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Velcade® (PS-341)

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软件介绍

Full Name: Velcade® (bortezomib) for Injection

Other Names: PS-341, MLN341, and LDP-341

Description: Proteasome inhibitor (intravenous)

Phase: APPROVED, US, EU

Company: Millennium Pharmaceuticals, Inc.

What It Is
Velcade is the first of a new class of medicines called proteasome inhibitors and the first treatment in more than a decade to be approved for patients with multiple myeloma. It was approved in the US on May 13, 2003 and in the European Union on April 27, 2004 for the treatment of myeloma patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy.

The development and FDA approval of Velcade is among the most rapid for a cancer treatment. As part of this accelerated approval, Millennium will be completing preclinical and clinical studies in myeloma, including a study of previously untreated myeloma patients. Velcade is also under investigation in Phase I and II studies for a wide variety of solid cancers, including prostate, colorectal, and lung cancer; and other hematologic cancers, such as lymphoma and leukemia.
How It Works
Overview
Velcade is a potent, specific, and reversible proteasome inhibitor and the first drug of this type to enter clinical trials. Proteasomes are present in all cells and function to help regulate cell growth. In nonclinical studies, normal cells appear to be able to recover from intermittent proteasome inhibition, but many types of cancer cells undergo apoptosis (programmed cell death) when proteasomes are inhibited, even for a short time.
Details on Velcade\'s Mechanism of Action
The proteasome is an enzyme complex that exists in all cells and plays an important role in degrading proteins involved in the cell cycle, growth of new blood vessels (angiogenesis), cell adhesion, cytokine production, apoptosis, and other important cellular processes. Many of the processes that rely on proteasome function can contribute to the growth and survival of cancer cells. Velcade is a potent but reversible inhibitor of the proteasome. By disrupting normal cellular processes, proteasome inhibition promotes apoptosis. Non-clinical data has demonstrated that cancer cells are more susceptible to the effects of proteasome inhibition than normal cells. Due to the reversibility of proteasome inhibition with Velcade, normal cells can recover from its effects, whereas cancer cells are more likely to undergo apoptosis.

In addition to its potential use as a single agent, non-clinical research suggests that when Velcade is combined with other chemotherapy treatments or radiation, there is an additive or even synergistic effect.
Details on Velcade\'s Mechanism of Action in Myeloma
Although the exact mechanisms are still under investigation, Velcade appears to act on myeloma cells in several ways. It appears to act directly on the myeloma cells to cause cell death as well as indirectly inhibiting their growth and survival by acting on the bone microenvironment.

Many of Velcade\'s anti-myeloma effects are thought to be due to its ability to block a key survival protein known as nuclear factor κB (NF-κB). NF-κB is found within the cell and acts as a transcription factor, turning on genes that cause production of proteins that stimulate cell growth.

When a cell receives an external signal, such as a growth factor, proteins such as NF-κB transfer the message to the nucleus of the cell, causing some type of response, such as cell growth. NF-κB also sends a message for cells to increase the expression of various molecules on their cell surface. In the case of myeloma, these surface molecules (adhesion molecules) allow myeloma cells to stick to cells in the bone marrow. This interaction stimulates the bone marrow cells to produce factors that promote the growth and survival of myeloma cells, such as interleukin 6 (IL-6) and vascular endothelial growth factor (VEGF), which promotes angiogenesis to nourish the tumor.

Therefore, by blocking NF-κB, Velcade inhibits myeloma cell growth and induces myeloma cell death. It also inhibits the production of growth and survival factors by blocking the production of adhesion molecules on the myeloma cell surface and the interaction between myeloma and bone marrow cells. Angiogenesis is also inhibited as a result.

The figure below, which is based on laboratory studies, shows one possible way in which Velcade may work.

Graphic provided by Millennium Pharmaceuticals, Inc.

Dosage and Administration The recommended dose of Velcade is 1.3 mg/m 2 /dose administered as an intravenous injection twice weekly for 2 weeks (days 1, 4, 8, and 11), followed by a 10-day rest period (days 12-21). Doses are typically given on Monday and Thursday or Tuesday and Friday. This 3-week period is considered a treatment cycle.

