Category Archives: Clinical Trial

Ruxolitinib Treatment Outperforms Best Available Therapy in Pooled Analysis

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By Patrick Daly

December 6, 2023

Patients with polycythemia vera (PV) who received ruxolitinib treatment achieved sustained hematocrit control over 80 weeks and had improved symptom control at week 16 compared with patients who received best available therapy (BAT), based on a post hoc pooled analysis of data from the RESPONSE and RESPONSE 2 trials.

The efficacy data were presented at the 65th American Society of Hematology Annual Meeting & Exposition in San Diego, California, by lead author, Claire Harrison, MD, of the Guy’s and St. Thomas’ NHS Foundation Trust in London, United Kingdom.

“Reductions in JAK2V617F allele burden were consistently observed through Week 208 in patients treated with ruxolitinib, including those who crossed over from BAT,” Dr. Harrison and colleagues reported.

The analysis assessed 371 pooled patients from RESPONSE and RESPONSE 2, of which 184 were treated with ruxolitinib and 187 with BAT. The cohort had a median age of 61.8 ± 11 years and most patients were White (88.1%) and male (62.5%). Hematocrit control was defined as hematocrit maintained below 45% starting week 16 plus one or less phlebotomy between baseline and week four.

At week 28, the proportion of patients with hematocrit control was 62.0% (95% CI, 54.5-69.0) in the ruxolitinib group versus 18.2% (95% CI, 12.9-24.5) in the BAT group. Further, 47.3% (95% CI, 39.9-54.8) of patients in the ruxolitinib group had sustained hematocrit control through week 80; authors noted nearly all patients in the BAT group had crossed over to the ruxolitinib group by that point.

The proportion of patients who achieved a 50% or greater reduction from baseline in Myeloproliferative Neoplasms Symptoms Assessment Form Total Symptom Score at week 16 was 48.7% (95% CI, 40.7-56.8) in the ruxolitinib group compared with 18.0% (95% CI, 12.5-24.6) in the BAT group (odds ratio, 4.3; 95% CI, 2.6-7.2), and the mean change in score was -4.4 ± 10.0 and 0.6 ± 6.9, respectively.

Additionally, patients randomized to ruxolitinib had consistently decreased JAK2V617F allele burden through week 208, and mean JAK2V617F allele burden decreased from 66.1% to 41.4% at four years.

“Taken together, these results provide further evidence of the patient benefit of ruxolitinib in patients with PV with or without splenomegaly,” Dr. Harrison and colleagues concluded.

Reference

Harrison C, Kiladjian JJ, Palandri F, et al. Ruxolitinib treatment in polycythemia vera results in reduction in JAK2 allele burden in addition to improvement in hematocrit control and symptom burden. Abstract #4553. Presented at the 65th ASH Annual Meeting & Exposition; December 9-12, 2023; San Diego, California.

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New Developments in MPN Management Provide Additional Options for Patients

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December 5, 2023

Kyle Doherty

Although myeloproliferative neoplasms (MPNs), which are comprised of essential thrombocythemia, polycythemia vera (PV), and myelofibrosis, remain relatively rare— with estimated annual incidence rates of 1.03, 0.84, and 0.47 per 100,000 individuals, respectively—there remains an unmet need for effective treatment options for patients with these diseases who progress on standard of care therapies.1 However, significant progress has been made in terms of understanding this group of disorders and developing treatment strategies to combat them, with Naveen Pemmaraju, MD, saying the medical field has entered a “golden era” of MPN treatment.

During a recent OncLive Peer Exchange® video series titled “Expert Insights Into the Management of MPNs,” Jamile M. Shammo, MD, explained, “MPNs represent a heterogeneous group of hematopoietic stem cell neoplasms that share common features. Myeloid proliferation is certainly something that we see [in MPNs], as well as a propensity for thrombotic events, symptoms that are related either to constitutional symptoms or splenomegaly related. All 3 entities tend to progress to higher myeloid neoplasms; essential thrombocythemia [to] PV that goes to myelofibrosis and then myelofibrosis can evolve into acute leukemia. Of course, the rate of progression varies from one entity to the other, with essential thrombocythemia having the lowest risk [of progression].”

The development of MPNs is almost always associated with mutations in JAK2, making this family of genes an attractive treatment target. JAK2 mutations are observed in approximately 95% of patients with PV and approximately 50% of both patients with essential thrombocythemia and myelofibrosis. Notably, the emergence of additional treatment targets also has sparked the development of novel agents in recent years.1

During the discussion, expert oncologists reviewed updated findings from ongoing and completed clinical trials in the field. They primarily focused on studies evaluating emerging agents in PV and myelofibrosis.

MANAGING PV

Abdulraheem Yacoub, MD, began the discussion on PV by noting that the JAK1/2 inhibitor ruxolitinib (Jakafi) has been the standard-of-care agent in PV since 2015. Prior to this, PV was historically managed with phlebotomy, hydroxyurea, and/or interferons. Ruxolitinib became the first FDA-approved drug for the treatment of patients with PV in December 2014 when it received an indication from the agency for patients who had an inadequate response to or were intolerant of hydroxyurea.2

“The introduction of ruxolitinib to the treatment landscape of patients with myelofibrosis has truly been transformative,” Shammo commented. “We all remember the patients we had in the clinic [in the past] and how we had simply nothing but supportive care to offer. Ruxolitinib was approved based on the results of 2 phase 3 studies. COMFORT-I [NCT00952289] randomly assigned patients [with myelofibrosis] to receive ruxolitinib or placebo and examined [spleen] volume reduction and reduction in total symptom score from baseline at 24 weeks. COMFORT-II [NCT00934544], which ran mostly in Europe, randomly assigned patients to be treated with ruxolitinib or best available therapy [as selected by the investigator]. This study [also evaluated] spleen volume reduction, but at week 48. In either trial, ruxolitinib was statistically significantly more active in attaining the primary end point and for that reason it was approved. Some might say that the evidence is perhaps less compelling than what you would [typically] find in a phase 3 study, but when you have multiple studies showing the same thing, that treatment with ruxolitinib improves [outcomes] compared with placebo or best available therapy, I tend to feel like it’s reasonable enough to believe that actually is the case.”

