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DUVELISIB

Duvelisib (also known as Copiktra or IPI-145) is an oral dual inhibitor of phosphoinositide-3-kinase-delta and gamma (PI3K-δ,γ), which has shown promising results in the treatment of various hematologic malignancies. This article explores how duvelisib is being used in clinical trials to treat conditions such as chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), peripheral T-cell lymphoma (PTCL), and other types of non-Hodgkin lymphoma (NHL). Clinical trials are investigating duvelisib as both a monotherapy and in combination with other treatments, examining its efficacy, safety, and potential to overcome resistance to previous therapies.

Table of Contents

What is Duvelisib?

Duvelisib (also known by the brand name Copiktra) is an oral medication used to treat certain types of blood cancers. It belongs to a class of drugs called phosphoinositide 3-kinase (PI3K) inhibitors [1]. Specifically, duvelisib is a dual inhibitor of the delta and gamma isoforms of PI3K (PI3K-δ,γ), which makes it particularly effective for certain types of blood cancers [2].

Duvelisib may also be referred to by other names in clinical and research settings, including:

  • IPI-145
  • VS-0145
  • ABBV-954

The medication comes in capsule form and is taken orally (by mouth), typically twice daily [3].

How Duvelisib Works

Duvelisib works by blocking specific enzymes called phosphoinositide 3-kinases (PI3Ks), which are important for the growth and survival of cancer cells. By inhibiting these enzymes, duvelisib stops the growth of cancer cells by blocking some of the signals needed for cell growth [4].

More specifically, duvelisib targets two forms of PI3K:

  • PI3K-delta (δ): Found primarily in white blood cells called B cells and T cells
  • PI3K-gamma (γ): Present in both malignant B cells and cells in the tumor microenvironment

By targeting both isoforms, duvelisib not only directly affects cancer cells but may also modify the surrounding environment that supports cancer growth. This dual inhibition mechanism distinguishes duvelisib from some other PI3K inhibitors that target only one isoform [5].

Medical Conditions Treated with Duvelisib

Duvelisib has been investigated for and is used to treat several types of blood cancers, including:

Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL)

Duvelisib has been approved for the treatment of relapsed or refractory (R/R) CLL or SLL in patients who have received at least two prior therapies [6]. CLL and SLL are essentially the same disease but manifest differently – CLL primarily affects the blood and bone marrow, while SLL mainly involves the lymph nodes.

Peripheral T-cell Lymphoma (PTCL)

Clinical trials have evaluated duvelisib for relapsed or refractory PTCL, a rare and aggressive type of non-Hodgkin lymphoma that develops from mature T cells [2].

Follicular Lymphoma (FL)

Duvelisib has been studied in the treatment of relapsed or refractory follicular lymphoma, which is the most common type of indolent (slow-growing) non-Hodgkin lymphoma [7].

Other Indolent Non-Hodgkin Lymphomas (iNHL)

This includes marginal zone lymphoma (MZL) and other slow-growing B-cell lymphomas [8].

The term “relapsed” means the cancer has returned after a period of improvement, while “refractory” means the cancer has not responded to treatment or has stopped responding.

Dosage and Administration

Duvelisib is typically administered as oral capsules. The standard dosage regimens studied in clinical trials include:

Standard Dosing

The most common dose used in clinical trials is 25 mg taken twice daily (BID) [3]. However, the dose may vary depending on the specific condition being treated and individual patient factors.

Dose Optimization

In some studies, different dosing strategies have been investigated:

  • Starting at 25 mg BID with potential escalation to 50 mg or 75 mg based on response and tolerance [2]
  • Higher initial doses (75 mg BID) followed by reduction to maintenance doses [2]
  • Intermittent dosing schedules (e.g., 2 weeks on, 2 weeks off) to potentially reduce side effects while maintaining efficacy [8]

Administration Guidelines

Duvelisib capsules should be swallowed whole with water and can generally be taken with or without food. However, patients should avoid grapefruit and grapefruit juice while taking duvelisib as these may affect how the medication works in the body [9].

Treatment typically continues until disease progression or unacceptable toxicity occurs. In some trials, treatment was given for a fixed duration (e.g., up to 18 cycles), after which patients who were benefiting could continue receiving additional cycles [1].

