Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-02-27
2003-01-07
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S283000
Reexamination Certificate
active
06503889
ABSTRACT:
The present invention relates to therapeutic pharmaceutical compositions comprising an effective amount of a pyrimidine derivative in combination with an effective amount of camptothecin or camptothecin derivatives, which are useful for the treatment of cancer.
The invention relates to the treatment of cancer, especially solid tumors, with associations of camptothecin derivatives and other anticancer drugs and the use of such associations for an improved treatment.
More specifically, the invention relates to anticancer treatments with associations of camptothecin derivatives such as irinotecan (CPT-11; Camptosar®), topotecan, 9-aminocamptothecin and 9-nitrocamptothecin and a pyrimidine derivative. Pyrimidine derivatives include uracil, thymine, cytosine, methylcytosine and thiamine containing compounds. Examples of such pyrimidine derivatives are capecitabine, gemcitabine and multi-targeted antifolate (MTA), also known as pemetrexed.
European patent EP 137,145, incorporated herein, describes camptothecin derivatives of the formula:
in which, in particular, R
1
is hydrogen, halogen or alkyl, X is a chlorine atom or NR
2
R
3
in which R
2
and R
3
, which may be identical or different, may represent a hydrogen atom, an optionally substituted alkyl radical, a carbocycle or a heterocycle which are optionally substituted, or alkyl radicals (optionally substituted) forming, with the nitrogen atom to which they are attached, a heterocycle optionally containing another hetero atom chosen from O, S and/or NR
4
, R
4
being a hydrogen atom or an alkyl radical and in which the group X—CO—O— is located in position 9, 10 or 11 on ring A.
These camptothecin derivatives are anticancer agents which inhibit topoisomerase I, among which irinotecan, in which X—CO—O— is [4-(1-piperidino-1-piperidino]carbonyloxy, is an active principle which is particularly effective in treatment of solid tumors, and in particular, colorectal cancer.
The European patent application EP 74,256 also describes other camptothecin derivatives which are also mentioned as anticancer agents, in particular, derivatives of a structure analogous to the structure given above and in which X—CO—O— is replaced with a radical —X′R′ for which X′ is O or S and R′ is a hydrogen atom or an alkyl or acyl radical.
Other camptothecin derivatives have also been described, for example, in the patents or patent applications EP 56,692, EP 88,642, EP 296,612, EP 321,122, EP 325,247, EP 540,099, EP 737,686, WO 90/03169, WO 96/37496, WO 96/38146, WO 96/38449, WO 97/00876, U.S. Pat. No. 7,104,894, JP 57 116,015, JP 57 116,074, JP 59 005,188, JP 60 019,790, JP 01 249,777, JP 01 246,287 and JP 91 12070 or in Canc. Res., 38 (1997) Abst. 1526 or 95 (San Diego—April 12-16), Canc. Res., 55(3):603-609 (1995) or AFMC Int. Med. Chem. Symp. (1997) Abst. PB-55 (Seoul—July 27-August 1).
Camptothecin derivatives are usually administered by injection, more particularly intravenously in the form of a sterile solution or an emulsion. Camptothecin derivatives, however, can also be administered orally, in the form of solid or liquid compositions.
CPT-11 is one of the most active new agents in colorectal cancer. Colorectal cancer is a leading cause of morbidity and mortality with about 300,000 new cases and 200,000 deaths in Europe and the USA each year (See P. Boyle, Some Recent Developments in the Epidemiology of Colorectal Cancer, pages 19-34 in
Management of Colorectal Cancer,
Bleiberg H., Rougier P., Wilke H. J., eds, (Martin Dunitz, London 1998); and—Midgley R. S., Kerr D. J., Systemic Adjuvant Chemotherapy for Colorectal Cancer, pages 126-27 in
Management of Colorectal Cancer,
Bleiberg H., Rougier P., Wilke H. J., eds, (Martin Dunitz, London 1998).) Although about fifty percent of patients are cured by surgery alone, the other half will eventually die due to metastatic disease, which includes approximately 25% of patients who have evidence of metastases at time of diagnosis.