Long-term data from 2 phase 3 trials, RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036), comparing the safety and efficacy of ruxolitinib with best available therapy in different patient populations with PV recently were published in The Lancet Haematology. RESPONSE enrolled adult patients with PV who were resistant to or intolerant of hydroxyurea and randomly assigned them 1:1 to receive either ruxolitinib (n = 110) or best available therapy (n = 112; hydroxyurea, interferon or pegylated interferon, pipobroman, anagrelide (Agrylin), approved immunomodulators, or observation without pharmacological treatment). RESPONSE-2 enrolled a higher-risk patient population; eligible patients had inadequately controlled PV without splenomegaly and were intolerant of or resistant to hydroxyurea with an ECOG performance status of 2 or less. They were randomly assigned to receive ruxolitinib (n = 74) or best available therapy (n = 75).3,4

Follow-up data from RESPONSE demonstrated that the 5-year overall survival (OS) rate was 91.9% (95% CI, 84.4%-95.9%) in the ruxolitinib group vs 91.0% (95% CI, 82.8%-95.4%) in the best available therapy arm. Most patients (88%) in the best available therapy arm crossed over to receive ruxolitinib, and no patients remained in this arm after week 80. There were 25 primary responders in the ruxolitinib arm, 6 of whom had progressed by the time of the final analysis. The 5-year probability of maintaining a primary composite response was 74% (95% CI, 51%-88%), the probability of maintaining complete hematological remission was 55% (95% CI, 32%-73%), and the probability of maintaining overall clinicohematological responses was 67% (range, 54%-77%).3

At a median follow-up of 67 months (IQR, 65-70), findings from RESPONSE-2 showed that the 5-year OS rate was 96% (95% CI, 87%-99%) in the ruxolitinib arm compared with 91% (95% CI, 80%-96%) in the best available therapy arm. In the ruxolitinib arm, 22% of patients (95% CI, 13%-33%) achieved durable hematocrit control with an estimated median duration of control not reached (NR) at week 260 (95% CI, 144-NR). Most patients in the best available therapy arm (77%) crossed over to ruxolitinib, no patients continued with best available therapy after week 80 per protocol, and the median duration of hematocrit control was not reported due to the small number of responders at week 80.4

In light of findings from RESPONSE and RESPONSE-2, investigators in both studies concluded that ruxolitinib is a safe and effective long-term treatment option for patients with PV for whom hydroxyurea proved ineffective.3,4

“Both studies have ong-term follow-up and have published 5-year data showing very durable responses,” Yacoub said. “There were very few late failures on ruxolitinib and no unexpected adverse effects were observed with longterm follow up. This has built a strong case for ruxolitinib as a standard treatment for patients [with PV] after hydroxyurea failure.”

Ropeginterferon Takes Center Stage

A more recent breakthrough for patients with PV was the emergence of the interferon ropeginterferon alfa-2b-njft (Besremi). In November 2021, ropeginterferon became the first agent to receive FDA approval for patients with PV regardless of their treatment history.5

Ropeginterferon was compared with hydroxyurea in the phase 3 PROUD-PV trial (NCT01949805) and its extension continuation study, CONTI-PV (NCT02218047). Eligible patients were 18 years or older and had earlystage PV with no history of cytoreductive treatment or less than 3 years of previous hydroxyurea treatment. Patients could opt to enter CONTI-PV after 1 year of initial treatment in PROUD-PV.6

Findings from the studies revealed that at a median follow-up of 182.1 weeks (IQR, 166.3- 201.7) patients in PROUD-PV who received ropeginterferon (n = 122) achieved complete hematological response with normal spleen size at a rate of 21% compared with 28% of patients who received hydroxyurea (n = 123). However, in CONTI-PV, 53% of patients in the ropeginterferon arm (n = 95) had a complete hematological response with improved disease burden at 36 months vs 38% of patients in the hydroxyurea arm (n = 74; P = .044). Moreover, at 36 months in CONTI-PV, the complete hematological response rate regardless of spleen criterion was 71% vs 51% in the investigative and comparator arms, respectively (P = .012); at 12 months in PROUD-PV these rates were 43% vs 46%, respectively (P = .63).6

Study authors concluded that ropeginterferon was effective in inducing hematological responses. Although noninferiority to hydroxyurea in terms of hematological response and normal spleen size was not observed at 12 months, improved responses vs hydroxyurea were present at 36 months. Thus, the authors wrote that ropeginterferon offers an effective and “safe long-term avenue for treatment with distinct features from hydroxyurea.”6

“It’s wonderful to have options because we get patients with PV [who] could not be any more different,” Yacoub said. “They have different goals of care, and at the end of the day, we are treating individual patients, not diseases. For each patient, we have to define what we are trying to achieve. There are patients who are going to live with the disease a lot longer. They have more high-risk presentations and would benefit from the maximum data that we have with the application of the effective agents. There are patients who have relatively low-risk disease, and they’re likely going to live their natural lives with some medical management from our end. We have to individualize our choices.”

Looking ahead, the phase 3 VERIFY trial (NCT05210790) is underway with the aim of adding rusfertide (PTG-300), a novel and potent hepcidin mimetic, to the PV treatment landscape. Rusfertide previously demonstrated clinical activity in early-phase studies, characterized by good tolerability and consistent and durable hematocrit control, as well as improvements in iron deficiency among patients who required higher than normal amounts of phlebotomies even after standard-of-care therapy.7

VERIFY is enrolling patients with PV who have received at least 3 phlebotomies in the previous 6 months or at least 5 in the previous 12 months as a result of inadequate hematocrit control, with or without concurrent cytoreductive therapy. Eligible patients will be randomly assigned 1:1 to receive either placebo plus ongoing therapy or rusfertide plus ongoing therapy.

Part 1a of the trial is the double-blind, placebo- controlled, add-on phase that will enroll parallel groups and last 32 weeks. During part 1b, patients who complete part 1a will receive rusfertide for 20 weeks. Patients who successfully complete part 1b will enter the long term extension phase, part 2, and will continue to be treated with rusfertide for 104 weeks. The primary end point is the proportion of patients achieving a response in from week 20 to week 32 in part 1A. The study was initiated in January 2022 and has a target enrollment of 250 patients.7

Managing Myelofibrosis

Patients with myelofibrosis have more FDA-approved treatment options than those with PV. To date, 3 Janus kinase (JAK) inhibitors have been approved for the treatment of patients with myelofibrosis: ruxolitinib, fedratinib (Inrebic), and pacritinib (Vonjo).

