PRT2527 + Zanubrutinib for Blood Cancers
Recruiting in Palo Alto (17 mi)
+24 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Waitlist Available
Sponsor: Prelude Therapeutics
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This trial is testing a new drug called PRT2527, which blocks a protein that helps cancer cells grow, in patients with certain blood cancers that have come back or did not respond to other treatments. It also tests PRT2527 in combination with another drug, zanubrutinib, which blocks a different protein involved in cancer growth. The goal is to find a safe and effective dose for these drugs.
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.
What data supports the idea that PRT2527 + Zanubrutinib for Blood Cancers is an effective drug?
The available research does not provide specific data on the effectiveness of PRT2527 + Zanubrutinib for Blood Cancers. Instead, it focuses on other treatments like ponatinib combined with chemotherapy for a type of blood cancer called Philadelphia chromosome-positive acute lymphoblastic leukemia. This combination has shown promising results, with high remission rates and acceptable safety. However, there is no direct comparison or data available for PRT2527 + Zanubrutinib in the provided information.
12345What safety data exists for the treatment 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 treatments such as imatinib mesylate, lestaurtinib, AZD1480, and ruxolitinib, each with their own safety profiles and adverse events. For PRT2527 + Zanubrutinib, specific clinical trial data would be needed to assess safety.
678910Eligibility Criteria
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
+3 more
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.
+7 more
Participant Groups
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.
4Treatment groups
Experimental Treatment
Group I: PRT2527/Zanubrutinib Combination in Lymphoid MalignanciesExperimental Treatment2 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 MalignanciesExperimental Treatment2 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 MalignanciesExperimental Treatment1 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 MalignanciesExperimental Treatment1 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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
UC San Diego Moores Cancer CenterLa Jolla, CA
Dana-Farber Cancer InstituteBoston, MA
University of Virginia Comprehensive Cancer CenterCharlottesville, VA
Laura and Isaac Perlmutter Cancer Center at NYU Langone HealthNew York, NY
More Trial Locations
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Who Is Running the Clinical Trial?
Prelude TherapeuticsLead Sponsor
BeiGeneIndustry Sponsor
References
Ponatinib-based therapy in adults with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the real-life OPAL study. [2021]The OPAL study is a French multicenter observational retrospective analysis of adults with relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia treated in a real-life setting by ponatinib. Twenty-nine patients were included since 2012. Median age was 55  years. The initial dose of ponatinib, combined to chemotherapy in half of the patients, was 45 mg/day in most instances. The remission rate was 90% and seven patients received allogeneic stem cell transplantation. Median disease-free and overall survival were only 3.5 and 9.9 months respectively. The outcome of patients with BCR-ABL mutation was similar to that of unmutated patients. With a median duration of exposure to ponatinib of 4 months, only 3 cardio-vascular events were recorded despite a high incidence of risk factors, and overall safety was acceptable. These results underline the place of ponatinib to induce early response in advanced disease and the need of new combinations to improve long-term outcome.
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. [2019]Combination of chemotherapy with a tyrosine-kinase inhibitor is effective in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia. Ponatinib is a more potent BCR-ABL1 inhibitor than all other tyrosine-kinase inhibitors and selectively suppresses the resistant T315I clones. We examined the activity and safety of combining chemotherapy with ponatinib for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia in this continuing phase 2 trial.
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. [2023]The combination of chemotherapy and ponatinib in Philadelphia chromosome-positive acute lymphoblastic leukaemia has the potential to be a new standard of care for the disease; however, long-term efficacy and safety data are needed. Our aim was to evaluate the long-term efficacy and safety of this regimen in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia in this ongoing phase 2 trial.
TKI-BiTE Combo Produces CMRs in Most with ALL. [2022]Early results from a phase II clinical trial show that the third-generation tyrosine kinase inhibitor ponatinib plus the bispecific T-cell engager blinatumomab can produce complete molecular remissions in most patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.
Successful Management of Decitabine prior to Full-Dose Idarubicin and Cytarabine in the Treatment of Refractory/Recurrent Acute Myeloid Leukemia. [2018]To investigate the safety and efficacy of the triple therapy of decitabine, idarubicin, and cytarabine in the treatment of refractory or recurrent acute myeloid leukemia (R/R AML).
[The efficacy of imatinib mesylate for patients with myeloproliferative neoplasm (MPN) with eosinophilia]. [2016]To evaluate the efficacy and safety of imatinib mesylate (imatinib) for myeloproliferative neoplasm (MPN) patients with eosinophilia.
