Posts Tagged ‘France’
Cell-Cycle Inhibitors
Mechanism Of Action
Progression through the cell cycle depends on numerous signaling pathways and checkpoints (e.g., the cyclin families of proteins, the cyclin-dependent kinases [CDKs]). Deregulation of these key cell-cycle checkpoints is observed in most cancer cells. Inhibition of these enzymes can result in cell-cycle arrest and, ultimately, cell death, usually by apoptosis. Targeting the machinery involved in the cell cycle aims to directly attack cells with a high turnover, such as cancer cells.
Alvocidib
Aventis and the National Cancer Institute (NCI) were developing alvocidib (Flavopiridol) together until Aventis discontinued its involvement in
February 2004. This synthetic flavenoid inhibits CDKs and is the first CDK inhibitor to enter trials; it is in Phase II trials for chronic lymphocytic leukemia. It has reached Phase III in France.
Preclinical research has demonstrated alvocidib’s ability to enhance both the radio- and chemosensitivity of a variety of cell lines and animal tumors. Ongoing experiments are analyzing this mechanism of action as well as further delineating alvocidib’s activity when administered alone. In a syngeneic mouse model of lym-phoma, alvocidib enhanced the tumor response to radiation, and in H460 human lung cancer cells, alvocidib enhanced the effects of docetaxel and radiation. Researchers examined the molecular pathway of alvocidib activity and found that this agent interacts synergistically with the tumor necrosis factor-related apoptosis-induced ligand (TRAIL). Alvocidib does so through a mechanism involving the downregulation of XIAP (X-linked inhibitor of apoptosis protein), resulting in apoptosis of human leukemia cells.
A Phase II study of alvocidib in patients with fludarabine-refractory chronic lymphocytic leukemia is complete. This trial was an open-label, multicenter study aiming to accrue up to 37 patients. Those registered before September 2000 received intravenous (IV) alvocidib continuously on days 1-3, and treatment was repeated every 14 days for a total of 12 courses in the absence of disease progression or unacceptable toxicity. Patients who were registered after September 2000 received IV alvocidib over one hour daily on days 1-3. Treatment was repeated every three weeks for a total of eight courses. Patients were to be followed every three months for the first year and then every six months for five years. The study aimed to assess toxicity, CR, PR, progression-free and overall survival, and the impact of alvocidib on normal T-cell subsets and immunoglobulinlevels. No data from this trial have been published.
A Phase I dose-escalation study is examining alvocidib combined with fludarabine and rituximab in patients with various lymphoproliferative disorders, including chronic lymphocytic leukemia. No data have been published.
Given the lack of data on the use of alvocidib for chronic lymphocytic leukemia, we examined results from Phase I and II studies of alvocidib as a single agent or in combination with chemotherapy in the treatment of other cancers. In a Phase II trial of single-agent alvocidib in patients with hormone-refractory metastatic prostate cancer, no objective responses were observed and only 11% of patients achieved stable disease as the best response. In addition, alvocidib administered at 40 or 50 mg/m2/day for a total of 72 hours was associated with significant toxicities that resulted in a high withdrawal rate from the study. A single-agent Phase II study of alvocidib therapy involving 33 renal-cell carcinoma patients resulted in 1 CR, 2 PRs, and 13 stable disease, but the study’s response criteria were not met. Alvocidib is being investigated in a variety of combination regimens with agents such as irinotecan, docetaxel, 5-FU and leucovorin, and paclitaxel and carboplatin. The majority of trials completed have set out to establish alvocidib’s safety and maximum tolerated dose.
Chronic Lymphocytic Leukemia:Current Therapies
Despite relatively good long-term survival rates, chronic lymphocytic leukemia is considered incurable. For many years, first-line therapy was dominated by the oral alkylating agent chlorambucil (GlaxoSmithKline’s Leukeran). The introduction of purine analogues as monotherapy or in combination with alkylating agents into current treatment strategies has vastly improved response rates, although no improvement in overall survival has yet been noted.
Patients with chronic lymphocytic leukemia do not have a wide choice of therapy options. The overall population is elderly and has a low tolerance for toxic chemotherapy regimens. Once patients have failed both chlorambucil and fludarabine (Schering AG and Berlex’s Fludara), the disease becomes extremely difficult to treat. The aim of current drug regimens is to obtain the highest possible rate and duration of remission while balancing the associated toxicity and infection rate in these patients. TABLE. Current Regimens Used for Chronic Lymphocytic Leukemia describes the current regimens used to treat chronic lymphocytic leukemia.
