IPI-145 + FCR for Chronic Lymphocytic Leukemia

Not currently recruiting at 1 trial location

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Dana-Farber Cancer Institute

Must not be taking: CYP3A inhibitors/inducers, QTc prolongers

Disqualifiers: CNS involvement, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 9

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug, IPI-145, combined with standard treatments for chronic lymphocytic leukemia (CLL). The researchers aim to determine if adding IPI-145 improves treatment outcomes for people with CLL. Participants will receive IPI-145 alongside fludarabine, cyclophosphamide, and rituximab, which are common CLL medications. This trial targets individuals with a confirmed diagnosis of CLL who have not yet received treatment. As a Phase 1/Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group, offering participants the chance to contribute to groundbreaking advancements in CLL treatment.

Will I have to stop taking my current medications?

The trial requires that you stop taking foods or medications that strongly affect CYP3A enzymes (which help process drugs in the body) at least one week before starting the study and throughout its duration.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that IPI-145, also known as duvelisib, raises some safety concerns. This drug is being developed to treat blood cancers like chronic lymphocytic leukemia (CLL). In some trials, patients taking duvelisib experienced serious side effects, such as infections and gastrointestinal issues like diarrhea. A 15% higher risk of death was also noted in some cases. However, other studies found that duvelisib was effective against cancer and considered safe for patients who had already tried other treatments.

The other drugs in the trial—fludarabine, cyclophosphamide, and rituximab (FCR)—are standard treatments for CLL. They are generally considered safe but can cause side effects like low blood counts and an increased risk of infections.

Overall, the safety of using IPI-145 with FCR remains under careful study. Due to the mixed findings on duvelisib's safety, participants should discuss potential risks with their doctors. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment for chronic lymphocytic leukemia?

Researchers are excited about the combination treatment of IPI-145 with FCR (Fludarabine, Cyclophosphamide, Rituximab) for Chronic Lymphocytic Leukemia (CLL) because it introduces a novel mechanism of action. IPI-145 is a small molecule inhibitor targeting PI3K-delta and PI3K-gamma, enzymes involved in the growth and survival of cancer cells. This dual inhibition may enhance the effectiveness of the standard FCR regimen, potentially leading to better patient outcomes. Additionally, the long-term maintenance with IPI-145 could help sustain remission and improve the quality of life for patients with CLL.

What evidence suggests that this trial's treatments could be effective for chronic lymphocytic leukemia?

Research has shown that IPI-145, also known as duvelisib, may help treat chronic lymphocytic leukemia (CLL). Studies indicate that duvelisib can be effective for patients who haven't responded to other treatments, providing another option. In this trial, participants will receive IPI-145 combined with fludarabine, cyclophosphamide, and rituximab (FCR), a well-known treatment for CLL. This combination has doubled the rates of complete remission, meaning more patients experience a full disappearance of cancer signs. Together, IPI-145 and FCR might effectively treat CLL by attacking cancer cells in different ways. ^{6 7 8 9 10}

Who Is on the Research Team?

Matthew S. Davids

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

This trial is for younger patients aged 18-65 with confirmed chronic lymphocytic leukemia (CLL) who need treatment but haven't had any yet. They should be relatively healthy, not pregnant, and free from other cancers unless it's low-risk or treated within the past 5 years. People with poor liver or kidney function, heart issues, certain infections or diseases like HIV are excluded.

Inclusion Criteria

I have been diagnosed with CLL and need treatment.

I have not received any treatment for chronic lymphocytic leukemia.

I can carry out all my self-care but cannot do heavy physical work.

Exclusion Criteria

I've been cancer-free for 5 years, except for certain low-risk types.

I have not had active tuberculosis in the last two years.

My cancer has spread to my brain or spinal cord.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Dose escalation to find the highest safe dose of IPI-145 in combination with FCR

35 days for Cycle 1, 28 days per subsequent cycle

Weekly visits during Cycle 1, Day 1 visits for subsequent cycles

Phase II Treatment

Treatment with IPI-145 at the Recommended Phase II Dose (RP2D) in combination with FCR

Up to 6 cycles

Day 1 visits for each cycle

Maintenance

IPI-145 maintenance therapy for up to 2 years after completing chemotherapy

Up to 2 years

Every other cycle Day 1 during maintenance

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Cyclophosphamide
• Fludarabine
• IPI-145
• Rituximab

Trial Overview The study tests a new drug called IPI-145 combined with standard CLL treatments: fludarabine, cyclophosphamide, and rituximab (FCR). It aims to see if adding IPI-145 improves outcomes for those who have never been treated for CLL before.

How Is the Trial Designed?

