Doxil®

What is Doxil?

Doxil® is a chemotherapy drug used in cancer treatment. It is a reformulated version of doxorubicin (Adriamycin®), a cancer drug that has been used for many years in traditional chemotherapy regimens in multiple myeloma.

Doxil is approved for use in combination with Velcade® (bortezomib, Takeda Oncology) to treat patients with myeloma who have not previously received Velcade and have received at least one prior therapy.

Doxil is also known as doxorubicin HCl liposome injection or pegylated liposomal doxorubicin (PLD). It is distributed by Janssen Products, LP in the United States. Doxil is also approved for the treatment of patients with ovarian cancer and in patients with AIDS-related Kaposi’s sarcoma.


How is Doxil used in multiple myeloma?

Doxil® (doxorubicin HCl liposome injection, Janssen) is typically used with other anticancer agents to treat cancer. Doxil is often used in place of conventional doxorubicin, and it is also used as part of novel combination therapies.

Doxil is approved by the FDA for use in combination with Velcade® (bortezomib, Takeda Oncology) to treat patients with myeloma who have not previously received Velcade and have received at least one prior therapy. Results of clinical trials show that that adding Doxil to a standard Velcade regimen reduced the risk of the disease progressing and prolonged the duration of response in patients with relapsed and refractory disease better than Velcade alone.

Doxil is being studied in combination with other approved myeloma drugs and in combination with new drugs in development for the treatment of relapsed and/or refractory myeloma. Doxil is also being studied as part of combination therapies for the treatment of newly diagnosed or previously untreated myeloma, also referred to as frontline therapy.

How does Doxil work?

Doxil is a reformulated version of the drug doxorubicin (Adriamycin®). Doxorubicin is a chemotherapy agent that belongs to a class of agents referred to as anthracyclines. Anthracyclines are used to treat cancer because they damage the DNA in cancer cells and cause them to die.

With Doxil, the doxorubicin is wrapped in a “fat bubble” (liposome), which serves to help slowly release the drug and may help reduce side effects. The liposomes are also coated with another substance, a process called pegylation, which helps the liposomes stay in the circulation longer.

What types of patients can benefit from Doxil therapy?

Results of the clinical trial that led to Doxil’s approval showed that the combination of Doxil and Velcade is effective in a wide range of patients with relapsed/refractory myeloma, including:

  • Older patients (≥65 years old) as well as younger patients
  • Patients who have previously received a stem cell transplant
  • Patients who have previously received Thalomid® (thalidomide, Celgene) or Revlimid® (lenalidomide, Celgene)
  • Patients who have previously received doxorubicin
  • Patients with “high-risk” disease (poor prognosis)
    • Velcade-Doxil was beneficial to patients with chromosome abnormalities and those with elevated levels of beta 2-microglobulin
  • Patients with impaired renal (kidney) function

How is Doxil administered?

Doxil® (doxorubicin HCl liposome injection, Janssen) is administered as an injection directly into the vein (intravenously, or IV). When Doxil is used along with Velcade® (bortezomib, Takeda Oncology) in the treatment of myeloma, the recommended dosing over each 28-day cycle is as follows:

  • Velcade is given at a dose of 1.3 mg/m2 intravenously or as an injection under the skin on days 1, 4, 8, and 11.
  • Doxil is given intravenously at a dose of 30 mg/m2 over a 1-hour infusion on day 4 after Velcade is given.

Although there is limited information available on use of Doxil in patients with myeloma with reduced liver (hepatic) function, it is recommended that patients with hepatic impairment receive a lower dose of Doxil.

How long is the treatment with Doxil?

The length of treatment with Doxil may differ from patient to patient and is based on how well the drug is working and if the side effects are manageable. In general, patients are treated for up to 8 cycles until their disease progresses or if they experience unacceptable toxicity.


What are Doxil side effects?

Like many other chemotherapy drugs, Doxil® (doxorubicin HCl liposome injection, Janssen) can have a number of different side effects. Side effects vary depending on an individual’s past health history and current multiple myeloma stage. Doxil is associated with less frequent side effects than conventional doxorubicin. The most common side effects observed in the clinical trial that led to the approval of combination therapy with Velcade® (bortezomib, Takeda Oncology) and Doxil were:

  • Gastrointestinal effects (ie, nausea, vomiting, diarrhea, and constipation)
  • Peripheral neuropathy
  • Fatigue
  • Low numbers of white blood cells known as neutrophils, a condition known as neutropenia
  • Low platelet counts, also referred to as thrombocytopenia
  • Fever
  • Anemia, or low numbers of red blood cells

Doxil may cause urine and other body fluids to turn a reddish-orange color. This nontoxic reaction is due to the color of the product and will go away as the drug is eliminated from the body.