Similar to PV, ruxolitinib became the first FDA-approved therapy for the treatment of patients with myelofibrosis, gaining an indication for patients with intermediate- and high-risk disease in November 2011. In August 2019, patients with intermediate- 2 or high-risk primary or secondary myelofibrosis gained fedratinib as an FDA-approved option. Finally, the FDA approved pacritinib in March 2022 for the treatment of adult patients with intermediate- or high-risk primary or secondary myelofibrosis with platelet levels below 50,000/μL.8-10

“The current NCCN [National Comprehensive Cancer Network] guidelines are really agnostic of the second-line therapy, which is interesting,” Raajit K. Rampal, MD, PhD, said. “You can start a patient who [at that time] has over 50,000 platelets on ruxolitinib or fedratinib. And if there is a need to change therapy, you could use any of these 3 agents. That’s an important message for our audience to remember, that the second line is not platelet restricted. We have an abundance of options.”

After summarizing updated data from pivotal trials of the already approved agents, the panelists shifted their focus to new findings from trials evaluating investigational therapies beyond JAK inhibitors in myelofibrosis. Updates from the studies were presented during the 2023 American Society of Clinical Oncology Annual Meeting in June.

Novel Agents Seek to Augment the Armamentarium

In the phase 2 ACE-536-MF-001 trial (NCT03194542), investigators examined the erythroid maturation agent luspatercept-aamt (Reblozyl) for the management of anemia in patients with myelofibrosis; it occurs in approximately 40% of patients. Investigators noted that luspatercept demonstrated anemia improvement across all cohorts of in the study, regardless of transfusion dependency and use of ruxolitinib. For example, 26.3% (95% CI, 13.4%- 43.1%) of patients who were red blood cell transfusion dependent and received prior ruxolitinib (n = 38) achieved transfusion independence following treatment with luspatercept.11

The phase 1/2 LIMBER study (NCT04455841) evaluated the safety and efficacy of the oral ALK2 inhibitor zilurgisertib alone and in combination with ruxolitinib in adult patients with intermediate 1 or 2 primary or secondary myelofibrosis. Among patients in the monotherapy group who were not transfusion dependent (n = 6), anemia improvement (hemoglobin increase of ≥ 1.5 g/ dL relative to baseline) occurred in 1 patient; this level of improvement was observed in 3 of 9 patients in the combination group. Zilurgisertib monotherapy or combination therapy with ruxolitinib was determined to be generally well tolerated and displayed the potential for therapeutic activity, the study authors concluded.12

Another phase 1/3 trial, XPORT-MF-034 (NCT04562389) evaluated a ruxolitinibcontaining combination, this time with the selective inhibitor of nuclear export selinexor (Xpovio) in patients with JAK inhibitor–naive myelofibrosis. At week 24, efficacy-evaluable patients (n = 22) achieved spleen volume reduction of at least 35% (SVR35) from baseline at a rate of 64%. Investigators noted that the combination displayed encouraging activity, and updated data will be made available at a future date.13

Finally, in a single-arm phase 2b study (NCT04217993) the oral, novel JAK/ACVR1 inhibitor jaktinib showed promising activity in patients with myelofibrosis who were intolerant to ruxolitinib. Efficacy-evaluable patients who received jaktinib (n = 44) achieved an SVR35 rate of 43% at 24 weeks, and the best spleen response rate was 55%. Notably, response was maintained for a minimum of 12 weeks in 80% of patients.14

“It’s exciting to have all these non-JAK inhibitors [in the pipeline],” Rampal said in conclusion. “Ultimately, hopefully, we can figure out what the best fit is for an individual patient. We’re not there yet, but with an abundance of data, we’ll get there. It’s also important to note that there are a number of agents that are earlier on [in development] that are moving along. Even beyond this next generation of non-JAK inhibitors already in the pipeline, there is a generation beyond that that is in clinical trial development.”

References

  1. McMullin MF, Anderson LA. Aetiology of myeloproliferative neoplasms. Cancers (Basel). 2020;12(7):1810. doi:10.3390/cancers12071810
  2. FDA approves ruxolitinib. News release. FDA. Updated February 22, 2016. Accessed October 18, 2023. bit.ly/3PVXObQ
  3. Kiladjian JJ, Zachee P, Hino M, et al. Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera
    (RESPONSE): 5-year follow up of a phase 3 study. Lancet Haematol. 2020;7(3):e226-e237. doi:10.1016/S2352-3026(19)30207-8
  4. Passamonti F, Palandri F, Saydam G, et al. Ruxolitinib versus bestavailable therapy in inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): 5-year follow up of a randomised, phase 3b study. Lancet Haematol. 2022;9(7):e480-e492. doi:10.1016/ S2352-3026(22)00102-8
  5. FDA approves treatment for rare blood disease. News release. FDA. November 12, 2021. Accessed October 18, 2023. bit.ly/3rXAt1u
  6. Gisslinger H, Klade C, Georgiev P, et al; PROUD-PV Study Group. Ropeginterferon alfa-2b versus standard therapy for polycythaemia
    vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study. Lancet Haematol.
    2020;7(3):e196-e208. doi:10.1016/S2352-3026(19)30236-4
  7. Verstovsek S, Kuykendall A, Hoffman R, et al. Verify: a phase 3 study of the hepcidin mimetic rusfertide (PTG-300) in patients with polycythemia vera. Blood. 2022;140(suppl 1):3929-3931. doi:10.1182/ blood-2022-163755
  8. Mascarenhas J, Hoffman R. Ruxolitinib: the first FDA approved therapy for the treatment of myelofibrosis. Clin Cancer Res. 2012;18(11):3008-3014. doi:10.1158/1078-0432.CCR-11-3145
  9. FDA approves fedratinib for myelofibrosis. News release. FDA. August 16, 2019. Accessed October 18, 2023. bit.ly/3s30OuX
  10. FDA approves drug for adults with rare form of bone marrow disorder. News release. FDA. March 1, 2022. Accessed October 18, 2023. bit.ly/3S0PVVj
  11. Gerds AT, Harrison C, Kiladjian JJ, et al. Safety and efficacy of luspatercept for the treatment of anemia in patients with myelofibrosis: results from the ACE-536-MF-001 study. J Clin Oncol.2023;41(suppl 16):7016.doi:10.1200/JCO.2023.41.16_suppl.7016
  12. Bose P, Mohan S, Oh S, et al. Phase 1/2 study of the activin receptor-like kinase (ALK)-2 inhibitor zilurgisertib (INCB000928,
    LIMBER-104) as monotherapy or with ruxolitinib (RUX) in patients (pts) with anemia due to myelofibrosis (MF). J Clin Oncol. 2023;41(suppl 16):7017. doi:10.1200/JCO.2023.41.16_suppl.7017
  13. Ali H, Kishtagari A, Maher KR, et al. Selinexor (SEL) plus ruxolitinib (RUX) in JAK inhibitor (JAKi) treatment-naïve patients with
    myelofibrosis: updated results from XPORT-MF-034. J Clin Oncol. 2023;41(suppl 16):7063. doi:10.1200/JCO.2023.41.16_suppl.7063
  14. Zhang Y, Zhou H, Xiao ZJ, et al. Jaktinib in patients (pts) with myelofibrosis (MF) who were intolerant to ruxolitinib (RUX): an open-label, single-arm phase 2b study. J Clin Oncol. 2023;41(suppl 16):7061.doi:10.1200/JCO.2023.41.16_suppl.7061