Efficacy of Duvelisib in Clinical Trials

The effectiveness of duvelisib has been evaluated in multiple clinical trials across different blood cancers. Here are some key findings:

Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

In the DUO trial, a Phase 3 study comparing duvelisib to ofatumumab in patients with relapsed or refractory CLL/SLL, duvelisib demonstrated significant improvement in progression-free survival (PFS) compared to the control arm [1]. The study also showed that duvelisib was effective in patients who had previously been treated with BTK inhibitors such as ibrutinib [10].

Peripheral T-cell Lymphoma (PTCL)

A Phase 2 study evaluating duvelisib in relapsed or refractory PTCL showed promising overall response rates (ORR). The study included a dose optimization phase to determine the optimal dose for these patients [2].

Follicular Lymphoma and other Indolent Non-Hodgkin Lymphomas

Clinical trials have demonstrated that duvelisib can achieve meaningful response rates in patients with refractory indolent non-Hodgkin lymphoma (iNHL), including follicular lymphoma. In one Phase 2 study, duvelisib showed activity in patients whose disease was refractory to both rituximab and chemotherapy or radioimmunotherapy [3].

Response Measures

The efficacy of duvelisib is typically measured by the following outcomes:

  • Overall Response Rate (ORR): The percentage of patients achieving either a complete response (CR) or partial response (PR) to treatment
  • Duration of Response (DOR): How long the response to treatment lasts
  • Progression-Free Survival (PFS): The time from start of treatment until disease progression or death
  • Disease Control Rate (DCR): The percentage of patients achieving CR, PR, or stable disease (SD) for a specified period
  • Overall Survival (OS): The time from start of treatment until death from any cause

Side Effects and Safety Profile

Like all medications, duvelisib can cause side effects. It’s important for patients to be aware of potential adverse reactions and to report any symptoms to their healthcare provider promptly.

Common Side Effects

The most commonly reported side effects in clinical trials include [11]:

  • Diarrhea
  • Neutropenia (low levels of neutrophils, a type of white blood cell)
  • Rash
  • Fatigue
  • Fever
  • Nausea
  • Cough
  • Upper respiratory infection
  • Pneumonia
  • Decreased appetite

Serious Side Effects

More serious adverse reactions that have been observed include [12]:

  • Infections: Including pneumonia and other serious infections
  • Diarrhea or colitis: Severe inflammation of the intestines
  • Cutaneous reactions: Severe skin reactions
  • Pneumonitis: Inflammation of lung tissue
  • Hepatotoxicity: Liver damage
  • Neutropenia: Severely low levels of neutrophils that can increase infection risk

Management of Side Effects

To manage these side effects, physicians may recommend:

  • Dose modifications (reductions or interruptions)
  • Prophylactic antibiotics to prevent certain infections
  • Medications to manage diarrhea or other symptoms
  • Regular monitoring of blood counts and liver function
  • In some cases, intermittent dosing schedules to reduce toxicity while maintaining efficacy [8]

It’s crucial for patients to communicate openly with their healthcare team about any side effects they experience, as early intervention can often prevent complications and allow continued treatment.

Drug Interactions

Duvelisib may interact with other medications, potentially affecting either the effectiveness of duvelisib or the other drug, or increasing the risk of side effects. Here are some important considerations:

CYP3A4 Interactions

Duvelisib is primarily metabolized by an enzyme called CYP3A4 in the liver. Medications that affect this enzyme can alter duvelisib levels in the body [13]:

  • Strong CYP3A4 inhibitors (such as ketoconazole, clarithromycin, and certain HIV medications) can increase duvelisib levels, potentially increasing side effects
  • Strong CYP3A4 inducers (such as rifampin, phenytoin, and St. John’s wort) can decrease duvelisib levels, potentially reducing its effectiveness

Food Interactions

While duvelisib can generally be taken with or without food, patients should avoid grapefruit and grapefruit juice as these can inhibit CYP3A4 and potentially increase duvelisib levels [14].

Other Medications

Particular attention should be paid when combining duvelisib with:

  • Other medications that may suppress the immune system
  • Medications that can cause liver toxicity
  • Medications that can cause diarrhea or colitis

Always inform all healthcare providers about all medications, supplements, and herbal products you are taking before starting duvelisib. Do not start new medications without consulting the healthcare provider who prescribed duvelisib.

