Proteasome Inhibitors

Neha Vapiwala, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: July 22, 2004

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In Part Two of our series on biologic therapies, we are performing an in-depth review of the major targeted therapies that are currently making headlines around the world.

Here, we will address bortezomib, the signature drug in a new class of targeted therapies called proteasome inhibitors. Please feel free to refer as needed to Part One, which presented the basic science principles behind targeted therapies and outlined all of the major classes of molecular inhibitors. Remember that the drugs have both generic and trade names, but we will use primarily the generic name in the following discussions.

I) Bortezomib (Velcade, PS 341 )

Background

Bortezomib is the first drug in the proteasome inhibitor class of anti-cancer agents to enter clinical trials. As discussed in Part One of this series, the proteasome is a protein complex that exists in all cells and plays a critical role in breaking down other proteins. The proteins destined for degradation typically regulate the cell cycle, new blood vessel growth (angiogenesis), cell adhesion, cytokine production, and programmed cell death (apoptosis), among other important cellular processes. These processes are important to the growth and survival of tumor cells. Bortezomib binds and reversibly inhibits the proteasome. By doing so, it disrupts normal cellular processes, leading to chaos in the cell and prompting the cell to die. Laboratory studies suggest that normal cells are less susceptible to damage from periodic proteasome inhibition; because bortezomib inhibition is reversible, normal cells tend to recover from its effects. In contrast, cancer cells tend to go "haywire" when proteasomes are inhibited even for a short time, and this typically results in programmed cell death.

Multiple myeloma (also called myeloma) is a hematologic cancer, meaning it starts in the blood. It is a cancer of the plasma cell, which is part of the immune system and helps make the antibodies (immunoglobulins) we need to help fight infection and disease. It is the second most common blood cancer (non-Hodgkin's lymphoma is first). It represents about 1% of all cancers and about 2% of all cancer deaths. About 45,000 Americans currently have myeloma, and the American Cancer Society states that about 14,600 new cases are diagnosed every year in the US.

Bortezomib appears to act on myeloma cells both directly as well as indirectly (through inhibition of their growth and survival by acting on the surrounding bone). Many propose that bortezomib's anti-myeloma activity is due in large part to its ability to block a key survival protein called nuclear factor κB (NF- κB). NF-κB is located inside the cell and plays a role in switching on certain genes. These genes then lead to production of proteins involved in cell growth. NF-κB also sends a message for cells to make and put certain molecules on their surface. In the case of myeloma, these surface molecules let the myeloma tumor cells stick to the bone marrow. By sticking there, the myeloma cells trigger the bone marrow to help them grow, and thus a vicious cycle of tumor growth is created.
When bortezomib blocks NF-κB, it prevents myeloma cell growth and favors myeloma cell death.

Current FDA-Approved Indications

Bortezomib is indicated for the treatment of multiple myeloma patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy. In other words, it is used as third-line therapy in myeloma patients who have demonstrated resistance to their last treatment.

Details of dose, administration, and duration of bortezomib therapy

The recommended dose of bortezomib is 1.3 mg/m 2/dose administered as an intravenous (IV) injection twice weekly for 2 weeks (days 1, 4, 8, and 11). This is 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 to and tolerability of the drug. In clinical trials, patients were able to receive bortezomib for up to 8 cycles, but those who were still benefiting were allowed to continue for additional cycles.

So what are the side effects of bortezomib?

Possible adverse side effects of bortezomib include:

  • Fatigue, malaise, weakness – 65%
  • Nausea – 64%
  • Diarrhea – 51%
  • Weight loss/ decreased appetite – 43%
  • Constipation – 43%
  • Low platelet counts – 43%
  • Peripheral neuropathy - 37%
  • Fever – 36%
  • Anemia – 32%

Review of the Pivotal Clinical Trials

1) SUMMIT Phase II trial in myeloma patients with advanced relapsed and refractory disease: Study 025

Materials & Methods

  • Open-label, single-arm study
  • 202 patients with progressive disease despite an average of six lines of therapy, many of which contained multiple different regimens
  • Patients received bortezomib (1.3 mg/m²) intravenously twice a week for 2 weeks, followed by a week off (1 cycle).
  • Cycle could be repeated up to eight times and dexamethasone could be added for patients with stable or progressive disease on bortezomib alone; average of 6 cycles given on the study
  • Responses were assessed using the rigorous Blad é criteria, which include two assessments performed 6 weeks apart and involve immunofixation electrophoresis (IF), a sensitive test for trace amounts of myeloma protein

Results

  • Overall response rate of 35%
    • Complete response, IF negative = 4%
    • Near-complete response, IF positive = 6%
    • Partial response = 17%
    • Minimal response = 8%
    • Stable disease = 24%
  • Median time to response was 38 days
  • Median duration of response was 14 months
  • Median overall survival was approximately 17 months, compared with a historical survivals of 6 to 9 months in these patients
  • Prognostic factors associated with decreased duration of response, time to progression, and overall survival included low albumin level, poor performance status, >50% plasma cells in the bone marrow, elevated C-reactive protein, and lower platelet counts.
  • Side effects were generally predictable and manageable.

