 20 million international Induction treatment is started with 4 weeks / unit / m ² / day, 5 days / week. Acetaminophen (500-1000mg)
Can be given in the clinic 30 minutes before receiving the first dose of INTRON® A. Subjects should be observed for 2 hours after the first dose. Acetaminophen (500-650 mg POq 4-6 hours) should be continued if necessary and 3000 mg
/ Day should not be exceeded.

(Maintenance treatment: 10 MIU / m ² S for 48 weeks)
(CTIW) After induction treatment, the subject continues on maintenance treatment,
INTRON® A, 10 million international units / m ² /
I receive three SCs every week for 48 weeks.

(Group B: PEG intron: PEG ₁₂₀₀₀₎
-Interferon α-2b, 6.0 μg / kg, SC
Subjects randomized to treatment group B once a week for 2 years had PEG ₁₂₀₀₀ -interferon α-2b, 6.0.
Receive once weekly for 2 years at μg / kg, SC for 2 years. Acetaminophen (500-1000 mg) can be given at the clinic 30 minutes before receiving the first dose of PEG intron. Subjects should be observed 2 hours after the first dose. Acetaminophen (500-650m
gPOq 4-6 hours) should be continued if necessary and should not exceed 3000 mg / day.

(Study Duration and Visit Schedule) PEG ₁₂₀₀₀ -interferon α2b (about 104
Week) or INTRON® A (Week 52) treatment as planned unless there is evidence of disease recurrence, unacceptable toxicity, or subject's requirement to discontinue treatment. You can continue. The tolerability and quality of life of each study procedure is assessed from clinical observations, routine laboratory tests, and assessment of quality of life over the course of treatment. After completion of treatment, subjects continue to be tracked for evidence of disease recurrence and complete quality of life assessments. If the melanoma recurs, further treatment is at the doctor's discretion. All subjects will be followed for survival regardless of when treatment is stopped. Relapse-free and overall survival analysis is also performed regardless of when treatment is stopped. Relapse-free and overall survival analysis is an event-waiting strategy.

The duration of the study is based on achieving a therapeutic response and is determined individually for each subject.

The study population includes male and female patients with cutaneous melanoma and is included if they meet the inclusion and exclusion criteria set forth below: (Subject inclusion criteria) The body is eligible for participation in the study if: a) The subject has histologically recorded primary cutaneous melanoma that meets one of the following staging criteria: Must: • Any stage primary melanoma in the presence of N1 regional lymph node metastasis detected by selective lymph node dissection or sentinel node biopsy with clinically insignificant regional lymph node metastasis (Arbitrary pTN ₁ M ₀ ). • Clinically overt N1 or N2a regional lymph node involvement synchronous with T _{1-4 of} primary melanoma (any pTrN
_1-2a M _0). • Local lymph node recurrence at any interval (any pTrN) after appropriate surgery for any depth of primary melanoma
_1-2a M _0). b) Subjects must have had complete resection of all known diseases with appropriate surgical margins within 56 days prior to randomization to the study. c) The subjects were Minna, JD et al.
f the Lung ", DeVita V et al., Can
cer: Principles and Practi
ced of Oncology, Lippincot
t, Philadelphia, PA 1989 53
Must have an ECOG performance state of 0 or 1 as defined on page 6. d) Subjects must be between the ages of 18-70. e) Subjects have adequate liver function as defined by the following parameters obtained within 14 days prior to the start of study treatment:
Must have renal and bone marrow functions.

1) Hematology:-Leukocyte count (WBC) ≥ 3,000 cells / μl-Hemoglobin concentration ≥ 9 g / dl 2) Kidney and liver function:-Serum creatinine ≤ 2.0 mg / dl or ≥ 50
Calculated creatinine clearance in ml / min-serum bilirubin <unless due to disease invasion
2 times the upper limit of normal (ULN)-AST / ALT (SGOT / SGPT) <2 of ULN
F) Subject has submitted an optional consent form prior to study participation, willing to participate in the study, and complete all follow-up assessments.