The length of treatment is determined on an individual basis, depending on a patient's response and tolerability. In clinical trials, patients were able to receive Velcade for up to 8 cycles, but patients who were still benefiting were allowed to continue for additional cycles.

If a patient experiences any severe side effects ( Grade 3 non-hematological or Grade 4 hematological toxicities, excluding neuropathy as discussed below), Velcade therapy should be stopped until the symptoms resolve. Velcade can then be started again at a 25% reduced dose.

Patients who experience neuropathic pain (pain associated with neuropathy) and/or peripheral neuropathy (abnormal or decreased sensation, or burning/tingling) on Velcade therapy should have their dose and/or schedule adjusted as indicated in the table below.

Recommended Dose Modification for Velcade-related Neuropathic Pain and/or Peripheral Neuropathy

Severity of Peripheral Neuropathy Signs and Symptoms Modification of Dose and Regimen

Grade 1* (paresthesias [sensations of numbness, tingling, or prickling] and/or loss of reflexes) without pain or loss of function	No action
Grade 1 with pain or Grade 2 (interfering with function but not with activities of daily living)	Reduce Velcade dose to 1.0 mg/m 2
Grade 2 with pain or Grade 3 (interfering with activities of daily living)	Withhold Velcade therapy until toxicity resolves. When toxicity resolves, reinitiate with a reduced dose of Velcade at 0.7 mg/m 2 and change treatment schedule to once per week.
Grade 4 (permanent sensory loss that interferes with function)	Discontinue Velcade

*The grades of severity listed here relate specifically to neuropathy
Potential Side Effects The most commonly reported side effects of Velcade (1.3 mg/m 2 ) in the two Phase II clinical trials in relapsed and refractory myeloma (SUMMIT and CREST) combined are shown in the table below. In single-arm studies such as these, it is often not possible to distinguish between drug-caused side effects and a patient抯 underlying disease. Keep in mind that each patient may react differently, and possibly unpredictably, to a particular treatment. In general, these side effects were manageable with medications, increased fluid intake, dose reductions or by stopping treatment temporarily, and/or other supportive care measures.

Side Effects Noted in the Phase II Velcade Trials (SUMMIT and CREST, 1.3 mg/m 2 )

Side Effect Percentage of Patients (N=228)

Asthenic conditions (fatigue, malaise, weakness)	65%
Nausea	64%
Diarrhea	51%
Decreased appetite or weight loss	43%
Constipation	43%
Low platelet counts	43%
Peripheral neuropathy*	37%
Fever	36%
Vomiting	36%
Anemia	32%

*includes patients who developed new symptoms and had aggravation
of their existing neuropathy
The most commonly seen severe adverse events (Grade 3 and 4) in these trials were:

Thrombocytopenia (a decrease in the number of platelets ; 30%)
Asthenic conditions (fatigue, malaise, or weakness; 18%)
Neutropenia (16%)
Peripheral neuropathy (14%)

Most patients are able to continue with Velcade therapy despite fatigue but should be cautious when operating machinery, including driving a car. In general, thrombocytopenia was transient, dropping during the dosing period and recovering during the rest period. Asthenic conditions were more commonly seen during the first and second cycle of treatment. Severe Grade 4 thrombocytopenia was uncommon unless a patient抯 initial platelet count was already low (less than 70,000; a normal platelet count in adults is 150,000 to 400,000).

