Folotyn (pralatrexate)

P1/2, N=13, Active, not recruiting, City of Hope Medical Center | Trial primary completion date: Jun 2024 --> May 2023

P1/2, N=13, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2023 --> Jun 2024 | Trial primary completion date: Dec 2023 --> Jun 2024

P3, N=504, Recruiting, Acrotech Biopharma Inc. | Not yet recruiting --> Recruiting

To further develop novel-lacutamab combinations, the combinability of lacutamab with therapies used in R/R or frontline PTCL e.g., pralatrexate or CHOP, respectively, was tested. These data inform the future development of lacutamab to provide additional therapeutic options that may improve outcomes for PTCL patients, including those who relapse or are refractory to available therapies. A Phase 2 study evaluating the combination of lacutamab with GemOx is ongoing (NCT04984837) based on pre-clinical observations that GemOx improves lacutamab-induced ADCC by NK cells.

The most common 1st line chemotherapy regimens overall were CHOP-based (N=506, 70%), including 60% receiving CHOP-like chemotherapy in both MER and LEO cohorts (CHOP [N=268, 37%], CHOEP [N=91, 13%] or EPOCH [N=75, 10%]), and 16% with CHOP-like in combination with novel agents in LEO cohort (BV+ [N=41, 9.3%], azacitidine+ [N=11, 2.5%], pralatrexate+ [N=10, 2.3%], lenalidomide+ [N=8, 1.9%]) (Table 1)...Outcomes continue to mature with longitudinal follow-up and ongoing accrual, which poise to shape benchmarks in the contemporary era. The lack of benefit of etoposide adding to CHOP induction and poor overall survival of non-ALCL subtypes underscores the unmet need of therapeutic breakthrough for non-ALCL frontline treatment, particularly through clinical trials with biomarker-guided approaches incorporating novel agents.

P3, N=504, Not yet recruiting, Acrotech Biopharma Inc.

P1/2, N=13, Active, not recruiting, City of Hope Medical Center | Recruiting --> Active, not recruiting | N=40 --> 13

PTCL-NOS patients have a dismal prognosis in Taiwan. Novel agents may improve the outcomes of PTCL-NOS patients. The usefulness of the novel prognostic index for PTCL-NOS needs further validation.

P1/2, N=40, Recruiting, City of Hope Medical Center | Trial completion date: Apr 2023 --> Dec 2023 | Trial primary completion date: Apr 2023 --> Dec 2023

There are several approved agents for the treatment of relapsed T-cell lymphomas including pralatrexate, romidepsin, belinostat, and brentuximab vedotin, but none of them are considered curative. As these studies mature, it is expected that the treatment for TCL will evolve so that each individual patient will be treated based on the biologic and molecular characteristics of their tumor type. The future for TCL remains promising.

Treatment strategies included narrow-band UVB therapy, topical corticosteroids, brentuximab, pralatrexate, and acitretin. The results raise the question as to whether the patients had MF misdiagnosed as AD that was unmasked by dupilumab or if MF truly is an adverse effect of treatment with dupilumab. Close monitoring of these patients and further investigation of the relationship between dupilumab and MF can shed more light on this question .

In summary, pralatrexate induces effective inhibition of gemcitabine-resistant pancreatic cancer. This may lead to the expansion of pralatrexate's application and offer benefit to gemcitabine-resistant pancreatic cancer patients in the future.

In addition, re-expression of RIPK3 in CT26 cells increased lytic cell death on treatment with tolinapant indicating its essential role in the necroptosis pathway.Objectives: 1) Characterize the single-agent activity of tolinapant in a range of TCL lines; 2) Determine the synergy of tolinapant in combination with drugs active against PTCL (romidepsin, pralatrexate) and HMAs (azacytidine-AZA; decitabine-DAC), and 3) Define the role of necroptosis in the mechanism of synergy. Thus, activation of the necroptosis pathway, is a possible mechanism for the high degree of synergy displayed when HMAs are used in combination with tolinapant in the TCL lines in vitro. These data provided the rationale for a phase 1-2 study of the combination of tolinapant and oral decitabine/cedazuridine treatment in relapsed/refractory PTCL (NCT05403450).