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Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis

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Zijian Fang, Giuditta Corbizi Fattori, Thomas McKerrell, Rebecca H. Boucher, Aimee Jackson, Rachel S. Fletcher, Dorian Forte, Jose-Ezequiel Martin, Sonia Fox, James Roberts, Rachel Glover, Erica Harris, Hannah R. Bridges, Luigi Grassi, Alba Rodriguez-Meira, Adam J. Mead, Steven Knapper, Joanne Ewing, Nauman M. Butt, Manish Jain, Sebastian Francis, Fiona J. Clark, Jason Coppell, Mary F. McMullin, et al.

Abstract

Current therapies for myeloproliferative neoplasms (MPNs) improve symptoms but have limited effect on tumor size. In preclinical studies, tamoxifen restored normal apoptosis in mutated hematopoietic stem/progenitor cells (HSPCs). TAMARIN Phase-II, multicenter, single-arm clinical trial assessed tamoxifen’s safety and activity in patients with stable MPNs, no prior thrombotic events and mutated JAK2V617F, CALRins5 or CALRdel52 peripheral blood allele burden ≥20% (EudraCT 2015-005497-38). 38 patients were recruited over 112w and 32 completed 24w-treatment. The study’s A’herns success criteria were met as the primary outcome ( ≥ 50% reduction in mutant allele burden at 24w) was observed in 3/38 patients. Secondary outcomes included ≥25% reduction at 24w (5/38), ≥50% reduction at 12w (0/38), thrombotic events (2/38), toxicities, hematological response, proportion of patients in each IWG-MRT response category and ELN response criteria. As exploratory outcomes, baseline analysis of HSPC transcriptome segregates responders and non-responders, suggesting a predictive signature. In responder HSPCs, longitudinal analysis shows high baseline expression of JAK-STAT signaling and oxidative phosphorylation genes, which are downregulated by tamoxifen. We further demonstrate in preclinical studies that in JAK2V617F+ cells, 4-hydroxytamoxifen inhibits mitochondrial complex-I, activates integrated stress response and decreases pathogenic JAK2-signaling. These results warrant further investigation of tamoxifen in MPN, with careful consideration of thrombotic risk.

Introduction

Myeloproliferative neoplasms (MPN) arise from mutations acquired by HSPCs, most frequently affecting the genes encoding the kinase JAK21,2,3,4 or the multi-functional protein CALR5,6. Currently JAK1/2 inhibitors can improve disease-related symptoms and overall survival but have a limited impact on clone size7,8, likely because they cannot discriminate between mutant and wild-type JAK2 or due to the acquisition of pharmacological resistance9,10,11. Allogeneic HSC transplantation remains the only curative treatment for MPN but can only be performed in a minority of patients due to its toxicity12, warranting investigation of new therapies.

Men exhibit a higher prevalence of myeloid neoplasia compared with women13,14. Furthermore, MPN subtypes with poorer prognosis (primary myelofibrosis and polycythemia vera, compared with essential thrombocythemia) have a higher prevalence in males than in females15,16,17. Additionally, the risk of secondary myelofibrosis, which worsens the outcomes of PV/ET, is higher for men than for women, regardless of their age17,18,19. However, the reasons underlying this gender difference are unclear. It is possible that sex-chromosome genes and gender-dependent differences in epigenetic regulation, metabolism or immune response partly account for sexual dimorphism in cancer20. Another explanation might be the loss of sex chromosomes with age, which preferentially occurs in males, perhaps suggesting a higher genomic instability in men21.

However, one key determinant of gender disparities in cancer might be the effect of sex hormones20. Estrogens regulate the self-renewal, proliferation, and apoptosis of mouse hematopoietic stem and progenitor cells (HSPCs)22,23. Estrogen receptors (ERs) are differentially expressed in mouse HSPC subsets22. ERα activation induces proliferation of mouse long-term HSCs22,23 and protects them from proteotoxic stress through the modulation of UPR24. The selective ER modulator (SERM) tamoxifen induces apoptosis of multipotent hematopoietic progenitors but spares normal HSCs22. In MPN mouse models, tamoxifen restores the physiological apoptosis levels in mutant HSCs and selectively eliminates these cells, but not their non-mutated counterparts22. Based on these preclinical studies, we conducted a Phase II, multicenter, single-arm A’herns design clinical trial assessing tamoxifen’s safety and activity in reducing molecular markers of disease burden in MPN (TAMARIN). Here we report the results of the TAMARIN study. In addition, we describe an exploratory analysis of HSPCs from study patients and associated laboratory research investigating the mechanism of action of tamoxifen in human MPN.

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MANIFEST-2 Meets Primary End Point With Pelabresib Plus Ruxolitinib in MF

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November 21, 2023

By Jordyn  Sava

The combination of pelabresib (CPI-0610), an investigational BET inhibitor, with the ruxolitinib (Jakafi), a JAK inhibitor, demonstrated a statistically significant and clinically meaningful improvement in the proportion of JAK inhibitor-naive patients with myelofibrosis (MF) achieving at least a 35% reduction in spleen volume (SVR35) at week 24 compared with placebo plus ruxolitinib, according to topline results from the phase 3 MANIFEST-2 study (NCT04603495).1

A total of 66% of patients treated with pelabresib plus ruxolitinib achieved SVR35 at week 24 vs 35% of patients given placebo plus ruxolitinib (95% CI, 21.6-39.3; P <.001), meeting the primary end point of the study.