Phase I dose escalation study of lestaurtinib in patients with myelofibrosis. [2021]We performed a multicenter, investigator initiated, phase I dose escalation study of the oral multi-kinase inhibitor lestaurtinib in patients with JAK2V617F positive myelofibrosis, irrespective of baseline platelet count. A total of 34 patients were enrolled. Dose-limiting toxicities were observed in three patients overall, at the 100 mg (n = 1) and 160 mg (n = 2) twice-daily dose levels. The maximum tolerated dose was 140 mg twice daily. Gastrointestinal toxicity was the most common adverse event. Sixteen patients were evaluable for response at 12 weeks. Seven patients had clinical improvement by International Working Group - Myeloproliferative Neoplasms Research and Treatment criteria. Meaningful reductions in JAK2V617F allele burden were not observed. To measure JAK2 inhibition in vivo, plasma from treated patients was assayed for its ability to inhibit phosphorylation of signal transducer and activator of transcription 5 (STAT5): doses lower than 140 mg had variable and incomplete inhibition. In this phase I study, although gastrointestinal adverse events were common, significant clinical activity with lestaurtinib was observed (ClinicalTrials.gov identifier: NCT00668421).
A phase I, open-label, multi-center study of the JAK2 inhibitor AZD1480 in patients with myelofibrosis. [2023]The anti-tumor activity of AZD1480, a potent, selective inhibitor of Janus-associated kinases 1 and 2, was demonstrated in preclinical models of myeloproliferative neoplasms. In a phase I clinical study, 35 patients with myelofibrosis received 2.5-70mg AZD1480 orally once daily (QD) or 10 or 15mg twice daily (BID) continuously during repeated 28-day cycles. Two patients experienced dose-limiting toxicities: one patient in the 2.5mg QD cohort had a grade 3 lung infiltration/acute pneumonia, and one patient receiving 50mg QD had grade 3 presyncope. Dosing was stopped at 70mg QD after the first patient experienced an adverse neurological event (AE) and evidence of low-grade neurological toxicity in patients on lower doses after the initial month of therapy became apparent. The most common AZD1480-related AEs were dizziness and anemia. AZD1480 was absorbed quickly and eliminated from the plasma rapidly, with a mean terminal half-life of 2.45-8.06h; accumulation was not observed after repeated daily dosing for 28 days. Four patients showed evidence of clinical improvement based on IWG-MRT 2006 criteria. AZD1480 was relatively well tolerated, however, low-grade, reversible neurological toxicity was therapy limiting and led to study termination.
Case Report: Avelumab and ruxolitinib to manage polycythemia vera and secondary metastatic Merkel cell carcinoma: a possible successful combination. [2023]We describe a case of second primary malignancy in a 65-year-old patient affected by polycythemia vera treated with the JAK 1/2 inhibitor ruxolitinib. The latter is recognized as a risk factor for the onset of non-melanoma skin cancers in many retrospective and perspective studies, but the concomitant use of ruxolitinib with new immunotherapies is very rarely reported, and the safety of this association is still not clear. In our case, ruxolitinib combined with the anti-PD-L1 avelumab demonstrated both safety and efficacy for hematological disease control and underlying carcinoma remission.
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. [2021]Ruxolitinib was recently approved for the treatment of patients with polycythemia vera who are resistant/intolerant to hydroxyurea based on data from the RESPONSE studies. This phase 3b, Expanded Treatment Protocol study (NCT02292446) of ruxolitinib for hydroxyurea-resistant/intolerant patients with polycythemia vera (N = 161: median exposure = 25.1 weeks) further evaluated the safety of ruxolitinib. Adverse events (AEs) led to dose adjustment/interruption in 37.9% of patients and study drug discontinuation in 8.7% of patients. The most common hematologic AEs included anemia and thrombocytosis; while headache and diarrhea were the most frequent nonhematologic AEs. At week 24, 45.3% of patients achieved hematocrit control; hematologic remission was seen in 18% of patients. At least, 50% of reduction in spleen length was achieved in 86.7% of patients from baseline at any time. The observed safety profile of ruxolitinib was consistent and the efficacy results were similar to the observed values in the RESPONSE studies.
Clinical Pharmacokinetics and Pharmacodynamics of Bosutinib. [2022]Chronic myeloid leukemia (CML) is a clonal myeloproliferative stem cell disorder. Bosutinib is an oral, once-daily SRC/ABL tyrosine kinase inhibitor with very potent inhibitory activity. Bosutinib is effective against all phases of intolerant or resistant Philadelphia chromosome-positive CML that do not harbor the T315I or V299LABL kinase domain mutations. Peak plasma concentrations of bosutinib occur at 4-6 h following oral administration, and dose-proportional increases in exposure are observed at doses ranging from 200 to 800 mg. Absorption of bosutinib increases with food. Bosutinib is distributed extensively into the tissues. It is highly plasma protein bound (94 %) and is primarily metabolized in the liver by cytochrome P450 3A4. Bosutinib is well tolerated overall and has a unique but manageable toxicity profile. This article provides a review of the available clinical pharmacokinetic, pharmacodynamic, and drug-drug interaction data on bosutinib in healthy subjects, patients with CML, and special populations.