We have demonstrated that epigenetic modifiers, such as decitabine and 5-azacytidine (Marchi et al; Br...Herein, we report on the differential clinical activity of adding the immune checkpoint inhibitor, pembrolizumab, to decitabine, pralatrexate, or the combination and we describe the role of cytokines as a biomarker of treatment response... These preliminary data suggest that the integration of pembrolizumab into an epigenetic backbone is safe and demonstrates encouraging responses in heavily pretreated patients with PTCL and CTCL. Pharmacodynamic data suggests that certain cytokines might have predictive value as biomarkers of disease response and progression. Interestingly, patients that responded (PR/CR) to the study drugs displayed a decline in cytokine levels, highlighting the prognostic implications of these cytokines.

Treatment data were recorded, including use of radiotherapy (RT), pralatrexate, romidepsin, brentuximab vedotin (BV), combination chemotherapy, allogeneic stem cell transplant (allo-SCT), and others. Given wide variation in disease behavior, treatment intensity should be tailored to each individual's clinical phenotype to optimally balance risk and benefit. Further efforts to define the molecular basis of CCTCLs are urgently needed to aid in the identification of more effective therapies.

The cell viability and cell cycle were detected to evaluate the anti-myeloma effect of the combination of pralatrexate (PTX) and methotrexate (MTX) with PAL. PAL could promote cell cycle genes and the G1 phase of MM cells. Moreover, PAL reduced the expression level of DHFR and exerted its anticancer effects on t (11;14) MM cells by targeting DHFR.

In the relapsed or refractory (R/R) setting, we often look to clinical trials or choose from 4 FDA-approved single agents-belinostat, brentuximab vedotin, romidepsin, and pralatrexate-based on tumor phenotype and side-effect profiles. Our goal in the R/R setting is achievement of complete remission followed by allogeneic transplant with curative intent in appropriate candidates or long-term disease control in others. Numerous investigational agents are advancing through trials and have potential to alter standards of care in the near future.

Only four agents are FDA-approved for the treatment of R/R PTCL including pralatrexate, romidepsin and belinostat and the objective response rate (ORR) is 25–30% with limited duration of response (DoR) is. The ORR and the OS of in the present study places BV among the active agents for PTCL. Safety concerns emerged about infections, claiming for a strict monitoring for these toxicities.

Tolinapant has demonstrated potent cytotoxic effects against a broad range of TCL lines both as a monotherapy and in combination with the HDAC Inhibitor, romidepsin. In in vitro studies, T cell lymphoma cell lines demonstrated varying sensitivity to tolinapant with certain cell lines being more resistant, even in the presence of TNF alpha. Interestingly, the addition of romidepsin appeared to overcome the intrinsic resistance to tolinapant in the absence of TNF alpha.

Common frontline (1L) regimens include brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP), and cyclophosphamide, doxorubicin, vincristine, and prednisone with or without the addition of etoposide (CHOP and CHOEP, respectively)...Additional model inputs were derived from: 1) ECHELON-2, with 5-year PFS rates of 51.4% (95% CI 42.8, 59.4) for A+CHP, 43.0% (95% CI 35.8, 50.0) for CHOP, and OS HR 0.72 (95% 0.53, 0.99); 2) published literature to inform PFS for consolidation and subsequent lines of therapy; and 3) expert clinicians’ opinion on commonly used regimens for relapsed/refractory PTCL (included in the model were brentuximab vedotin, romidepsin, pralatrexate, ifosfamide in combination with carboplatin and etoposide [ICE], and gemcitabine-based regimens)...Conclusions The durable and significant improvements in PFS and OS of A+CHP vs CHOP in the 5-year follow-up data from ECHELON-2 estimated an increase in the number of 1L PTCL patients who remain progression free and alive for greater than 10 years. This improvement in outcomes may translate into an increased prevalence of PTCL patients, reflecting an increased number of patients in remission and options to undergo transplant therapy when necessary.