Group I: IPI-145 Experimental Treatment 4 Interventions

Phase I-Dose escalation will occur using a standard 3-3 dose escalation beginning in dose level 1 with dose cohorts and escalation. * Each treatment cycle lasts 28 days (except cycle 1, which is 35 days) during which time IPI-145 will be taken twice daily. The study begins with 1 week of IPI-145 monotherapy. * Fludarabine, cyclophosphamide, rituximab (iFCR) - FCR will subsequently be introduced after 1 week and administered at standard dosing for up to 6 cycles, with dose reductions permitted. IPI-145 will be continued through the course of chemotherapy and for up to 2 years maintenance after completing chemotherapy Phase II - 20 additional patients treated with IPI-145 at the Recommended Phase II Dose (RP2D) + fludarabine, cyclophosphamide, rituximab (FCR) with standard dosing.

Cyclophosphamide is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Cytoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in European Union as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Canada as Neosar for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma
• Rheumatoid arthritis

Approved in Japan as Endoxan for:

• Breast cancer
• Ovarian cancer
• Multiple myeloma
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Verastem, Inc.

Industry Sponsor

Trials

42

Recruited

2,800+

Secura Bio, Inc.

Industry Sponsor

Trials

9

Recruited

200+

Published Research Related to This Trial

In a study involving 561 patients with chronic lymphocytic leukaemia, the standard treatment of fludarabine, cyclophosphamide, and rituximab showed a longer median progression-free survival of 55.2 months compared to 41.7 months for the bendamustine and rituximab combination, indicating that the standard therapy is more effective.

However, the bendamustine and rituximab combination was associated with significantly fewer severe side effects, such as neutropenia and infections, making it a potentially safer alternative for patients, especially those over 65 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Eichhorst, B., Fink, AM., Bahlo, J., et al.[2022]

The combination therapy of fludarabine, cyclophosphamide, and rituximab (FCR) achieved a high complete remission (CR) rate of 70% in 224 previously untreated patients with chronic lymphocytic leukemia (CLL), indicating its efficacy as an initial treatment.

Despite the high response rate, the treatment was associated with significant side effects, including grade 3 to 4 neutropenia in 52% of treatment courses and a notable incidence of infections, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. Keating, MJ., O'Brien, S., Albitar, M., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3952498/

Long-term results of the fludarabine, cyclophosphamide, ... The addition of rituximab to fludarabine and cyclophosphamide (FC) doubled the complete remission rate and remission duration of FC to 72% and 80 months, ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4824541/

Fludarabine, Cyclophosphamide, and Multiple-Dose ... Combination chemotherapy with fludarabine and cyclophosphamide (FC) results in complete remission (CR) rates of up to 38% in patients with previously untreated ...

3. ashpublications.org ashpublications.org/blood/article/142/21/1784/497479/Sustained-remissions-in-CLL-after-frontline-FCR

Sustained remissions in CLL after frontline FCR treatment with ... Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) achieves durable remissions, with flattening of the progression-free survival (PFS) ...

4. haematologica.org haematologica.org/article/view/6537/35997

Impact of dose intensity on outcome of fludarabine, ... Fludarabine-cyclophosphamide-rituximab (FCR) is now considered to be the most efficient drug combination in chronic lymphocytic leukemia (CLL) patients for ...

5. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.2008.17.2619

Chemoimmunotherapy With Low-Dose Fludarabine and ... FCR-Lite is highly effective in previously untreated CLL patients. Grade 3/4 neutropenia was dramatically reduced compared to standard FCR and ...

6. healthtree.org healthtree.org/cll/community/articles/duvelisib-risk-benefit-warning-cll

FDA Warns About Risk-Benefit Balance of Duvelisib for CLL Duvelisib was found to increase the risk of death by 15% and was associated with severe side effects, including serious infections, diarrhea/colitis, skin ...

7. ashpublications.org ashpublications.org/blood/article/122/21/677/70748/Preliminary-Safety-and-Efficacy-Of-IPI-145-a

Preliminary Safety and Efficacy Of IPI-145, a Potent Inhibitor Of ... IPI-145 is an oral, potent PI3K-δ,γ inhibitor currently in development for the treatment of hematologic (heme) malignancies.

8. frontiersin.org frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.1070660/full

Safety and efficacy of dual PI3K-δ, γ inhibitor, duvelisib in ... IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells. Blood (2014) 124(24):3583–6. doi: 10.1182/blood-2014-07 ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6220789/

Duvelisib, an oral dual PI3K‐δ, γ inhibitor, shows clinical ... Duvelisib demonstrated favorable clinical activity and an acceptable safety profile in these high‐risk, heavily pretreated, relapsed/refractory iNHL patients.

10. clinicaltrials.gov clinicaltrials.gov/study/NCT03370185

Phase 2 Study of Duvelisib in Previously Treated Patients ... A Phase 2 Study of Duvelisib Efficacy and Safety in Patients With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) Previously Treated ...