Subject Exclusion Criteria Subjects are not eligible for participation in the study if: a) any of chemotherapy, immunotherapy, hormonal therapy, or radiation therapy for melanoma Subjects who have previously received the b) Subjects with evidence of distant or non-local lymph node metastasis, metastasis in transit, or positive lymph nodes with an unknown primary tumor. c) Subjects that cannot be completely resected surgically because the disease has spread extensively outside the joint capsule. d) Subjects who have previously received interferon alpha for any reason (although such patients could still be treated according to the methods of the present invention, but only from this enrollment study). Excluded). e) Severe cardiovascular disease, ie Bruce RA:
"Evaluation of Functional
Capacity and ExerciseTole
lance of Cardiac Subject
s "Mod. Concepts Cardiovasc
Dis 1956; a subject with arrhythmia requiring chronic treatment, congestive heart failure (NYHA class III or IV), or symptomatic ischemic heart disease, as defined by 25-321. f) Subjects with a history of neuropsychological disorders requiring hospitalization. g) Subjects with thyroid dysfunction that does not respond to treatment. h) Subjects with uncontrolled diabetes. i) Subjects with a previous history of malignancy other than non-melanoma skin or cervical cancer that was surgically treated in situ within the last 5 years. j) Subjects with a seropositive history of HIV. k) Subjects who are pregnant, lactating or fertile and have not performed effective contraceptive measures. l) Subjects with active and / or uncontrolled infection, including active hepatitis. m) Subjects with medical conditions requiring chronic systemic corticosteroids. n) Subjects known to be actively abusing alcohol or drugs. o) Subjects who have received any experimental treatment within 30 days prior to randomization in this study. p) Subjects who have not recovered from the effects of recent surgery.

Subject Discontinuation Criteria It is the right and obligation of the clinical researcher to discontinue treatment of any subject whose health or well-being may be jeopardized by the continuation of the study.

The subject was identified for one of the following reasons:
Can be discontinued before completion of the study: a) The subject manifests a recorded progression or relapse of the disease, as defined herein above. b) The subject has a clinically significant adverse event, as determined by the principal investigator. c) Request that the subject withdraw from the study. d) Subject cannot complete evaluation / visit of the study due to unforeseen circumstances. e) The subject manifests in the investigator's opinion other circumstances that warrant withdrawal from the study. f) The subject manifests severe depression or any other psychiatric disorder requiring hospitalization. g) Subjects experience a significant allergic response to the drugs of this study as evidenced by angioedema, bronchoconstriction, or anaphylaxis. h) The subject receives treatment with a prohibited medication as set forth herein above. i) The subject experiences recurrent toxicity despite dose alterations as described herein below.

All subjects are followed for survival regardless of when the study is stopped. Subjects who discontinue for reasons other than disease recurrence should also be followed for recurrence and survival.

Analysis of Primary and Secondary Endpoints The primary endpoint is the progression free survival (PFS) period, defined as the period from randomization to progression or death. PFS is
Recurrences are assessed by clinical observations, recurrences are recorded by appropriate radiography and histological methods, and independent central review (Independent Center)
ral Review).

Secondary endpoints are overall survival, safety, quality of life, and population pharmacokinetics (PK). Safety and tolerability are assessed from clinical observations over the course of treatment and routine laboratory tests. Health-related quality of life (HQL) is assessed from the HQL questionnaire. Population pharmacokinetics is assessed from regular serum sampling in the PEG Intron group.

Subjects enrolled in group A who have not been able to tolerate the IV induction dose regimen despite altering the dose should discontinue this IV regimen but not the study. After resolution of the toxicity, those subjects may enter an INTRON® A maintenance phase with a full maintenance dose.

In order to increase progression-free survival, a method as an adjuvant therapy to untreated patients with melanoma and final surgery to treat patients who have undergone treatment, Disclosed are methods that include administering an effective amount of pegylated interferon alpha (eg, preferably, pegylated interferon alpha-2b).

[0078]

The present invention fulfills the need for improved therapies for treating patients with melanoma with higher patient compliance.