Special Populations

Special considerations may apply when using duvelisib in certain patient populations:

Elderly Patients

Many clinical trials of duvelisib have included elderly patients, as CLL/SLL and indolent non-Hodgkin lymphomas often affect older individuals. In general, no major differences in efficacy have been observed based on age, though older patients may sometimes experience more side effects and may require closer monitoring [11].

Patients with Hepatic (Liver) Impairment

Since duvelisib is metabolized in the liver, patients with liver impairment may process the drug differently. Dose adjustments may be necessary, and liver function should be monitored regularly during treatment [14].

Patients with Renal (Kidney) Impairment

Based on available data, mild to moderate kidney impairment does not significantly affect duvelisib exposure, so dose adjustments are generally not required. However, the drug has not been extensively studied in patients with severe kidney impairment [14].

Pregnancy and Breastfeeding

Duvelisib may cause harm to a developing fetus based on its mechanism of action and findings from animal studies. Women of reproductive potential should use effective contraception during treatment and for a period after the last dose. Breastfeeding is not recommended during treatment with duvelisib [1].

Ongoing Research and Future Directions

Research on duvelisib continues to evolve, with several promising areas of investigation:

Combination Therapies

Researchers are exploring the potential benefits of combining duvelisib with other anti-cancer agents to enhance efficacy. Some notable combinations under investigation include:

  • Duvelisib + Venetoclax: This combination targets different survival pathways in cancer cells and is being studied in CLL/SLL and other lymphomas [15]
  • Duvelisib + Immunotherapy: Combinations with immune checkpoint inhibitors like nivolumab or pembrolizumab are being evaluated in various cancers [16]
  • Duvelisib + Chemotherapy: Studies are examining whether adding duvelisib to conventional chemotherapy regimens can improve outcomes [9]

Expanded Indications

While currently focused on blood cancers, research is exploring the potential of duvelisib in other conditions:

  • Solid Tumors: Early studies are evaluating duvelisib’s potential role in certain solid tumor types [17]
  • Inflammatory Conditions: The PI3K pathway is involved in various inflammatory processes, suggesting potential applications beyond cancer [12]

Novel Dosing Strategies

Alternative dosing approaches are being investigated to optimize the balance between efficacy and tolerability:

  • Intermittent Dosing: Research suggests that scheduled breaks in treatment may reduce toxicity while maintaining effectiveness [8]
  • Lower Starting Doses: Studies are evaluating whether starting at lower doses and adjusting as needed might improve the safety profile [18]

Biomarker Research

Scientists are working to identify biomarkers that might predict which patients are most likely to benefit from duvelisib or who might be at higher risk for specific side effects, enabling more personalized treatment approaches [19].

As research continues, the role of duvelisib in cancer treatment is likely to evolve, potentially offering new options for patients with difficult-to-treat hematologic malignancies and possibly expanding to other indications.

Category Details
Drug Information – Generic name: Duvelisib – Brand names: Copiktra, IPI-145, VS-0145 – Class: Dual PI3K-δ,γ inhibitor – Administration: Oral capsules (typically 15-25 mg twice daily)
Key Indications Under Study – Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) – Peripheral T-cell Lymphoma (PTCL) – Follicular Lymphoma (FL) – Indolent Non-Hodgkin Lymphoma (iNHL) – Richter Syndrome – Other hematologic malignancies
Notable Clinical Trials – DUO: Phase 3 trial comparing duvelisib vs. ofatumumab in CLL/SLL – NCT01882803: Phase 2 trial in refractory indolent NHL – NCT03372057: Phase 2 trial in relapsed/refractory PTCL – NCT04038359: Phase 2 trial comparing intermittent dosing schedules – Multiple combination therapy trials with venetoclax, nivolumab, etc.
Key Efficacy Findings – Demonstrated improved progression-free survival compared to ofatumumab in CLL/SLL – Showed activity in ibrutinib-resistant CLL – Demonstrated responses in refractory NHL – Showed promise in relapsed/refractory PTCL – Various combination therapies showing early promising results
Common Side Effects – Hematologic: neutropenia, anemia, thrombocytopenia – Gastrointestinal: diarrhea, colitis, nausea – Infections – Fatigue – Rash – Liver enzyme elevations – Pneumonitis
Dosing Strategies Being Explored – Continuous dosing: 25 mg BID in 28-day cycles – Intermittent dosing: 2 weeks on/2 weeks off – Dose escalation: starting at lower doses (15 mg) and increasing as tolerated – Lead-in periods with single agents before combination therapy – Lower maintenance doses after initial higher doses
Combination Approaches – With BCL-2 inhibitors (venetoclax) – With immune checkpoint inhibitors (nivolumab, pembrolizumab) – With BTK inhibitors (acalabrutinib) – With monoclonal antibodies – With chemotherapy agents – Before or after CAR-T cell therapy
Current Development Status – FDA approved for: – CLL/SLL after at least two prior therapies – Follicular lymphoma after at least two prior therapies – Ongoing trials in multiple indications and combinations – Exploring optimal dosing schedules to improve tolerability – Investigating biomarkers of response