In the Phase II trials, the neuropathy seen was mostly Grade 1 (mild) or Grade 2 (moderate). The incidence of severe (Grade 3) neuropathy during treatment was lower in patients without neuropathy at the start of the study than in patients with evidence of neuropathy at that time. Severe peripheral neuropathy was reversible in approximately three quarters of patients over a median period of 99 days. (See Clinical Trials section below for more information.) Preclinical Studies Velcade has been tested extensively in laboratory studies and in animals. These studies show that Velcade:

induced cancer cell apoptosis
had a unique mechanism of action
affected the tumor microenvironment
appeared to have additive activity with a variety of chemotherapy agents and with radiation therapy

Velcade continues to be tested in preclinical studies in combination with a variety of agents, and results of several studies were presented at ASH 2003. Synergistic anti-myeloma effects were reported in preclinical models when Velcade was combined with agents such as oblimersen (Bcl-2 antisense, Genasenase? Genta Inc.), COX-2 inhibitors (NS398), histone deacetylase inhibitors (ie, SAHA and LAQ824), and others. Clinical Trials On May 13, 2003, Velcade received accelerated approval in the United States for the treatment of multiple myeloma patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy.The approval was based on the data from the Phase II SUMMIT registration trial and the Phase II CREST trial (see below). At that time, the recently ended confirmatory Phase III APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial of Velcade in relapsed and refractory myeloma was underway. As part of the accelerated approval, Millennium will be completing preclinical and phase IV clinical studies.

On April 24, 2004, the European Commission also approved Velcade for use in the same myeloma patient population梩hose who have received at least two prior therapies and have progressed on their most recent therapy. Velcade is now marketed in the 15 member states of the European Union, the 10 accession member countries, plus Norway and Iceland.

Millennium had filed an NDA (New Drug Application) with the Food and Drug Administration (FDA) in January, 2003 and a Marketing Authorization Application (MAA) to the European regulatory agency in February, 2003 for approval to market Velcade as a treatment for relapsed and refractory myeloma. Velcade received Fast Track designation for myeloma from the FDA, which meant that the FDA would facilitate and expedite the development and review of the application. It was granted Priority Review by the FDA on March 10, 2003. Velcade had also received Orphan Drug designation for myeloma, which is granted to certain drugs used to treat rare diseases affecting fewer than 200,000 Americans. Phase I Single agent, refractory disease . In a Phase I trial designed to determine dosing that included patients with advanced refractory myeloma, Velcade reduced serum myeloma protein levels and myeloma cell numbers in the bone marrow. ( Orlowski, et al. Journal of Clinical Oncology . 2002;20(22):4420-4427 .)

Velcade/Doxil ?/sup>, relapsed/refractory disease . Velcade in combination with Doxil (pegylated liposomal doxorubicin, Ortho Biotech) has been evaluated in a Phase I study in patients with refractory hematologic malignancies in order to determine the maximum tolerated dose and dose-limiting toxicities. ( Orlowski et al. Blood. 102(11). Abstract 1639 .) The study included 24 patients with relapsed and refractory myeloma, about half of whom had disease that did not respond to previous therapy with anthracyclines (doxorubicin or related compounds). Patients received Velcade doses of 0.9 to 1.5 mg/m 2 in addition to 30 mg/m 2 of Doxil.

Preliminary results presented at ASH 2003 suggest that this combination has significant activity in refractory myeloma and other refractory malignancies. Of the 22 myeloma patients evaluable for response at the time, 5 achieved a complete response, 3 a near complete response, and 8 a partial response. In addition, responses were seen in 9 of 13 patients who had previously not responded to or progressed on anthracycline therapy.

The most common side effects included fatigue, nausea, vomiting, constipation, diarrhea, neutropenia, thrombocytopenia, and neuropathy, and were generally manageable. Grade 3 or 4 dose-limiting toxicities seen during the first cycle of therapy included single episodes of diarrhea, low blood pressure, confusion, and fainting; low sodium levels in the blood; neutropenia; and constipation. Grade 3 or 4 toxicities seen in later cycles included fatigue, low blood cell counts, neuropathy, constipation, diarrhea, palmar plantar erythrodysesthesia (PPE) , and impotence. These toxicities led to dose reductions in patients receiving Velcade at the 1.4 or 1.5 mg/m 2 dose level. Therefore, the investigators recommend that the Velcade dose to be tested in combination with Doxil in future studies be 1.3 mg/m 2 .