Further, the key secondary end points of symptom improvement in patients achieving at least a 50% reduction in total symptom score (TSS50) and absolute change in total symptom score (TSS) from baseline at week 24 were also promising with a strong positive trend favoring pelabresib plus ruxolitinib combination with TSS reduced by 15.99 points at week 24 at baseline vs 14.05 points at week 24 in the placebo plus ruxolitinib arm (Δ -1.94; 95% CI, -3.92-0.04, P =.0545), using least square mean estimate.

“Pelabresib is a first-in-class oral inhibitor of BET proteins, primarily those containing the BD1 and BD2 domains. It’s being developed currently in myelofibrosis. It has been tested in other diseases, but it has shown significant activity in myelofibrosis,” said Joseph M. Scandura, MD, PhD, Weill Cornell Medicine,in an interview with Targeted OncologyTM.

“I believe MANIFEST-2 provides us with valuable evidence that the addition of pelabresib offers meaningful improvements over JAK inhibitor monotherapy as a first-line approach for patients with myelofibrosis,” said John Mascarenhas, MD, director of the adult leukemia program at The Tisch Cancer Institute at Mount Sinai, New York, in a press release.1 “The pelabresib and ruxolitinib combination therapy significantly reduced spleen volume—the best prognostic indicator we have at our disposal for long-term myelofibrosis patient outcomes. Based on insights from MANIFEST-2, pelabresib represents a promising and well-tolerated therapeutic option for a community in need of innovation.”

MANIFEST-2 is an ongoing, randomized, double-blind, phase 3 trial where 430 patients with JAK inhibitor-naive MF were randomly assigned in a 1:1 ratio to receive upfront pelabresib plus ruxolitinib vs ruxolitinib alone.2

Patients aged ≥ 18 years with a confirmed diagnosis of MF, adequate hematologic, renal, and hepatic function, and an ECOG performance status of ≤ 2 were eligible for inclusion in the trial. Enrollment was also open to patients who had at least 2 symptoms with an average score ≥ 3 or an average total score of ≥ 10 over the 7-day period prior to randomization using the MFSAF v4.0, a prognostic risk-factor score of intermediate-1 or higher per Dynamic International Prognostic Scoring System (DIPSS) scoring system, and a spleen volume of ≥ 450 cm3.

If patients had splenectomy or splenic irradiation in the previous 6 months, chronic or active conditions and/or concomitant medication use that would prevent them from receiving treatment, or had previously been treated with any JAK or BET inhibitor for treatment of a myeloproliferative neoplasm, they were excluded from the study.

Additional findings showed that treatment with the combination also showed significant improvements in both key secondary end points within an analysis of patients classified as intermediate risk who made up over 90% of patients in MANIFEST-2. DIPSS Int-1 and Int-2 was a predefined stratification factor in the protocol for the MANIFEST-2 trial. Here, TSS was reduced by 15.18 points at week 24 with pelabresib plus ruxolitinib vs 12.74 points at week 24 in the placebo plus ruxolitinib arm (Δ -2.44; 95% CI, -4.48- -0.40; P <.02).1

Another key secondary end point, TSS50, was met among 52% of patients treated with pelabresib and ruxolitinib at week 24 vs 46% treated with placebo plus ruxolitinib (95% CI, -3.5-15.5; P =.216).1 Among patients at intermediate-risk, 55% of patients achieved TSS50 in the pelabresib and ruxolitinib treatment arm at week 24 compared with 45% in the placebo plus ruxolitinib arm (95% CI, 0.35-19.76; P <.05).

Following a Type C meeting with the FDA in September 2023, absolute change in TSS was included as a key secondary end point in the study. Per clinical protocol, this continuous end point was created to directly measure change in the average TSS from baseline to week 24 to help accurately estimate the magnitude of symptom burden reduction among patients with MF.

Findings from MANIFEST-2 also demonstrated that more patients achieved hemoglobin response (≥ 1.5 g/dL from baseline)in the pelabresib and ruxolitinib arm vs the placebo and ruxolitinib arm. For safety, the safety profile of pelabresib and ruxolitinib was consistent with what was previously observed with the combination and no new safety signals were observed. Adverse events of anemia were seen less frequently among patients in the pelabresib and ruxolitinib arm than those in the placebo and ruxolitinib arm.

Findings from the phase 3 MANIFEST-2 study will be further presented during an oral presentation at the 65th American Society for Hematology Annual Meeting and Exposition. Based on this encouraging data, continued conversations with regulatory agencies will occur with hopes of submitting a new drug application for combination of pelabresib and ruxolitinib in MF to the FDA in the middle of 2024.

“Myelofibrosis patients experience a severely diminished quality-of-life due to symptoms such as severe fatigue, night sweats, bone pain and fever—symptoms that can leave them bedridden for days and with limited ability to participate in daily activities. Reducing symptom burden is a primary goal of myelofibrosis treatment,” said Ruben A. Mesa, MD, FACP, president and executive director, Atrium Health Levine Cancer Center and Atrium Health Wake Forest Baptist Comprehensive Cancer Center, in a press release.1 “Total symptom score assessment is a validated tool to document the challenges that patients encounter on a daily basis. The symptom reduction shown in MANIFEST-2 is an important result that should be strongly considered when evaluating the efficacy of the pelabresib and ruxolitinib combination therapy for myelofibrosis.”