TABLE. Current Regimens Used for Chronic Lymphocytic Leukemia
| Regimen Components | Dose | |||
| Regimen | Agent | Availability | Common Toxicities | |
| Chlorambucil (single agent) | Chlorambucil (GlaxoSmith-Kline’s Leukeran) | US ,France, Germany, Italy, S, UK | Chlorambucil: 10 mg/m2/d on days 1 -7. Cycle repeated every 28 days. | • Myelosuppression
• Mild gastrointestinal disturbances • Increased risk of secondary malignancy |
| Fludarabine (single agent) | Fludarabine (Berlex’s Fludara, Schering’s Fludara/Fludar/ Bebeflur, generics) | US ,France, Germany, Italy, Spain, UK, Japan | Fludarabine (oral): 40 mg/m2/d on days 1-5, (IV) 25 mg/m2/d on days 1 -5. Cycle repeated every 28 days. | • Myelosuppression
• Increased infection • Neurotoxicity • Malaise/fatigue • Nausea/vomiting • Anorexia |
| Fludarabine/ cyclophosphamide (FC) | Fludarabine (Berlex’s Fludara, Schering’s Fludara/Fludar/ Bebeflur, generics) | US ,France, Germany, Italy, Spain, UK, Japan | Fludarabine (oral): 40 mg/m2/d on days 1-3, (IV) 25 mg/m2/d on days 1 -3. Cycle repeated every 28 days. | • Myelosuppression
• Increased infection • Neurotoxicity (fludarabine) • Alopecia (more common with cyclophosphamide) |
| Cyclophosphamide (Bristol-Myers Squibb’s Cytoxan/ Endoxan/ Endoxana,
Baxter’s Endoxan/ Endoxana, Shionogi’s Endoxan, Pfizer’s Neosar/Cyclostin, generics) |
US ,France, Germany, Italy, Spain, UK, Japan | Cyclophosphamide: 250 mg/m2/d on days 1 -3. Cycle repeated every 28 days. | • Malaise/fatigue
• Nausea/vomiting • Anorexia • Hemorrhagic cystitis (cyclophosphamide) • Neutropenia |
|
| Fludarabine/ cyclophosphamide/ mitoxantrone (FCM) | Fludarabine (Berlex’s Fludara, Schering’s Fludara/Fludar/ Bebeflur, generics) | US ,France, Germany, Italy, Spain, UK, Japan | Fludarabine (oral): 40 mg/m2/d on days 1-3, (IV) 25 mg/m2/d on days 1 -3. Cycle repeated every 28 days. | • Myelosuppression
• Increased infection • Neurotoxicity (fludarabine) • Alopecia (more common with cyclophosphamide) |
| Cyclophosphamide
(Bristol-Myers Squibb’s Cytoxan/ Endoxan/ Endoxana, Baxter’s Endoxan/ Endoxana, Shionogi’s Endoxan, Pfizer’s Cyclostin, generics) Mitoxantrone (Serono Lab/Wyeth/ Takeda’s Novantrone, Baxter’s Onkotrone, generics) |
US ,France, Germany, Italy, Spain, UK, Japan
US ,France, Germany, Italy, Spain, UK, Japan |
Cyclophosphamide: 200 mg/m2/d on days 1 -3. Cycle repeated every 28 days.
Mitoxantrone: 6 mg/m2/d on day 1. Cycle repeated every 28 days. |
• Malaise/fatigue
• Nausea/vomiting • Anorexia • Hemorrhagic cystitis (cyclophosphamide • Cardiac toxicity (mitoxantrone) |
|
| CHOP | Cyclophosphamide (Bristol-Myers Squibb’s Cytoxan/ Endoxan/ Endoxana, Baxter’s Endoxan/ Endoxana, Shionogi’s Endoxan, Pfizer’s Neosar/Cyclostin, generics) | US ,France, Germany, Italy, Spain, UK, Japan | Cyclophosphamide: 750 mg/m2/d on day 1. Cycle repeated every 28 days. | • Myelosuppression
• Increased infection • Alopecia • Malaise/fatigue • Nausea/vomiting • Anorexia • Hemorrhagic cystitis (cyclophosphamide) |
| Doxorubicin (Pfizer’s Adriamycin/ Adriblastine, Bristol-Myers Squibb’s Rubex, Kyowa’s Adriacin, generics) | US ,France, Germany, Italy, Spain, UK, Japan | Doxorubicin: 50 mg/m2/d on day 1. Cycle repeated every 28 days. | ||
| Vincristine (Eli Lilly/EG Labo/Lilly-Shionogi’s Oncovin, generics) | US ,France, Germany, Italy, Spain, UK, Japan | Vincristine: 1.4 mg/m2/d on day 1. Cycle repeated every 28 days. | ||
| Prednisone3 (generics) | US ,France, Germany, Italy, Spain | Prednisone/ Prednisolone: 50 mg/m2 on days 1-5. Cycle repeated every 28 days. | ||
| Prednisolone (generics) | US ,France, Germany, Italy, Spain, UK, Japan | |||