This combination will be evaluated in a Phase II trial being conducted through the Cancer and Leukemia Group B (CALGB), a national clinical research group sponsored by the National Cancer Institute. Phase II SUMMIT trial, relapsed/refractory disease . Final results of the multicenter Phase II SUMMIT trial of Velcade in patients with advanced relapsed and refractory myeloma were published in the New England Journal of Medicine in June 2003. ( Richardson et al. N Engl J Med. 2003;348:2609-2617 .) The data showed an impressive 35% overall response rate considering their condition and multiple lines of previous therapy.

This open-label, single-arm study (also known as Study 025) included 202 patients who had progressive disease despite having received an average of six lines of therapy, many of which contained multiple different regimens. Patients received Velcade (1.3 mg/m2) intravenously twice a week for 2 weeks, followed by a week off (1 cycle). The cycle could be repeated up to eight times and dexamethasone could be added for patients with stable or progressive disease on VELCADE alone. Responses were assessed using the rigorous Blad é criteria.
View the Blad é Criteria . (EBMT/IBMTR/ABMTR criteria; Blad?J et al. Br J Haematol . 1998;102(5):1115-1123.)

In the SUMMIT trial, an additional response category桸ear-CR梬as added. Near CR was similar to CR, being defined as having stable bone disease, normal calcium, and complete disappearance of M protein, but patients in this category had a positive rather than a negative immunofixation electrophoresis test. Responses to Velcade in 193 evaluable patients are presented in the table below. These responses were clinically meaningful; patients with complete and partial responses experienced increased levels of hemoglobin and normal immunoglobulins, as well as improved quality of life. In addition, 18% of patients who did not respond to Velcade alone improved their response with the addition of dexamethasone. (Jagannath et al. Proc Am Soc Clin Oncol . 2003;22:582. Abstract 2341.)

Response to Velcade Alone in the SUMMIT Trial

Response: Blad é criteria (↓M protein) Percent patients

Complete response; IF* negative (100%)	4%	Overall response 35%
Near-complete response; IF positive ? (100%)	6%
Partial response (≥50%)	17%
Minimal response (≥25%)	8%
Stable disease	24%

*IF = immunofixation (a sensitive test for trace amounts of M protein)
?100% reduction in M protein but still detectable by IF
In the study, the average number of cycles of treatment received was six. The median (midpoint) time to response was 38 days (range, 30 to 127 days) and the median duration of response was 14 months. (Berenson et al. Proc Am Soc Clin Oncol . 2003;22:581. Abstract 2337.) The median overall survival was approximately 17 months, compared with a historically expected survival of 6 to 9 months in this patient population.

Additional SUMMIT data presented at ASH 2003 showed that certain prognostic factors that indicated high tumor burden were associated with decreased duration of response, time to progression, and overall survival. These prognostic factors included factors such as low albumin level, poor performance status , >50% plasma cells in the bone marrow, elevated C-reactive protein , and lower platelet counts. However, factors such as older age, chromosome 13 deletion, beta-2 microglobulin level, and type or number of prior therapies were not predictive of these time to event parameters. (Richardson et al. Blood . 2003;102(11). Abstract 1629.)

In the SUMMIT trial, adverse events were generally predictable and manageable with medications, increased fluid intake, dose reductions or by stopping treatment temporarily, and/or other supportive care measures as needed. The most commonly reported events are indicated in the table below.

Side Effects Noted in the SUMMIT Trial

Side effect Percentage of Patients (N=202)

Nausea	64%
Diarrhea	49%
Fatigue	49%
Low platelet counts	44%
Constipation	43%
Vomiting	36%
Peripheral neuropathy*	35%
Loss of appetite	34%
Fever	34%
Anemia	31%

