PRT2527 + Zanubrutinib for Blood Cancers

Not currently recruiting at 30 trial locations

Overseen By Study Contact (Please Do Not Disclose Personal Information)

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Prelude Therapeutics

Must not be taking: Strong CYP3A4 inhibitors

Disqualifiers: CNS involvement, Severe pulmonary disease, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug called PRT2527 for treating certain blood cancers that have returned or don't respond to standard treatments. The study aims to assess the safety of this drug alone and its effectiveness when combined with other medications like zanubrutinib (a Bruton's tyrosine kinase inhibitor) or venetoclax. Suitable candidates for this trial include those with specific blood cancers, such as aggressive B-cell lymphoma or myeloid malignancies, who haven't responded to standard treatments. Participants will receive the medication through an IV once a week, and some will also take pills as part of the combination therapy. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop all current medications, but you cannot take strong CYP3A4 inhibitors within 15 days of starting the study treatment. Also, you must wait at least 5 half-lives of any other investigational or approved therapies or 14 days, whichever is shorter, before starting the study treatment.

Will I have to stop taking my current medications?

The trial requires that you stop taking strong CYP3A4 inhibitors at least 15 days before starting the study treatment. Additionally, you must wait at least 5 half-lives of your current medication or 14 days, whichever is shorter, before beginning the trial.

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

Research has shown that PRT2527 was safe in earlier studies. Patients tolerated it well both alone and when combined with zanubrutinib. These studies found that PRT2527 was generally well-tolerated across different dose levels.

For the combination of PRT2527 with venetoclax, early results also suggest it is manageable for patients with certain blood cancers. Although data collection continues, the findings support further research, indicating the treatment does not pose major safety concerns at the initial doses tested.

Overall, these findings suggest that PRT2527, whether used alone or with another drug, is reasonably safe for human use at this stage of research. However, since this is early-stage research, ensuring safety remains a key focus as the research progresses. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about PRT2527 and its combinations because these treatments offer a unique approach to tackling blood cancers. Unlike traditional chemotherapy, which targets rapidly dividing cells, PRT2527 may work by inhibiting specific proteins essential for cancer cell survival, offering a more targeted attack. The combination with Zanubrutinib, a BTK inhibitor, or Venetoclax, which targets the BCL-2 protein, could enhance this effect, potentially leading to more effective treatments with fewer side effects. This targeted strategy represents a shift from the broader, less specific mechanisms of existing therapies, potentially leading to better outcomes for patients with lymphoid and myeloid malignancies.

What evidence suggests that this trial's treatments could be effective for blood cancers?

Research has shown that PRT2527 may help treat certain blood cancers that have returned or resisted other treatments. Studies have found it effective in patients who have tried therapies like CAR-T therapy. In this trial, some participants will receive PRT2527 with zanubrutinib, a cancer drug that has shown early promise in lymphoid cancers. For myeloid cancers, researchers are testing PRT2527 with venetoclax, another cancer treatment, in a separate trial arm. These combinations aim to improve outcomes by attacking cancer cells in different ways. Early findings suggest it is safe and shows promise in effectiveness. ^{1 2 5 6 7}

Are You a Good Fit for This Trial?

This trial is for adults with certain aggressive blood cancers like B-cell lymphoma, mantle cell lymphoma, or chronic leukemia that have stopped responding to standard treatments. Participants must be in good physical condition (ECOG 0 or 1), able to follow the study plan, and have proper organ function. They can't join if they've had recent cancer treatment that conflicts with the study drugs, severe heart issues, lung disease with low oxygen levels, or a history of other cancers except some skin and localized cancers.

Inclusion Criteria

I am fully active or can carry out light work.

Echocardiogram (or multigated acquisition [MUGA] scan) indicating a left ventricular ejection fraction of ≥ 50%

Willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures

Exclusion Criteria

I have been treated with a CDK9 inhibitor before.