 ────────────────────────────────────────────────── ─── Continuation of Front Page (71) Applicant 596129215 2000 Galloping Hill Road, Kenilworth, New Jersey 07033-0530, US A (72) Inventor Esser Helen Rose United States of America New Jersey 07090, Westfield, Belvidele Avenue 755 F-term (reference) 4C084 AA02 DA22 NA03 NA03 NA05 ZB261

Claims (27)

[Claims] 1. Use of pegylated interferon alpha for the manufacture of a medicament for treating a patient having a surgically removed melanoma, the medicament comprising a therapeutically effective dose of pegylated interferon alpha. Is administered to such patients for a period of time sufficient to increase the progression-free survival. 2. The method of claim 2, wherein the PEGylated interferon is PE
The use according to claim 1, which is G-interferon α-2a or PEGylated interferon α-2b. 3. The use according to claim 2, wherein said patient is an untreated patient. 4. The use according to claim 3, wherein the untreated patient is a patient with a newly diagnosed melanoma. 5. The use according to claim 1, wherein said patient is a treatment experienced patient. 6. The use according to claim 5, wherein the treatment-experienced patient is intolerant to or resistant to interferon α. 7. The use of claim 1, wherein said period is at least about 24 months. 8. The use according to claim 1, wherein the PEGylated interferon alpha is administered after surgical resection of primary melanoma. 9. The method wherein the PEGylated interferon α is P
EGylated interferon α-2b and the effective amount is about 3.0 micrograms / kg administered weekly.
The use according to claim 1, which is in the range of ~ 9.0 micrograms / kg. 10. The PEGylated interferon α,
2. The use of claim 1, wherein the use is pegylated [alpha] -2a and the effective amount is in the range of about 200 micrograms to 250 micrograms administered weekly. 11. Use of pegylated interferon alpha for the manufacture of a medicament for treating a patient having surgically removed cutaneous melanoma, the medicament comprising an effective amount of pegylated interferon alpha. The use, wherein the patient is administered once a week for a period of time sufficient to increase progression-free survival. 12. The PEGylated interferon α,
PEGylated interferon α-2b and said effective amount is about 3.0 micrograms / weekly administered.
12. Use according to claim 11, which is in the range from kg to 9.0 micrograms / kg. 13. The method wherein the PEGylated interferon α is P
12. The use of claim 11, which is EGylated [alpha] -2a and wherein the effective amount is in the range of about 200 micrograms to 250 micrograms administered weekly. 14. The use according to claim 11, wherein said period is at least about 100 weeks. 15. PEGylated interferon alpha for the manufacture of a medicament for treating a patient with cutaneous melanoma
Wherein the patient has about 3.0 micrograms / gram.
Use wherein kg to about 9.0 micrograms / kg of PEGylated interferon alpha-2b is administered once a week for a period sufficient to increase progression-free survival. 16. The use according to claim 15, wherein said period is about 100 weeks. 17. About 4.5 to about 6.5 micrograms /
16. Use according to claim 15, wherein kg of PEGylated interferon alpha-2b is administered once a week. 18. A therapeutically effective dose of PE for administration to a patient with melanoma within about 60 days after surgery in a protocol over a period of at least about 100 weeks.
A method comprising the step of commercializing G-interferon α. 19. The method wherein the PEGylated interferon α is P
About 3.0 micrograms / kg, which is EGylated interferon α-2b and wherein the effective amount is administered once a week
20. The method of claim 18, wherein said method is in the range of about to about 9.0 micrograms / kg. 20. The method wherein the PEGylated interferon α is P
20. The method of claim 18, wherein the method is EGylated [alpha] -2a and the effective amount is in the range of about 200 micrograms to 250 micrograms administered weekly. 21. A kit comprising PEGylated interferon α and instructions for treating a patient having surgically removed cutaneous melanoma, wherein the medicament comprises an effective amount of PEGylated interferon α. A kit wherein the kit is administered to the patient once a week for a period sufficient to increase progression-free survival. 22. The PEGylated interferon α is P
EGylated interferon α-2b and the effective amount is about 3.0 micrograms / kg administered weekly.
22. The kit of claim 21, wherein said kit is in the range of -9.0 micrograms / kg. 23. The PEGylated interferon α,
PEGylated interferon α-2a, and wherein the effective amount is about 200 micrograms administered once a week.
22. The kit of claim 21, which is in the range of 250 micrograms. 24. The kit of claim 21, wherein said period is at least about 100 weeks. 25. A kit comprising PEGylated interferon alpha and instructions for treating a patient having cutaneous melanoma, wherein the patient has about 3.0 micrograms / kg to about 9.0 micrograms. / Kg of PEGylated interferon α-2b administered once a week for a period sufficient to increase survival without progression. 26. The kit of claim 25, wherein said period is about 100 weeks. 27. About 4.5 to about 6.5 micrograms /
26. The kit of claim 25, wherein kg of PEGylated interferon alpha-2b is administered once a week.