*includes patients who developed new symptoms and had aggravation
of their existing neuropathy
CREST trial, relapsed/refractory disease . Results of a smaller, similarly designed Phase II dose-ranging trial (CREST, Study 024) of Velcade in 54 patients with earlier stage disease were also impressive. In this study, patients had either progressed on front-line therapy or relapsed at any time after front-line therapy. Their median number of prior therapies was 3 (range, 1 to 7). Overall responses of 30% and 50% were seen at the two doses tested (1.0 or 1.3 mg/m2, respectively). Complete responses were seen in 4% of patients in both dose groups. ( Jagannath et al. Blood. 2002;100(11):812a. Abstract 3207 ).
Combined Phase II analyses . Additional data from both Phase II trials were evaluated to examine the long-term safety and effectiveness of Velcade in responders who continued treatment in an extension trial (Study 029). This data was presented at the 39th American Society of Clinical Oncology (ASCO) meeting in Chicago in June 2003. During the trial and extension, Velcade (with or without dexamethasone) was administered for a total of up to 24 cycles (approximately 18 months). During that time, the side effect profile was similar to that seen during the first 6 months of treatment, with no increase in side effects.

Data on patients in the Phase II trials who received high-dose dexamethasone after they had not responded to, or relapsed after, treatment with Velcade alone was also presented at ASCO in 2003. (Jagannath et al. Proc Am Soc Clin Oncol . 2003;22:582. Abstract 2341.) Of the total 101 evaluable patients who had dexamethasone added to their Velcade regimen, 22% had an improved response. Responses to combination therapy were seen in patients who were refractory to both Velcade and dexamethasone as single agents. Side effects with the combination were similar to those seen with Velcade alone.

A follow-up analysis of the Phase II safety data regarding neuropathy was reported at ASH in December 2003. ( Richardson, et al. Blood . 2003;102(11). Abstract 512. ). Overall, about 35% of patients experienced peripheral neuropathy, which was mostly Grade 1 (mild) or Grade 2 (moderate). However, 80% of patients entered these trials with some evidence of peripheral neuropathy. The incidence of severe (Grade 3) neuropathy during treatment was lower in patients without neuropathy at the start of the study than in patients with evidence of neuropathy at that time (3% vs. 16%, respectively). Importantly, severe peripheral neuropathy was reversible in 74% of patients over a median period of 99 days (3.3 months).

Because of the rate of thrombocytopenia seen in the phase II trials, data from the trials and other studies were further analyzed to determine the relationship between therapy and platelet counts. (Lonial et al. Blood . 2003;102(11). Abstract 1632.) The data suggest that Velcade temporarily suppresses the formation of platelets rather than being directly toxic to bone marrow cells. The lowest platelet counts seen during therapy were consistent and averaged about 40% of the platelet counts at baseline. The development of severe thrombocytopenia with Velcade therapy appears to be related to a patient抯 platelet count prior to starting therapy; it was uncommon for a patient to develop severe Grade 4 thrombocytopenia unless his or her initial platelet count was already low (less than 70,000). A normal platelet count in adults is 150,000 to 400,000.

An analysis of limited data on myeloma patients with renal disease in the phase II trials suggests that Velcade can be given safely in patients with severe renal impairment, with response rates and toxicity comparable to those seen in patients with less severe renal impairment. (Jagannath, et al. Blood . 2003;102(11). Abstract 828.) Phase III APEX trial, relapsed/refractory disease . Data are being evaluated from the recently ended Phase III APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial in relapsed and refractory myeloma. The trial is comparing Velcade with high-dose dexamethasone, a recognized standard of care in this setting. Velcade (1.3 mg/m 2 ) is administered as an injection for eight 3-week cycles followed by three 5-week cycles. Patients receiving high-dose dexamethasone who experience progressive disease may be eligible to receive Velcade as part of a companion study being conducted at each site.

In December 2003, an independent data monitoring committee recommended an early end to the APEX trial. This was because the findings of a pre-specified interim analysis found a statistically significant improvement in time to disease progression梩he primary endpoint of the trial梚n patients receiving Velcade compared to patients receiving high-dose dexamethasone. Based on the recommendation of the committee and the notification of regulatory authorities, Millennium halted the control arm of the study. This allowed patients who were currently receiving dexamethasone the option to immediately crossover to Velcade treatment.