REFERENCES:
  1. MorphoSys’ phase 3 study of pelabresib in myelofibrosis demonstrates statistically significant improvement in spleen volume reduction and strong positive trend in symptom reduction. News release. MorphoSys AG. November 20, 2023. Accessed November 21, 2023. https://tinyurl.com/2n9swrer
  2. Phase 3 study of pelabresib (CPI-0610) in myelofibrosis (MF) (MANIFEST-2) (MANIFEST-2). ClinicalTrials.gov. Updated September 25, 2023. Accessed November 21, 2023. https://www.clinicaltrials.gov/study/NCT04603495

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Pelabresib Plus Ruxolitinib Improves Spleen Volume Reduction in JAK Inhibitor-Naive Myelofibrosis

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November 21, 2023

By Ryan Scott

Treatment with the combination of pelabresib (CPI-0610) and ruxolitinib (Jakafi) led to a statistically significant and clinically meaningful improvement in spleen volume reduction vs placebo plus ruxolitinib in patients with JAK inhibitor-naive myelofibrosis, meeting the primary end point of the phase 3 MANIFEST-2 trial (NCT04603495).1

Findings showed that 66% of patients treated with the combination of pelabresib and ruxolitinib experienced a spleen volume reduction of at least 35% (SVR35) at week 24 vs 35% of patients treated with placebo plus ruxolitinib (31% difference; 95% CI, 21.6%- 39.3%; P < .001).

Furthermore, patients in the pelabresib and ruxolitinib group experienced a median reduction in total symptom score (TSS) of 15.99 points at week 24, reduced from 28.26 at baseline, compared with a reduction of 14.05 points, reduced from 27.36, in those treated with placebo plus ruxolitinib (delta, –1.94; 95% CI, –3.92 to 0.04; P = .0545).

Notably, findings revealed that a higher percentage of patients experienced a hemoglobin response of an increase of at least 1.5 g/dL from baseline when treated with the combination of pelabresib and ruxolitinib compared with those given placebo and ruxolitinib.

Detailed findings from MANIFEST-2 will be presented at the 2023 ASH Annual Meeting in December. MorphoSys, the developer of pelabresib, will continue to review data and plans to submit a new drug application to the FDA and a marketing authorization application to the European Medicines Agency for pelabresib in combination with ruxolitinib in myelofibrosis by the middle of 2024.

“I believe MANIFEST-2 provides us with valuable evidence that the addition of pelabresib offers meaningful improvements over JAK inhibitor monotherapy as a first-line approach for patients with myelofibrosis,” John Mascarenhas, MD, director of the Adult Leukemia Program at The Tisch Cancer Institute at Mount Sinai in New York, New York, said in a news release. “The pelabresib and ruxolitinib combination therapy significantly reduced spleen volume—the best prognostic indicator we have at our disposal for long-term outcomes [for patients with myelofibrosis]. Based on insights from MANIFEST-2, pelabresib represents a promising and well-tolerated therapeutic option for a community in need of innovation.”

The randomized, double-blind, placebo-controlled MANIFEST-2 trial enrolled patients at least 18 years of with a confirmed diagnosis of myelofibrosis with adequate hematologic, renal, and hepatic function. Furthermore, patients must have a prognostic risk-factor score of intermediate-1 or higher per the Dynamic International Prognostic Scoring System; a spleen volume of 450 cm3 or more; and an ECOG performance status 2 or less. Exclusion criteria include splenectomy or splenic irradiation in the previous 6 months; medication use that would prohibit treatment; or prior administration of any JAK or BET inhibitor for treatment of a myeloproliferative neoplasm.2

Eligible patients were randomly assigned 1:1 to receive pelabresib in combination with ruxolitinib or placebo plus ruxolitinib.

TSS response from baseline at week 24 and the proportion of patients with at least a 50% reduction in TSS (TSS50) were key secondary end points.1

Patients with intermediate-risk disease comprised more than 90% of patients in the study population, and in this population, pelabresib plus ruxolitinib reduced by a median TSS by 15.18 points at week 24 from the baseline median TSS of 28.20, compared with a median reduction of 12.74 points at week 24 from a baseline TSS of 27.53 in the placebo plus ruxolitinib arm (delta, –2.44; 95% CI, –4.48 to –0.40; P < .02). This difference was statistically significant.

At week 24, 52% of patients in the pelabresib arm achieved at least a 50% reduction in TSS (TSS50) vs 46% in the placebo arm (6% difference; 95% CI, –3.5% to 15.5%; P = .216). In intermediate-risk patients, TSS50 was achieved by 55% of those in the pelabresib arm compared with 45% in the placebo arm (10% difference; 95% CI, 0.35%-19.76%; P < .05).

Regarding safety, pelabresib and ruxolitinib remained in line with the previously observed safety profile, and no new safety signals were reported. Notably, instances of anemia as an adverse effect were less frequent in patients treated with pelabresib plus ruxolitinib compared with those treated with placebo plus ruxolitinib.

“[Patients with] myelofibrosis experience a severely diminished quality of life due to symptoms such as severe fatigue, night sweats, bone pain and fever—symptoms that can leave them bedridden for days and with limited ability to participate in daily activities. Reducing symptom burden is a primary goal of myelofibrosis treatment,” Ruben A. Mesa, MD, FACP, president and executive director of Atrium Health Levine Cancer Center and Atrium Health Wake Forest Baptist Comprehensive Cancer Center, said in a news release.

References

  1. Morphosys’ phase 3 study of pelabresib in myelofibrosis demonstrates statistically significant improvement in spleen volume reduction and strong positive trend in symptom reduction. News release. Morphosys. November 20, 2023. Accessed November 21, 2023.
  2. Phase 3 study of pelabresib (CPI-0610) in myelofibrosis (MF) (MANIFEST-2). ClinicalTrials.gov. Updated September 25, 2023. Accessed November 21, 2023.

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$72 Million Funds Neoantigen-based Cancer Vaccine Candidates

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November 14, 2023

(Precision Vaccinations News)

Nouscom recently announced the completion of its Series C equity financing, raising $72 million that will be used to continue advancing and expanding Nouscom’s wholly-owned clinical pipeline to achieve multiple clinical value catalysts.

As of November 13, 2023, the funding proceeds will support the following initiatives:

Readout from Nouscom’s ongoing randomized Phase 2 clinical trial for NOUS-209, an off-the-shelf vaccine targeting 209 shared neoantigens, in combination with pembrolizumab for the treatment of Mismatch Repair/Microsatellite Instable Metastatic Colorectal Cancer.

Final readout from the ongoing Phase 1b study and advancement of NOUS-209 monotherapy in Lynch Syndrome carriers investigating the potential to intercept, prevent, or delay cancer before it occurs. LS carriers have a genetic predisposition to and, consequently, a higher risk of developing certain cancers. Promising initial results from this study were reported on October 31, 2023.