| Cyclophosphamide, Vincristine, Prednisone | Cyclophosphamide (Bristol-Myers Squibb’s Cytoxan/ Endoxan/ Endoxana, Baxter’s Endoxan/ Endoxana, Shionogi’s Endoxan, Pfizer’s Neosar/Cyclostin. generics) | US ,France, Germany, Italy, Spain, UK, Japan | Cyclophosphamide: 750 mg/m2/d on day. Cycle repeated every 28 days. | • Myelosuppression
• Increased infection • Alopecia • Malaise/fatigue • Nausea/vomiting • Anorexia • Hemorrhagic cystitis (cyclophosphamide) |
| Vincristine (Eli Lilly/EG Labo/Lilly-Shionogi’s Oncovin, generics) | US ,France, Germany, Italy, Spain, UK, Japan | Vincristine: 1 mg/m2/d on day 1. Cycle repeated every 28 days. | ||
| Prednisone3 (generics) | US ,France, Germany, Italy, S | Prednisone/ Prednisolone: 50 mg/m2 on days 1-5. Cycle repeated every 28 days. | ||
| Prednisolone (generics) | US ,France, Germany, Italy, Spain, UK, Japan | |||
| Pentostatin/ cyclophosphamide | Pentostatin (SuperGen/ Wyeth/
Pfizer’s Nipent, Nihonkayaku’s Coforin) |
US ,France, Germany, Italy, Spain, UK, Japan | Pentostatin: 4 mg/m2/d on day 1. Cycle repeated every 28 days. | • Myelosuppression (mild)
• Increased infection • Malaise/fatigue • Fever • Nausea/vomiting • Anorexia • Hemorrhagic cystitis (cyclophosphamide) |
| Cyclophosphamide (Bristol-Myers Squibb’s Cytoxan/ Endoxan/ Endoxana, Baxter’s Endoxan/ Endoxana, Shionogi’s Endoxan, Pfizer’s Cyclostin, generics) | US ,France, Germany, Italy, Spain, UK, Japan | Cyclophosphamide: 600 mg/m2/d on day 1. Cycle repeated every 28 days. | ||
| Cladribine (single agent) | Cladribine (Ortho-Biotech’s Leustatin, Japananssen-Cilag’s Leustatin/ Leustatine/ Leustat, generics) | US ,France, Germany, Italy, Spain, UK, Japan | Cladribine: 0.14 mg/kg/d on days 1 -5. | • Myelosuppression
• Increased infection • Malaise/fatigue • Fever • Rash • Headache |
| Alemtuzumab (single agent) | Alemtuzumab (Berlex’s Campath, Schering’s Mab Campath) | US ,France, Germany, Italy, Spain, UK | Alemtuzumab: escalating dose of 3, 10,30 mg/d for week 1, followed by 30 mg/d for 3 days per week. | • Myelosuppression
• Increased infection • Anemia • Fever • Nausea/vomiting • Rash • Fatigue • Urticaria • Rigors • Transient Cytopenia |
a. Prednisolone is used where prednisone is not available.
IV = Intravenous; MAB = Monoclonal antibody.
Chlorambucil (Single Agent)
Overview
For the past 40 years, first-line treatment of chronic lymphocytic leukemia has been limited mainly to the alkylating agent chlorambucil (GlaxoSmithKline’s Leukeran). Although newer agents are being used with increasing frequency, chlorambucil still garners a significant patient share in the United States, France, Germany, Italy, Spain, and the United Kingdom. This popularity is the result of its preferable toxicity profile, which is advantageous in chronic lymphocytic leukemia — a disease with an elderly population that is less able to cope with high toxicities.
Mechanism Of Action
Chlorambucil is an alkylating agent. Alkylation of DNA results in breaks in the DNA molecule as well as cross-linking of the twin strands, thus interfering with DNA replication and transcription of RNA and ultimately causing cell death.
Clinical Performance
A variety of schedules are in use. Chlorambucil is an agent that can be administered with or without the corticosteroids prednisone or prednisolone (both generic). No evidence from randomized trials exists to prove that adding a corticosteroid enhances the efficacy of chlorambucil or other alkylating agents. However, physicians often include them in cases of bulky disease requiring a rapid response or when chlorambucil produces severe hematologic toxicity.