The APEX trial had enrolled approximately 670 patients whose disease had progressed despite one to three previous therapies. The trial was being conducted in 95 sites in the United States, Canada, and Europe. Due to the early end to the trial, the data from the study are expected to be available sometime during the first half of 2004. Ongoing Clinical Trials Velcade is being evaluated alone and in combination with a variety of agents in patients with refractory disease as well as in previously untreated myeloma patients. There are over 25 ongoing or planned clinical trials of Velcade in myeloma. Preliminary results from some of these trials, as well as a list of ongoing trials, are presented below.
Phase I and I/II Velcade/thalidomide/dexamethasone, refractory disease . Velcade is being evaluated in an ongoing Phase I/II clinical trial in combination with thalidomide, with subsequent addition of dexamethasone in patients resistant to post-autologous stem cell transplant salvage therapies. ( Zangari et al. Blood. 2003;102(11). Abstract 830 .) Preliminary results suggest that the combination of Velcade and thalidomide is active in patients who had previously received thalidomide梞ore than half of these refractory patients achieved at least a partial response. Toxicities appear to be generally manageable and included gastrointestinal events, fatigue, peripheral neuropathy, and hematologic toxicities. No cumulative grade 3 or 4 neuropathy was observed during the first 4 cycles of therapy.

Velcade/melphalan, relapsed/refractory disease . Velcade is also being evaluated in combination with melphalan in a Phase I/II trial in 15 patients with relapsed or refractory myeloma. (Yang et al. Blood. 2003;102(11). Abstract 826.) Patients receive reduced-dose Velcade (0.7 mg/m 2 ) plus melphalan at various doses (0.025 to 0.25 mg/kg). Preliminary results presented at the 2003 ASH meeting suggest that this combination is effective and well tolerated. Low blood cell counts (neutrophils, red blood cells, and platelets) were the only grade 3 toxicities observed. Mild or moderate side effects included nausea, fever, fatigue, diarrhea, low blood cell counts, and neuropathy.
Phase II Previously untreated myeloma . Very preliminary results from a small number of patients in an ongoing Phase II trial of Velcade in previously untreated myeloma, which were presented at the 2003 ASH meeting, are encouraging. ( Jagannath et al. Blood. 2003;102(11). Abstract 1650. ) Patients receive Velcade (1.3 mg/m 2 twice-weekly for 2 weeks, followed by a week off; maximum 6 cycles) and dexamethasone is added if they do not achieve a partial response after 2 cycles or a complete response after 4 cycles. Preliminary results from 12 patients who had received six cycles of therapy show a 75% response rate (partial response and near complete response) with a manageable adverse event profile similar to that seen in other Velcade clinical trials in relapsed or refractory disease. However, it is still too early to draw any conclusions regarding use of Velcade in this patient population.

Velcade/doxorubicin/dexamethasone, primary therapy . A Phase II study of Velcade, adriamycin (doxorubicin), and dexamethasone as primary therapy for myeloma is currently being conducted in England.

Ongoing Velcade Clinical Trials in Myeloma as of April 2004 Phase II

Phase II study of Velcade +/- dexamethasone in previously untreated myeloma patients ? View trial information
Phase II study of Velcade, adriamycin and dexamethasone as primary therapy for myeloma ? View trial information
UARK 2003-33, Total Therapy III: A Phase 2 Study Incorporating Bone Marrow Microenvironment (ME) - Co-Targeting Bortezomib into Tandem Melphalan-Based Autotransplants with DT PACE for Induction/Consolidation and Thalidomide + Dexamethasone for Maintenance ? View trial information Phase I
Studying the Pharmacokinetics and Pharmacodynamics of Velcade (bortezomib) in Patients with Relapsed Multiple Myeloma ? View trial information
A Pilot Study of VDT (Velcade, Doxil ? and Thalidomide) as Salvage Therapy for Patients with Relapsed or Refractory Multiple Myeloma (MM) ? View trial information
Phase I study of Velcade and thalidomide in patients with refractory disease (University of Arkansas) ? View trial information

For More Information on Clinical Trials:
BrandName Velcade 3.5mg,GenericName bortezomib,Unit1x1,Price Class$1,312.89美圆。如果了解该药更多资讯，咨询电话:022—84277462

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