Completion of a Phase 1b study evaluating NOUS-PEV, a personalized cancer immunotherapy, in combination with a checkpoint inhibitor in patients with advanced melanoma and entry into randomized Phase 2 trials in indications with high unmet medical needs.

Nouscom has also exclusively out-licensed VAC-85135, an off-the-shelf immunotherapy developed under a multi-project agreement, which is currently under evaluation in a Phase 1 clinical trial for the treatment of Myeloproliferative Neoplasms sponsored by Janssen Research & Development and Bristol Myers Squibb.

Dr. Marina Udier, Chief Executive Officer of Nouscom, commented in a press release, “…. This financing will allow us to further accelerate development across our wholly-owned clinical portfolio reporting multiple clinical trial readouts, including from our ongoing randomized Phase 2 clinical trial with NOUS-209.”

“These Phase 2 data, if positive, have the potential to position Nouscom’s neoantigen-based cancer vaccines amongst the most thrilling developments in the field.”

According to a Review Article published by the journal Frontiers in Immunology in February 2023, Neoantigen vaccines are based on epitopes of antigenic parts of mutant proteins expressed in cancer cells. These highly immunogenic antigens may trigger the immune system to combat cancer cells.

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Azacitidine, Venetoclax, Ruxolitinib Shows Encouraging Responses in MPNs

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October 19, 2023

Sabrina Serani

The combination of azacitidine, venetoclax (Venclexta), andruxolitinib(Jakafi) for the treatment of myeloproliferative neoplasms in blastic phase (MPN-BP) did not demonstrate any treatment-related toxicity in patients, and patients’ quality-of-life improved, according to a study published in the British Journal of Haematology.1

Azacitidine and venetoclax were used to control BP transformation, and ruxolitinib was added to control constitutional symptoms. The overall response rate was 80%, and the complete remission (CR) rate was 40%. The median overall survival was 13.4 months (95% CI, 4.2-13.4), with a median follow-up of 10.0 months (range, 4.2-13.4).

“[Patients with] MPN-BP have a poor prognosis with the current treatment options, and standards of care unless they are offered [allogeneic stem cell transplant, (allo-SCT)]. Unfortunately, there is a lack of treatment guidelines for the management of allo-SCT-ineligible MPN-BP patients,” study authors wrote. “We observed encouraging hematological responses, which were prolonged for some patients. In addition, the combination appeared manageable, without unexpected adverse events.”

Five patients with myelofibrosis (MF) were enrolled in the study. One had primary MF, and 4 had secondary MF. The median patient age was 76 (range, 72-84) years. Three patients were treated exclusively outpatient. There were 2 CRs and 2 partial response remissions. Investigators noted that all patients could complete their activities of daily living, and clinical spleen reduction ≥50% was observed.

At best response, the median platelet count was 150 × 109/L (range, 60–380) with a median improvement of 125 × 109/L (range, 5–200), and median hemoglobin level was 10.6 g/dL (range, 9.0–13.8) with a median gain of 2.7 g/dL (range, 1.5–7.6).

Three patients died due to disease progression; however, there were no deaths due to treatment reported. Observed adverse events (AEs) included neutropenia (n = 4, 80%), anemia (n = 2, 40%), and thrombocytopenia (n = 1, 20%). Febrile neutropenia was reported in 2 patients during the initial cycle. Grade 4 neutropenia was the primary reason reported for postponing a cycle.

Patients were administered ruxolitinib and a dose ≥10 mg twice daily. Venetoclax was administered orally at a dose of 200-400 mg on days 1-14. Azacitidine was administered subcutaneously at a dose of 50 or 75 mg/m2 on days 1-7. The median cycle duration was 29 days (range, 27-38). A median of 11 cycles (range, 5-14) was administered to patients, and the median time to best response was 4 cycles (range, 3-9).

“Further studies are needed to confirm these promising results,” study authors wrote.1

The combination of venetoclax and azacitidine are also being studied in a phase 3 trial of patients with treatment-naïve acute myeloid leukemia, as well as a phase 1 trial of pediatric and young adult patients with hematologic malignancies.2,3

REFERENCES:
1. Systchenko T, Chomel JC, Gallego-Hernanz P, et al. Combination of azacitidine, venetoclax and ruxolitinib in blast phase myeloproliferative neoplasms. Br J Haematol. 2023;202(2):284-288. doi:10.1111/bjh.18853
2. A study of venetoclax in combination with azacytidine versus azacytidine in treatment naïve participants with acute myeloid leukemia who are ineligible for standard induction therapy. News release.National Cancer Institute. Accessed October 13, 2023. https://tinyurl.com/my5yh7nm
3. Venetoclax and azacytidine for the treatment of hematologic malignancies in pediatric and young adult patients. News release. National Cancer Institute. Accessed October 13, 2023. https://tinyurl.com/my5yh7nm

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Bomedemstat as an investigative treatment for myeloproliferative neoplasms

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By Hugh Young Rienhoff Jr. & Harinder Gill

Abstract

Introduction

Myeloproliferative neoplasm (MPN) is a heterogeneous group of hematopoietic stem cell disorders characterized by clonal proliferation of one of more of the hematopoietic stem cell lineages. Clinical manifestations result from uncontrolled myeloproliferation, extramedullary hematopoiesis with splenomegaly and excessive inflammatory cytokine production. Currently available therapy improves hematologic parameters and symptoms but does not adequately address the underlying neoplastic biology. Bomedemstat has thus far demonstrated clinical efficacy and tolerability in the treatment of MPNs with recent evidence of impacting the malignant stem cell population.

Areas covered

This review summarizes the mechanisms of action, pharmacokinetics and pharmacodynamics, safety and efficacy of bomedemstat in MPN with specific emphasis on essential thrombocythemia (ET) and myelofibrosis (MF).

Expert opinion

In patients with MPNs, bomedemstat appears effective and well tolerated. The signs and symptoms of these diseases are managed as a reduction in the frequency of mutant cells was demonstrated in patients with ET and MF. Ongoing and planned studies of bomedemstat in MPN will establish the position of bomedemstat in MPNs and may help to redefine treatment endpoints of MPNs in the future.

KEYWORDS:

  • Bomedemstat
  • lysine-specific demethylase-1
  • LSD1
  • myeloproliferative neoplasm
  • polycythemia vera
  • essential thrombocythemia
  • myelofibrosis

Article highlights

  • Myeloproliferative neoplasm (MPN) are clonal hematopoietic stem cell disorders characterized by uncontrolled cellular proliferation, cytokine mediated symptoms and clonal instabilty leading to leukemic progression.