2) CREST trial, relapsed/refractory disease: Study 024

  • Smaller Phase II study similar to SUMMIT
  • 54 patients who had either progressed on front-line therapy or relapsed at any time after front-line therapy
  • 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.

3) Study 029:

  • Bortezomib with or without dexamethasone was given for a total of up to 24 cycles (approximately 18 months)
  • No major increase in side effects
  • High-dose dexamethasone after failure to respond to bortezomib led to improved response in 22%

4) APEX trial (Assessment of Proteasome Inhibition for Extending Remissions) in relapsed/refractory myeloma .

  • Recently completed Phase III trial of 670 patients done in the US, Canada, and Europe.
  • Compared bortezomib with high-dose dexamethasone, which is a recognized standard of care in this setting
  • Bortezomib (1.3 mg/m 2) is administered as an injection for eight 3-week cycles, followed by three 5-week cycles
  • In December 2003, an independent data monitoring committee recommended early closure of the APEX trial
    • This was because an interim analysis found a statistically significant improvement in time to disease progression—the primary endpoint of the study—in patients getting bortezomib compared to those getting high-dose dexamethasone.
    • The early study termination gave patients who were getting dexamethasone the option to immediately switch over to bortezomib.

Current Areas of Cancer Research with Bortezomib: Open Clinical Trials

Bortezomib is being evaluated in numerous early phase studies for a variety of solid cancers, including prostate, colorectal, and lung cancer, as well as other hematologic cancers, such as lymphoma and leukemia. In addition to its potential use as a single agent, laboratory research suggests that combining bortezomib with chemotherapy or radiation therapy can result in improved outcomes. The rationale behind this combination approach is to take advantage of the additive benefits of both treatments, and possibly even synergistic effects. Synergy is when two or more agents interact so that their combined effect is even greater than the sum of their individual effects.

Listed below are some of the latest clinical trials that are currently enrolling patients, along with the study sponsors. Note that while bortezomib continues to be investigated as a single agent therapy, it is increasingly being incorporated as an adjunctive agent within a whole treatment regimen. Depending on the tumor type, this regimen may contain varying combinations of chemotherapy, radiation therapy, surgery, hormonal agents, and even other targeted therapies.

Multiple myeloma
  • Phase II study of bortezomib +/- dexamethasone in previously untreated myeloma patients
  • Phase II study of bortezomib, adriamycin and dexamethasone as primary therapy for myeloma
  • A Pilot Study of VDT (Velcade, Doxil ® and Thalidomide) as Salvage Therapy for Patients with Relapsed or Refractory Multiple Myeloma (MM)
  • Phase I study of bortezomib and thalidomide in patients with refractory disease. University of Arkansas
Non-small cell and small cell lung cancer:
  • Phase 2 Study of VELCADE Alone or VELCADE® plus Docetaxel in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer. Millennium Pharmaceuticals
  • Phase II Study of Gemcitabine, Carboplatin, and Bortezomib in Patients With Chemotherapy-Naïve Advanced or Recurrent Non-Small Cell Lung Cancer. SWOG
  • Phase II Study of Bortezomib in Patients With Recurrent or Refractory Extensive-Stage Small Cell Lung Cancer Previously Treated With Platinum-Based Therapy. SWOG

Gastrointestinal:

  • Phase II Study of Bortezomib With or Without Irinotecan in Patients With Adenocarcinoma of the Gastroesophageal Junction or Stomach. Cornell University Medical College
  • Phase II Study of Bortezomib as First-Line Systemic Therapy in Patients With Unresectable Locally Advanced or Metastatic Adenocarcinoma of the Bile Duct or Gallbladder. Fox Chase Cancer Center
  • Phase II Study of Bortezomib in Patients With Hepatocellular Carcinoma. ECOG

Genitourinary:

  • Phase I Study of Bortezomib and Mitoxantrone in Patients With Advanced or Metastatic Androgen-Independent Prostate Cancer. M.D. Anderson Cancer Center
  • Phase II Study of Bortezomib in Patients With Previously Treated Advanced Transitional Cell Carcinoma of the Urothelium. Cancer and Leukemia Group B (CALGB)

Brain:

  • Phase I Study of Bortezomib in Patients With Recurrent Glioma. NCI

For further information, please see Targeted Therapy Basics.



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