Comprehensive profiling of clinical JAK inhibitors in myeloproliferative neoplasms. [2023]Small molecule inhibitors targeting JAK2 provide symptomatic benefits for myeloproliferative neoplasm (MPN) patients and are among first-line therapeutic agents. However, despite all having potent capacity to suppress JAK-STAT signaling, they demonstrate distinct clinical profiles suggesting contributory effects in targeting other ancillary pathways. Here, we performed comprehensive profiling on four JAK2 inhibitors either FDA-approved (ruxolitinib, fedratinib, and pacritinib) or undergoing phase 3 studies (momelotinib) to better outline mechanistic and therapeutic efficacy. Across JAK2-mutant in vitro models, all four inhibitors demonstrated similar anti-proliferative phenotypes, whereas pacritinib yielded greatest potency on suppressing colony formation in primary samples, while momelotinib exhibited unique erythroid colony formation sparing. All inhibitors reduced leukemic engraftment, disease burden, and extended survival across patient-derived xenograft (PDX) models, with strongest effects elicited by pacritinib. Through RNA-sequencing and gene set enrichment analyses, differential suppressive degrees of JAK-STAT and inflammatory response signatures were revealed, which we validated with signaling and cytokine suspension mass cytometry across primary samples. Lastly, we assessed the capacity of JAK2 inhibitors to modulate iron regulation, uncovering potent suppression of hepcidin and SMAD signaling by pacritinib. These comparative findings provide insight into the differential and beneficial effects of ancillary targeting beyond JAK2 and may help guide the use of specific inhibitors in personalized therapy.
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. [2014]The myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are a heterogeneous but related group of hematological malignancies characterized by clonal expansion of one or more myeloid lineages. The discovery of the Jak2 V617F gain of function mutation highlighted Jak2 as a potential therapeutic target in the MPNs. Herein, we disclose the discovery of a series of pyrazol-3-yl pyrimidin-4-amines and the identification of 9e (AZD1480) as a potent Jak2 inhibitor. 9e inhibits signaling and proliferation of Jak2 V617F cell lines in vitro, demonstrates in vivo efficacy in a TEL-Jak2 model, has excellent physical properties and preclinical pharmacokinetics, and is currently being evaluated in Phase I clinical trials.
Ponatinib therapy in recurrent Philadelphia chromosome-positive central nervous system leukemia with T315I mutation after Allo-HSCT. [2021]Central nervous system leukemia (CNSL) relapse is relatively common among Philadelphia chromosome-positive (Ph+) leukemia patients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT). The prognosis of patients is dismal for those with a BCR-ABL T315I mutation, which is resistant to TKIs including second-generation drugs. We assessed ponatinib for nine patients with recurrent Ph+ CNSL and a T315I mutation after allo-HSCT, including five patients with Ph+ acute lymphoblastic leukemia and four with chronic myelogenous leukemia. Five patients experienced isolated CNSL relapse, and four experienced CNSL with hematologic relapse. All patients received ponatinib combined with intrathecal chemotherapy, and four patients with hematologic relapse received systemic chemotherapy and/or donor lymphocyte infusion. All patients achieved a deep molecular response and central nervous system remission (CNSR) at a median time of 1.5 (range: 0.7-3) months after ponatinib treatment. Two patients experienced a second CNSL relapse due to ponatinib reduction, but they achieved CNSR again after an increase to the standard dosage. Six patients developed graft versus host disease. By April 1, 2019, eight patients were alive, and one died of pneumonia. The median time of survival after the first CNSL relapse posttransplantation was 18 (range: 11.2-48.5) months. Our data from a small number of samples suggests that ponatinib is effective for recurrent Ph+ CNSL patients with a BCR-ABL T315I mutation after allo-HSCT and warrants broader clinical evaluation.
The pan-PIM inhibitor INCB053914 displays potent synergy in combination with ruxolitinib in models of MPN. [2023]Aberrant JAK2 tyrosine kinase signaling drives the development of Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. However, JAK2 kinase inhibitors have failed to significantly reduce allele burden in MPN patients, underscoring the need for improved therapeutic strategies. Members of the PIM family of serine/threonine kinases promote cellular proliferation by regulating a variety of cellular processes, including protein synthesis and the balance of signaling that regulates apoptosis. Overexpression of PIM family members is oncogenic, exemplified by their ability to induce lymphomas in collaboration with c-Myc. Thus, PIM kinases are potential therapeutic targets for several malignancies such as solid tumors and blood cancers. We and others have shown that PIM inhibitors augment the efficacy of JAK2 inhibitors by using in vitro models of MPNs. Here we report that the recently developed pan-PIM inhibitor INCB053914 augments the efficacy of the US Food and Drug Administration-approved JAK1/2 inhibitor ruxolitinib in both in vitro and in vivo MPN models. INCB053914 synergizes with ruxolitinib to inhibit cell growth in JAK2-driven MPN models and induce apoptosis. Significantly, low nanomolar INCB053914 enhances the efficacy of ruxolitinib to inhibit the neoplastic growth of primary MPN patient cells, and INCB053914 antagonizes ruxolitinib persistent myeloproliferation in vivo. These findings support the notion that INCB053914, which is currently in clinical trials in patients with advanced hematologic malignancies, in combination with ruxolitinib may be effective in MPN patients, and they support the clinical testing of this combination in MPN patients.