  • Conventional therapeutic approaches in MPN are not adequate in altering the underlying disease biology.

  • Lysine specific demethylase 1 (LSD1) is overexpressed in the malignant hematopoietic stem cell population in MPN.

  • Bomedemstat, an inihibitor of MPN, effectively controls cellular proliferation and reverses disease biology in mouse models of MPN.

  • Phase 2 studies in essential thrombocythemia and myelofibrosis has demonstrated that Bomedemstat is highly efficacious and safe.

Declarations of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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MWTX-003 Wins FDA Fast Track Designation for Polycythemia Vera

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Kristi Rosa

The FDA has granted fast track designation to the investigational, anti-TMPRSS6 monoclonal antibody, MWTX-003 (DISC-3405), for use in the treatment of patients with polycythemia vera, according to an announcement from Disc Medicine, Inc.1

Patients with hematologic diseases such as polycythemia vera, myelodysplastic syndrome (MDS), and beta-thalassemia are known to develop high levels of iron, which leads to survival and quality-of-life complications.2 MWTX-003 was designed to boost the production of hepcidin, which suppresses serum iron. Preclinical data in animal models of beta-thalassemia and polycythemia vera have confirmed this ability.

“We are delighted to have received fast track designation for MWTX-003, which highlights the unmet need for [patients with] polycythemia vera and the potential of MWTX-003 in a disease where there are few treatment options,” John Quisel, JD, PhD, president and chief executive officer of Disc Medicine, Inc., stated in a press release.1 “We believe MWTX-003 is uniquely positioned to address the needs of [patients with] polycythemia vera and are excited to initiate a phase 1 trial in the coming months.”

Preclinical studies have demonstrated strong pharmacodynamic effects that are reflective of TMPRSS6 inhibition.3 Specifically, a single administration of MWTX-003 led to an approximate 70% suppression of serum iron that lasted for 3 weeks. Moreover, in non-clinical GLP safety studies, the agent showcased a strong toxicity profile.

In a model of beta-thalassemia, treatment with MWTX-003 resulted in significant effects on disease hallmarks such as iron overload, ineffective erythropoiesis, and splenomegaly. The production of hepcidin was boosted up to 4-fold, serum and liver iron was reduced by approximately 60% to 65%, red blood cell production increased, and spleen weight decreased.

MWTX-003 was in-licensed from Mabwell Therapeutics, and in November 2022, the FDA accepted an investigational new drug application for the agent.1 In January 2023, the clinical-stage biopharmaceutical company shared development plans for MWTX-003 which consisted of establishing phase 1 proof-of-mechanism; this was planned for initiation in the second half of 2023, and would examine hepcidin, iron, and other hematologic parameters.3

They also shared plans to advance the agent into point-of-care studies focused on polycythemia vera. In a phase 1b/2a proof-of-concept study, they hope to evaluate the safety and pharmacokinetic profile of MWTX-003 in patients with polycythemia vera. These data could provide clarity on the regulatory development path for the agent, according to Disc Medicine.

There is interest in examining the agent in additional POC studies spanning a range of indications, including hereditary hemochromatosis, beta-thalassemia, and MDS.

References

  1. Disc Medicine receives FDA fast track designation for MWTX-003 for the treatment of polycythemia vera. News release. Disc Medicine, Inc. September 20, 2023. Accessed September 21, 2023. https://ir.discmedicine.com/news-releases/news-release-details/disc-medicine-receives-fda-fast-track-designation-mwtx-003
  2. MWTX-003. Disc Medicine, Inc. website. Accessed September 21, 2023. https://www.discmedicine.com/our-pipeline/mat-2-inhibitor/
  3. Novel anti-TMPRSS6 monoclonal antibody portfolio: exclusive in-licensing agreement with Mabwell Therapeutics. Disc Medicine, Inc. January 20, 2023. Accessed September 21, 2023. https://ir.discmedicine.com/static-files/549caf12-e7be-45ff-8667-86908e4e6bdd

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Ezobresib by Bristol-Myers Squibb for Myelofibrosis: Likelihood of Approval

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September 14, 2023

Ezobresib is under clinical development by Bristol-Myers Squibb and currently in Phase II for Myelofibrosis. According to GlobalData, Phase II drugs for Myelofibrosis have a 40% phase transition success rate (PTSR) indication benchmark for progressing into Phase III. GlobalData’s report assesses how Ezobresib’s drug-specific PTSR and Likelihood of Approval (LoA) scores compare to the indication benchmarks. 

GlobalData tracks drug-specific phase transition and likelihood of approval scores, in addition to indication benchmarks based off 18 years of historical drug development data. Attributes of the drug, company and its clinical trials play a fundamental role in drug-specific PTSR and likelihood of approval.

Ezobresib overview

Ezobresib (BMS-986158) is under development for the treatment of solid tumors including triple-negative breast cancer, small-cell lung cancer, epithelial ovarian cancer, peritoneal cancer, renal cell carcinoma, fallopian tube cancer, Burkitt’s lymphoma/leukemia, Uveal melanoma, Uterine carcinosarcoma, NUT-midline carcinoma, Non-small cell lung cancer, metastatic hormone refractory (castration resistant, androgen-Independent) prostate cancer, blood cancer (hematologic malignancies), primary myelofibrosis (PMF), post-essential thrombocythemia (ET) or post-polycythemia vera (PV) myelofibrosis. It is administered orally as a capsule. The drug candidate acts by targeting bromodomain and extra-terminal (BET) proteins. It was under development for Ewing sarcoma.

Bristol-Myers Squibb overview

Bristol-Myers Squibb (BMS) is a specialty biopharmaceutical company that is engaged in discovery, development, licensing and manufacturing, marketing, distribution and sale of medicines and related medical products to patients with serious diseases. Its primary focus is on cancer, cardiovascular, immunology and fibrotic therapeutic projects. The company offers its products across the world to wholesalers, retail pharmacies, medical professionals, hospitals and government entities. BMS provides its products in the US, Europe, and Japan. The company conducts research to focus on the discovery and development of novel medicines that address serious diseases in areas of significant unmet medical need. BMS is headquartered in New York City, New York, the US.

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