Mean corrected QT interval of > 470 msec following triplicate ECG measurement or history of long QT syndrome

I have a severe lung condition that causes low oxygen levels.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive escalating doses of PRT2527 as monotherapy and in combination with zanubrutinib or venetoclax to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D)

Approximately 2 years

Weekly visits for dose administration

Dose Confirmation

Participants receive treatment at the RP2D in indication-specific cohorts to confirm the dose

Approximately 2 years

Weekly visits for dose administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• PRT2527

Trial Overview The trial is testing PRT2527 alone and combined with Zanubrutinib in patients who have relapsed or refractory hematologic malignancies. It's a Phase 1 study focusing on finding the safest dose that works (PR2D) while checking how well these treatments work against these types of blood cancers.

How Is the Trial Designed?

Group I: PRT2527/Zanubrutinib Combination in Lymphoid Malignancies Experimental Treatment 2 Interventions

PRT2527 will be administered by intravenous infusion once weekly at the dose level assigned during the dose escalation phase and at the defined RP2D dose for indication specific cohort during the dose confirmation phase. Zanubrutinib will be administered orally as combination therapy once or twice daily.

Group II: PRT2527/Venetoclax Combination in Myeloid Malignancies Experimental Treatment 2 Interventions

PRT2527 will be administered by intravenous infusion once weekly at the dose level assigned during the dose escalation phase and at the defined RP2D dose for indication specific cohort during the dose confirmation phase. Venetoclax will be administered orally as a combination therapy once daily.

Group III: PRT2527 Monotherapy in Myeloid Malignancies Experimental Treatment 1 Intervention

PRT2527 will be administered by intravenous infusion once weekly at the dose level assigned during the dose escalation phase and at the defined RP2D dose for indication-specific cohorts during the dose confirmation phase.

Group IV: PRT2527 Monotherapy in Lymphoid Malignancies Experimental Treatment 1 Intervention

PRT2527 will be administered by intravenous infusion once weekly at the dose level assigned during the dose escalation phase and at the defined RP2D dose for indication-specific cohorts during the dose confirmation phase.

Who Is Running the Clinical Trial?

Prelude Therapeutics

Lead Sponsor

Trials

11

Recruited

910+

BeiGene

Industry Sponsor

Trials

216

Recruited

32,500+

Published Research Related to This Trial

In a phase 2 trial involving 76 adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia, the combination of chemotherapy and ponatinib achieved a 3-year event-free survival rate of 70%, indicating its long-term efficacy.

The treatment was associated with significant adverse events, primarily infections and liver function abnormalities, but the protocol adjustments after initial patient treatment reduced the risk of serious complications, including myocardial infarction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: long-term follow-up of a single-centre, phase 2 study. Jabbour, E., Short, NJ., Ravandi, F., et al.[2023]

In a phase II clinical trial, the combination of ponatinib, a third-generation tyrosine kinase inhibitor, and blinatumomab, a bispecific T-cell engager, achieved complete molecular remissions in most patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.

These early results suggest a promising therapeutic strategy for this challenging type of leukemia, highlighting the potential efficacy of combining targeted therapies with immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TKI-BiTE Combo Produces CMRs in Most with ALL. [2022]

In a study of 21 patients with refractory or recurrent acute myeloid leukemia (R/R AML), the triple therapy of decitabine, idarubicin, and cytarabine (D-IA) resulted in a 47.6% complete remission rate after one treatment cycle, indicating significant efficacy.

The treatment was generally well tolerated, with no treatment-related mortalities reported, although common side effects included hematological toxicity and infections, suggesting a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Management of Decitabine prior to Full-Dose Idarubicin and Cytarabine in the Treatment of Refractory/Recurrent Acute Myeloid Leukemia. Zhao, H., Xu, L., Yang, Y., et al.[2018]

Imatinib mesylate was highly effective in treating myeloproliferative neoplasm (MPN) patients with eosinophilia, achieving a 100% hematological remission rate and an 85.7% complete molecular remission rate over a median follow-up of 16 months.

The treatment was generally safe, with mild myelosuppression occurring in 37.5% of patients, indicating that imatinib is well-tolerated in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The efficacy of imatinib mesylate for patients with myeloproliferative neoplasm (MPN) with eosinophilia]. Zhang, Y., Qin, TJ., Zhou, CL., et al.[2016]

AZD1480, a selective inhibitor of Janus-associated kinases 1 and 2, showed anti-tumor activity in preclinical models and was tested in a phase I clinical study involving 35 patients with myelofibrosis, where some patients experienced clinical improvement.