Serious side effects seen with Doxil-Velcade combination therapy

In the trial that led to Doxil’s approval, a number of patients with relapsed myeloma receiving Velcade-Doxil combination therapy experienced serious (Grade 3) or less commonly, very serious (Grade 4) side effects during the course of their treatment. These serious side effects included:

  • Neutropenia
  • Thrombocytopenia
  • Anemia
  • Fatigue
  • A marked loss of strength
  • Diarrhea
  • Peripheral neuropathy
  • Hand-foot syndrome (HFS), a severe skin reaction resulting in redness, tenderness, and possibly peeling of the palms of the hand and soles of the feet

Other possible serious side effects of Doxil therapy

Although rare, severe infusion-related reactions, such as difficulty breathing or low blood pressure, may occur, most often during the first cycle of treatment. If such a reaction occurs, the infusion of Doxil will be temporarily stopped until symptoms have resolved and the infusion will be restarted at a slower rate. Doxil will be discontinued if the reaction is severe.

A potential side effect of long-term Doxil therapy is damage to the heart muscle (myocardial damage). Myocardial damage is related to the total dosage of doxorubicin a patient has received over time, which includes both conventional doxorubicin and Doxil. For this reason, it is generally recommended that patients receive a total of no more than 550 mg/m2 of doxorubicin over time. A lower total cumulative dose may be recommended if a patient has received radiotherapy to the area of the heart, or therapy with other agents that are potentially toxic to the heart, such as cyclophosphamide.

Fortunately, Doxil is potentially less toxic to heart muscle than conventional doxorubicin. This is mainly because there are much lower circulating levels of free doxorubicin in the blood when Doxil is used.

Doxil can cause harm to a fetus, so it should not be used during pregnancy. Women must use effective contraception during and for 6 months after treatment with Doxil.

How are side effects of Velcade-Doxil managed?

Patients experiencing side effects with Velcade-Doxil may have their dose reduced or delayed until symptoms resolve.


What have Doxil clinical trials shown?

 

Doxil clinical studies resulted in an FDA approval for multiple myeloma treatment.

Doxil clinical studies resulted in an FDA approval for multiple myeloma treatment.

Doxil® (doxorubicin HCl liposome injection, Janssen) was approved for use in combination with Velcade® (bortezomib, Takeda Oncology) to treat patients with myeloma who have not previously received Velcade and have received at least one prior therapy. The approval was based on results of a planned interim analysis of an international Phase III trial (DOXIL-MMY-3001) that compared the combination to Velcade alone in 646 patients with relapsed/refractory myeloma.

The results of this study show that showed that adding Doxil to the standard Velcade regimen reduced the risk of the disease progressing and prolonged the duration of response in patients with relapsed and refractory disease compared with Velcade alone.

  • The combination significantly extended the median time to disease progression (TTP) from 6.5 months to 9.3 months. The 15-month survival rate for Doxil plus Velcade was 76% compared with 65% for Velcade alone.
  • On average, responses to the combination lasted 10.2 months compared with 7 months with Velcade alone.
  • The benefits of the combination were consistently seen across a variety of patient types, including older patients, those with prior stem cell transplantation or exposure to Thalomid or doxorubicin, and patients with markers of high-risk disease.
  • After a follow-up of 8.6 years, overall survival was similar for patients in the Velcade-Doxil group and the Velcade group.

Learn about other FDA approved drugs for multiple myeloma treatment.

What have other clinical studies shown?

A variety of combination therapies that include Doxil have shown to be effective in patients who have previously received other therapies. Doxil has been combined with agents such as Velcade, Revlimid® (lenalidomide, Celgene), Thalomid® (thalidomide, Celgene), and/or dexamethasone in a number of 3- and 4-drug regimens.

Likewise, a variety of Doxil combination therapies have been shown to be effective in treating newly diagnosed myeloma. Examples include:

  • Doxil, Revlimid, and low-dose dexamethasone [Rachid AmJHematol 2014]
  • Revlimid, Velcade, Doxil, and dexamethasone [Jakubowiak Blood 2011]
  • Velcade and Doxil
  • Doxil, Velcade, Cyclophosphamide, and dexamethasone, a regimen referred to as ABCD

How is Doxil currently being studied in myeloma?

Doxil is being studied in combination with various approved and investigational agents for use in treating myeloma.

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