First-line chlorambucil therapy (plus or minus prednisone) in untreated chronic lymphocytic leukemia patients produces complete response rates of 4-12% and overall response rates of approximately 40-60%. Recent trials have shown that first-line fludarabine therapy (discussed later) provides superior response rates compared with chlorambucil; however, the two compounds’ long-term survival rates are not significantly different.
Chlorambucil does have a less toxic side-effect profile and is therefore the preferred therapy in older patients (65 or older) and those with a poor performance status who are unable to tolerate the severe myelosuppression caused by fludarabine. Another well-established benefit of chlorambucil is its oral formulation, although an oral formulation of fludarabine has become available in some countries.
Comments Closed
Clofarabine
(British Approved Name, US Adopted Name, rINN)
Drug Nomenclature
International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):
Adverse Effects, Treatment, and Precautions
As for Fludarabine Phosphate, although neurotoxicity is less severe. Capillary leak syndrome resulting from cytokine release has occurred with clofarabine, causing respiratory distress, hypotension, pleural and pericardial effusions, and multi-organ failure. Prophylactic corticosteroids may be useful, but clofarabine must be stopped immediately if signs or symptoms of capillary leak syndrome develop (respiratory status and blood pressure should be monitored during infusion). Other adverse effects include anxiety, flushing, tachycardia, hypotension, hepatotoxicity, haematuria, myalgia, arthralgia, and headache. Renal and hepatic function, and complete blood counts, should be monitored during clofarabine therapy. Hydration should be maintained during treatment to minimise the risk of tumour lysis syndrome and other adverse effects.
Pharmacokinetics
Clofarabine is about 47% bound to plasma proteins. About 50 to 60% of a dose is excreted unchanged in the urine and it has a terminal half-life of about 5 hours.
Uses and Administration
Clofarabine, a purine nucleoside analogue, is used as an antimetabolite antineoplastic in the treatment of relapsed or refractory acute lymphoblastic leukaemia in patients aged 1 to 21 years. A dose of 52 mg/m is given daily for 5 days, by intravenous in fusion over 2 hours. A longer infusion time should be considered in children weighing less than 20 kg to reduce anxiety and irritability, and to avoid high clofarabine concentrations. The course may be repeated every 2 to 6 weeks, depending on the patient’s recovery from bone-marrow depression and other adverse effects. Treatment is usually assessed after 2 treatment cycles. Clofarabine is under investigation for the treatment of acute myeloid leukaemia, myelodysplastic syndrome, and solid tumours.
Proprietary Preparations
Czech Republic: Evoltra;
France: Evoltra;
Portugal: Evoltra;
United Kingdom (UK): Evoltra;
United States of America (US and USA): Clolar
Comments Closed
Chlormadinone Acetate
Drug Approvals
(BANM, US Adopted Name, rINNM)
International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish): Acetato de clormadinona; Chlormadinone, Acetate de; Chlormadinoni Acetas; NSC-92338.
6-Chloro-17-hydroxypregna-4,6-diene-3,20-dione acetate.
CAS — 1961-77-9 (chlormadinone); 302-22-7 (chlormadinone acetate).
ATC — C03DB06
Pharmacopoeias. In China, France, and Japan.
Adverse Effects and Precautions
As for progestogens in general (see Progesterone). See also under Hormonal Contraceptives.
Effects on the skin. A report of auto-immune dermatitis in a patient associated with chlormadinone acetate.
Interactions
As for progestogens in general (see Progesterone). See also under Hormonal Contraceptives.
Uses and Administration
Chlormadinone acetate is a progestogen structurally related to progesterone that has anti-androgenic activity. It is given either alone or with an oestrogen in the treatment of menstrual disorders such as menorrhagia and endometriosis in oral doses of 2 to 10 mg daily either cyclically or continuously. It may also be used as the progestogen component of combined oral contraceptives at a dose of 1 to 2 mg daily, particularly in women with androgen-dependent conditions such as acne and hirsutism. Chlormadinone acetate has been used in some countries in the management of prostatic hyperplasia and prostate cancer oral doses of 25 or 50 mg, respectively have been given twice daily.
Preparations
Proprietary Preparations
France: Luteran
Germany: Gestafortin
Japan: Prostal
Mexico: Lutoral.
Multi-ingredient
Chile: Belara Lovinda
Czech Republic: Belara
France: Belara
Germany: Balanca Belara Esticia Gestamestrol N Neo-Eunomin Ovosistoin
Hungary: Belara
Israel: Belara
Italy: Belara
Mexico: Belara Lutoral-E Secuentex-21
Portugal: Belara Libeli
Russia: Belara
Spain: Belara
Switzerland: Belara
Venezuela: Belara.