FAQ

  • What is duvelisib and how does it work? Duvelisib (also known as Copiktra or IPI-145) is an oral dual inhibitor of phosphoinositide-3-kinase-delta and gamma (PI3K-δ,γ). It works by blocking these enzymes which are important for the survival and growth of cancer cells, particularly in blood cancers. By inhibiting these pathways, duvelisib helps to stop cancer cell growth and can cause cancer cell death. It specifically targets signaling pathways that are often overactive in various types of lymphomas and leukemias.
  • What types of cancer is duvelisib being studied for in clinical trials? Duvelisib is primarily being studied for hematologic (blood) malignancies, including chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), peripheral T-cell lymphoma (PTCL), follicular lymphoma (FL), indolent non-Hodgkin lymphoma (iNHL), and transformed lymphomas like Richter syndrome. Some trials are also exploring its potential in solid tumors, particularly in combination with other treatments like immunotherapy. The drug has shown particular promise in patients whose cancer has relapsed or become refractory to previous treatments.
  • What are the common dosing regimens for duvelisib in clinical trials? In most clinical trials, duvelisib is typically administered orally in capsule form at doses ranging from 15 mg to 75 mg, taken twice daily (BID). The most common dose being studied is 25 mg twice daily in 28-day treatment cycles. Some trials explore different dosing strategies, including dose escalation approaches (starting at lower doses and increasing as tolerated) and intermittent dosing schedules (such as 2 weeks on, 2 weeks off) to potentially reduce side effects while maintaining efficacy. For certain combinations with other drugs, doses may be adjusted to find the optimal balance of efficacy and tolerability.
  • What combination therapies with duvelisib are being investigated? Researchers are investigating duvelisib in combination with several other medications. These include immune checkpoint inhibitors (like nivolumab and pembrolizumab), BCL-2 inhibitors (venetoclax), BTK inhibitors (acalabrutinib), monoclonal antibodies (ofatumumab), chemotherapy agents (docetaxel), and other targeted therapies. These combinations aim to enhance anti-cancer effects through synergistic mechanisms, potentially overcoming resistance to single-agent treatments. For example, the combination of duvelisib with venetoclax targets different survival pathways in cancer cells, potentially increasing effectiveness in difficult-to-treat blood cancers.
  • What are the common side effects of duvelisib reported in clinical trials? Common side effects of duvelisib reported in clinical trials include hematological toxicities (decreased blood cell counts like neutropenia, anemia, and thrombocytopenia), gastrointestinal issues (diarrhea, nausea, colitis), infections, fatigue, rash, liver enzyme elevations, and inflammation of the lungs (pneumonitis). Some trials have noted that intermittent dosing schedules may help reduce the frequency and severity of adverse events. Patients in clinical trials are typically monitored closely for these side effects, which can often be managed with dose modifications, temporary treatment interruptions, or supportive care.

Ongoing Clinical Trials on DUVELISIB

  • Study Comparing Duvelisib with Gemcitabine or Bendamustine for Patients with Relapsed or Resistant T Cell Lymphoma Originating from T Follicular Helper Cells

    Recruiting

    1 1 1 1
    Investigated drugs:
    Belgium Czechia Denmark France Germany Italy +3