While AZD1480 was relatively well tolerated, it caused low-grade neurological toxicity that limited therapy and led to the study's termination, highlighting the need for careful monitoring of side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I, open-label, multi-center study of the JAK2 inhibitor AZD1480 in patients with myelofibrosis. Verstovsek, S., Hoffman, R., Mascarenhas, J., et al.[2023]

In a phase 3b study involving 161 patients with polycythemia vera resistant or intolerant to hydroxyurea, ruxolitinib demonstrated a safety profile consistent with previous studies, with 37.9% of patients experiencing adverse events that required dose adjustments.

Ruxolitinib was effective, achieving hematocrit control in 45.3% of patients and significant spleen size reduction in 86.7%, indicating its potential as a viable treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy findings from the open-label, multicenter, phase 3b, expanded treatment protocol study of ruxolitinib for treatment of patients with polycythemia vera who are resistant/intolerant to hydroxyurea and for whom no alternative treatments are available. Foltz, L., Pica, GM., Zerazhi, H., et al.[2021]

Four JAK2 inhibitors (ruxolitinib, fedratinib, pacritinib, and momelotinib) were studied for their effects on myeloproliferative neoplasms (MPNs), showing similar anti-proliferative effects but distinct clinical profiles, particularly with pacritinib demonstrating the strongest potency in reducing colony formation and extending survival in patient-derived models.

The study revealed that pacritinib not only suppresses JAK-STAT signaling but also significantly modulates iron regulation by inhibiting hepcidin and SMAD signaling, suggesting its potential for broader therapeutic benefits beyond just targeting JAK2.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comprehensive profiling of clinical JAK inhibitors in myeloproliferative neoplasms. Kong, T., Yu, L., Laranjeira, ABA., et al.[2023]

The Jak2 V617F mutation is a key target for treating myeloproliferative neoplasms (MPNs), and the compound 9e (AZD1480) has been identified as a potent Jak2 inhibitor that effectively inhibits cell signaling and proliferation in Jak2 V617F cell lines in laboratory studies.

In preclinical models, 9e demonstrated significant efficacy in reducing disease symptoms and has favorable physical and pharmacokinetic properties, leading to its evaluation in Phase I clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery of 5-chloro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (AZD1480) as a novel inhibitor of the Jak/Stat pathway. Ioannidis, S., Lamb, ML., Wang, T., et al.[2014]

Bosutinib is an effective oral treatment for chronic myeloid leukemia (CML) that works against all phases of the disease, except for cases with specific mutations (T315I or V299LABL).

The drug is well tolerated with a manageable toxicity profile, and its absorption is enhanced when taken with food, showing dose-proportional increases in plasma concentration from 200 to 800 mg.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Pharmacokinetics and Pharmacodynamics of Bosutinib. Abbas, R., Hsyu, PH.[2022]

In the OPAL study involving 29 adults with relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia, ponatinib achieved a high remission rate of 90%, indicating its efficacy in inducing early responses in advanced disease.

Despite a median treatment duration of 4 months and a high incidence of cardiovascular risk factors among patients, only 3 cardiovascular events were reported, suggesting that ponatinib has an acceptable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ponatinib-based therapy in adults with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the real-life OPAL study. Tavitian, S., Uzunov, M., Bérard, E., et al.[2021]

In a phase 2 trial involving 37 adult patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia, the combination of chemotherapy and ponatinib resulted in an impressive 2-year event-free survival rate of 81%.

While the treatment was effective, it was associated with significant side effects, including infections and thrombotic events, highlighting the need for careful monitoring and management of vascular risk factors during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a single-centre, phase 2 study. Jabbour, E., Kantarjian, H., Ravandi, F., et al.[2019]

In a phase I study involving 34 patients with JAK2V617F positive myelofibrosis, the maximum tolerated dose of the multi-kinase inhibitor lestaurtinib was determined to be 140 mg twice daily, with gastrointestinal toxicity being the most common side effect.