In colorectal cancer patients resistant to 5-FU, single agent CPT-11 tested in two large phase III randomized trials resulted in a longer survival and a better quality of life compared with supportive care only (D. Cunningham, S. Pyrhönen, R D. James et al, The Lancet, 352 (9138):1413-1418 (1998)) and also in a longer survival without deterioration in quality of life compared with 5-FU/FA best infusional regimens (P. Rougier, E. van Cutsem et al; The Lancet, 352 (9138):1407-1418 (1998)). CPT-11 is therefore the reference treatment in metastatic colorectal cancer (MCRC) after failure on prior 5-FU treatment.
CPT-11 has also been shown to be at least as active as the so-called standard 5-FU/FA bolus in chemotherapy naive patients with MCRC [Proc. Am. Soc. Clin. Oncol., vol 13 (1994), (Abstr. # 573); J. Clin Oncol, 14(3):709-715 (1996); J. Clin Oncol, 15(1):251-260 (1997).
Combinations of irinotecan (CPT-11) and 5-FU have already been studied in phase I studies in Japan, indicating in preliminary results that concurrent administration is feasible in terms of safety (L. Saltz et al., Eur. J. Cancer 32A, suppl 3: S24-31 (1996))
A study relating to CPT-11 published by D. Cunningham, Eur. J. Cancer, 32A suppl. 3:S1-8 (1996) concluded that CPT-11 offers a different cytotoxic approach that may complement the use of 5-FU/folinic acid in colorectal cancer.
To demonstrate the efficacy of a combination, it may be necessary to compare the maximum tolerated dose of the combination with the maximum tolerated dose of each of the separate constituents in the study in question. This efficacy may be quantified, for example by the log
10
cells killed, which is determined by the following formula:
log
10
cell killed=
T
-
C
(days)/3.32×
T
d
in which T-C represents the time taken for the cells to grow, which is the mean time in days for the tumors of the treated group (T) and the tumors of the treated group (C) to have reached a predetermined value (1 g for example), and T
d
represents the time in days needed for the volume of the tumor in the control animals (T. H. Corbett et al., Cancer, 40, 2660.2680 (1977); F. M. Schabel et al., Cancer Drug Development, Part B, Methods in Cancer Research, 17, 3-51, New York, Academic Press Inc. (1979)). A product is considered to be active if the log
10
cell kill is greater than or equal to 0.7. A product is considered to be very active is the log
10
cell kill is greater than 2.8.
The efficacy of a combination may also be demonstrated by determination of the therapeutic synergy. A combination manifests therapeutic synergy if it is therapeutically superior to one or the other of the constituents used at its optimum dose (T. H. Corbett et al., Cancer Treatment Reports, 66,1187 (1982)).
It has now been found that the combination of camptothecin derivatives with pyrimidine derivatives is especially effective in the treatment of solid tumors, such as ovarian, NSCLC and colorectal cancer. Among the effective pyrimidine derivatives are gemcitabine, MTA, and capecitabine.
Gemcitabine exhibits antitumor activity. The salt of gemcitabine, 2′-deoxy-2′,2′-difluorocytidine monohydrochloride, is provided for clinical use as an intravenous solution for treatment of solid tumors such as non-small cell lung cancer (NSCLC).
Gemcitabine exhibits cells phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and also blocking the progression of cells through the G1/S-phase boundary. Gemcitabine is metabolized intracellularly by nucleoside kinases to the active diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. The cytotoxic effect of gemcitabine is attributed to a combination of two actions of the diphosphate and the triphosphate nucleosides, which leads to inhibition of DNA synthesis. First, gemcitabine diphosphate inhibits ribonucleotide reductase, which is responsible for catalyzing the reactions that generate the deoxynucleoside triphosphates for DNA synthesis. Inhibition of this enzyme by the diphosphate nucleoside causes a reduction in the concentrations of deoxynucleotide
Aventis Pharma S.A.
Finnegan Henderson Farabow Garrett & Dunner LLP
Goldberg Jerome D.
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