Glossary

  • PI3K Inhibitor: A class of drugs that block phosphoinositide 3-kinase (PI3K) enzymes, which are involved in cellular functions like growth, proliferation, and survival. Duvelisib specifically inhibits the delta and gamma isoforms of PI3K, which are important in certain blood cancers.
  • Chronic Lymphocytic Leukemia (CLL): A type of cancer that affects white blood cells called lymphocytes, particularly B lymphocytes, in the bone marrow. It typically progresses slowly and is the most common type of leukemia in adults.
  • Small Lymphocytic Lymphoma (SLL): A type of non-Hodgkin lymphoma affecting the same type of cells as CLL. SLL and CLL are essentially the same disease but manifest differently—SLL primarily affects lymph nodes while CLL affects bone marrow and blood.
  • Peripheral T-cell Lymphoma (PTCL): A diverse group of aggressive T-cell lymphomas that develop from mature T-cells and typically occur outside the bone marrow. These are generally more difficult to treat than B-cell lymphomas.
  • Follicular Lymphoma (FL): A type of non-Hodgkin lymphoma that begins in the B-lymphocytes and typically grows in lymph nodes throughout the body. It's usually slow-growing (indolent) but can transform into a more aggressive form.
  • Indolent Non-Hodgkin Lymphoma (iNHL): Slow-growing forms of non-Hodgkin lymphoma that typically don't cause symptoms until later stages. Types include follicular lymphoma, marginal zone lymphoma, and small lymphocytic lymphoma.
  • Richter Syndrome: A rare condition where CLL or SLL transforms into an aggressive form of lymphoma, most commonly diffuse large B-cell lymphoma. It occurs in approximately 2-10% of CLL patients.
  • Overall Response Rate (ORR): The percentage of patients whose cancer shrinks or disappears after treatment. It combines complete responses (CR) and partial responses (PR) to treatment.
  • Progression-Free Survival (PFS): The length of time during and after treatment that a patient lives with the disease but it does not get worse. It's measured from the start of treatment until disease progression or death.
  • Complete Response (CR): The disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured.
  • Partial Response (PR): A decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment. Typically defined as at least a 30% decrease in measurable disease.
  • Duration of Response (DOR): The period from the time of initial response to treatment until documented tumor progression or death.
  • Maximum Tolerated Dose (MTD): The highest dose of a drug that does not cause unacceptable side effects. This is often determined in Phase 1 clinical trials.
  • Dose-Limiting Toxicity (DLT): Side effects that are severe enough to prevent an increase in dose or that require a decrease in dose in clinical trials.
  • Pharmacokinetics (PK): The study of how a drug is absorbed, distributed, metabolized, and excreted by the body. PK parameters include maximum concentration (Cmax), time to maximum concentration (Tmax), and area under the curve (AUC).
  • Relapsed/Refractory: Describes cancer that has returned after a period of remission (relapsed) or that has not responded to previous treatments (refractory).
  • Bruton's Tyrosine Kinase (BTK): An enzyme important for B-cell development and function. BTK inhibitors like ibrutinib are used to treat certain B-cell malignancies.
  • CAR-T Cell Therapy: A type of treatment in which a patient's T cells are changed in the laboratory to contain a gene for a special receptor called a chimeric antigen receptor (CAR) that binds to a certain protein on cancer cells.
  • Disease Control Rate (DCR): The percentage of patients who achieve complete response, partial response, or stable disease. It's a broader measure of treatment benefit than ORR.

References

  1. https://clinicaltrials.gov/study/NCT02004522
  2. https://clinicaltrials.gov/study/NCT03372057
  3. https://clinicaltrials.gov/study/NCT01882803
  4. https://clinicaltrials.gov/study/NCT04688658
  5. https://clinicaltrials.gov/study/NCT01476657
  6. https://clinicaltrials.gov/study/NCT03370185
  7. https://clinicaltrials.gov/study/NCT04707079
  8. https://clinicaltrials.gov/study/NCT04038359
  9. https://clinicaltrials.gov/study/NCT05057247
  10. https://clinicaltrials.gov/study/NCT04209621
  11. https://clinicaltrials.gov/study/NCT02711852
  12. https://clinicaltrials.gov/study/NCT04487886
  13. https://clinicaltrials.gov/study/NCT02307461
  14. https://clinicaltrials.gov/study/NCT01836861
  15. https://clinicaltrials.gov/study/NCT02640833
  16. https://clinicaltrials.gov/study/NCT04193293
  17. https://clinicaltrials.gov/study/NCT05508659
  18. https://clinicaltrials.gov/study/NCT03961672
  19. https://clinicaltrials.gov/study/NCT05010005