Despite some patients showing clinical improvement after 12 weeks, the study did not find meaningful reductions in the JAK2V617F allele burden, indicating that while there may be some clinical benefits, the drug's effectiveness in reducing the underlying mutation was limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I dose escalation study of lestaurtinib in patients with myelofibrosis. Hexner, EO., Mascarenhas, J., Prchal, J., et al.[2021]

A 65-year-old patient with polycythemia vera treated with the JAK 1/2 inhibitor ruxolitinib developed a second primary malignancy, highlighting the potential risk of non-melanoma skin cancers associated with this treatment.

Despite the risks, the combination of ruxolitinib and the anti-PD-L1 immunotherapy avelumab was found to be both safe and effective in managing the patient's hematological condition and achieving remission of the underlying carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case Report: Avelumab and ruxolitinib to manage polycythemia vera and secondary metastatic Merkel cell carcinoma: a possible successful combination. Masucci, C., Passucci, M., Scalzulli, E., et al.[2023]

In a study of nine patients with recurrent Philadelphia chromosome-positive CNS leukemia and a T315I mutation after allogeneic stem cell transplantation, ponatinib combined with intrathecal chemotherapy led to a deep molecular response and central nervous system remission within a median of 1.5 months.

Despite some patients experiencing a second CNS relapse due to dosage reduction, they were able to regain remission with an increased dose of ponatinib, indicating its potential effectiveness in managing this challenging condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ponatinib therapy in recurrent Philadelphia chromosome-positive central nervous system leukemia with T315I mutation after Allo-HSCT. He, JB., Zhang, X., Guo, ZW., et al.[2021]

The pan-PIM inhibitor INCB053914 enhances the effectiveness of the JAK1/2 inhibitor ruxolitinib in treating myeloproliferative neoplasms (MPNs), showing improved inhibition of cell growth and induction of apoptosis in both laboratory and animal models.

INCB053914 not only boosts the efficacy of ruxolitinib against primary MPN patient cells but also prevents persistent myeloproliferation in vivo, suggesting that this combination therapy could be a promising treatment strategy for MPN patients currently undergoing clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The pan-PIM inhibitor INCB053914 displays potent synergy in combination with ruxolitinib in models of MPN. Mazzacurati, L., Collins, RJ., Pandey, G., et al.[2023]

Citations

1. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/4501/534009/Preliminary-Results-of-a-Phase-1-Dose-Escalation

Preliminary Results of a Phase 1, Dose-Escalation Study of ... Conclusions: PRT2527 as monotherapy and in combo with zanu had an acceptable safety profile and evidence of preliminary activity in pts with R/R ...

2. preludetx.com preludetx.com/wp-content/uploads/2024/11/Lewis_CDK9_PRT2527-02_ASH_Poster_Dec2024.pdf

Preliminary Results of a Phase 1, Dose‑Escalation Study of ... • Here, we report the preliminary data from the phase 1 study of PRT2527 as ... with zanubrutinib across a range of R/R lymphoid malignancies, ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05665530

NCT05665530 | A Study of PRT2527 as Monotherapy and ... The purpose of this study is to evaluate the safety, tolerability, recommended phase 2 dose (PR2D), and preliminary efficacy of PRT2527 as a monotherapy and in ...

4. investors.preludetx.com investors.preludetx.com/news-releases/news-release-details/prelude-therapeutics-presents-preliminary-results-phase-1-dose

Release Details PRT2527 demonstrated activity across a range of relapsed/refractory lymphoid malignancies, including patients who received prior CAR-T therapy.

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0006497124072598

Preliminary Results of a Phase 1, Dose-Escalation Study ... PRT2527 as monotherapy and in combo with zanu had an acceptable safety profile and evidence of preliminary activity in pts with R/R lymphoid malignancies.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05665530

NCT05665530 | A Study of PRT2527 as Monotherapy and ... The purpose of this study is to evaluate the safety, tolerability, recommended phase 2 dose (PR2D), and preliminary efficacy of PRT2527 as a monotherapy and in ...

7. withpower.com withpower.com/trial/phase-1-lymphoma-2-2023-d773d

PRT2527 + Zanubrutinib for Blood Cancers The provided research does not contain specific safety data for the treatment PRT2527 + Zanubrutinib for blood cancers. The studies mentioned focus on other ...