The resistance mechanisms of PDX were associated with reduced cellular uptake of PDX and/or overexpression of DNMT3B. Epigenetic alterations were also considered to play a role in the resistance mechanism. The combination of DAC and PDX exhibited synergistic activity, and thus, this approach might improve the clinical efficacy of PDX.

P1/2, N=40, Recruiting, City of Hope Medical Center | Trial completion date: Apr 2021 --> Apr 2023 | Trial primary completion date: Apr 2021 --> Apr 2023

HTS identified classes of systemic agents which demonstrate preferential effectiveness against aggressive thyroid cancers, particularly those with mutant TP53. Preclinical validation in both orthotopic and PDX models, which are accurate in vivo models mimicking tumor microenvironment, may support initiation of early phase clinical trials in non-BRAF mutated or refractory to BRAF/MEK inhibition ATC.

Peripheral T-cell lymphomas (PTCL) are rare lymphoproliferative disorders with poor outcomes and high rates of relapse. Other treatment options in the relapsed and refractory setting include histone deacetylase inhibitors, pralatrexate, and salvage multiagent chemotherapy regimens. Current research is underway regarding combination therapies and the use of other novel agents.

P2b, N=74, Recruiting, University of Virginia | Not yet recruiting --> Recruiting

P2b, N=74, Not yet recruiting, University of Virginia

The efficacy of this model has been demonstrated through its successful ability to predict drug-disease associations previously identified in literature, including cimetidine, idarubicin, pralatrexate for these conditions. In addition, nadolol, a beta blocker, has also been identified in this study to bind to the EphB2-ephrinB2 complex, and the possibility of this drug treating multiple cancers is still relatively unexplored.

PLX showed a 6-fold better RFC substrate affinity compared to methotrexate, and 2-fold better than levoleucovorin (l-LV). In conclusion, the combination of PLX and BLS showed additivity in various lymphoma cell lines, with a schedule-dependent synergism in B-cell lymphoma. Based on these data, proficient inhibition of HDAC activity by BLS holds promise in sensitization of tumor cells to PLX.

Only four agents are FDA-approved for the treatment of R/R PTCL including pralatrexate, romidepsin and belinostat. The ORR of 30% and the OS of in the present study places BV among the active agents for PTCL. Safety concerns emerged about infections, claiming for a strict monitoring for these toxicities.

First line therapies were categorized as treatment with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), Intensive chemotherapy (HyperCVAD, VCAP-AMP-VECP, or EPOCH), vs others (Interferon and zidovudine, Gemcitabine Oxaliplatin, Pralatrexate, and Gemcitabine cisplatin dexamethasone)...We also showed the suboptimal activity of frontline regimens for ATLL and lack of unifying therapeutic approach for this lymphoma in the US. Multi-institutional clinical trials exploring novel therapeutic frontline options to improve response rates, which translate in better OS are desperately needed in this population.

Pralatrexate demonstrated effective inhibition of cell growth and viability. The higher potency of pralatrexate compared to methotrexate, a drug with high levels of toxicity, suggests pralatrexate may be a safer alternative to methotrexate as an effective chemotherapeutic agent in the treatment of patients with high-risk neuroblastoma.

She initially received 2 cycles of ifosfamide, carboplatin, etoposide with disease progression. Then she received 2 cycles of pralatrexate 30 mg/m2/dose weekly x 3 doses in combination with cyclophosphamide, doxorubicin, prednisone (PRX-CHP) with resolution of cytopenias and significant reduction in bone marrow involvement by HSTL (partial response per International Pediatric Non-Hodgkin Lymphoma Response Criteria [IPNHLRC])[4]... Pralatrexate-containing chemotherapy induces response in pediatric patients with refractory HSTL.

In patients with relapsed/refractory PTCL, alisertib was not statistically significantly superior to the comparator arm.

For PTCL and CTCL combined, 41% of patients received prior romidepsin, 5% received prior belinostat, 12% received prior pralatrexate, and 32% received prior brentuximab. Cerdulatinib has shown good tolerability and clinical activity in PTCL and CTCL. Complete and durable responses across a spectrum of PTCL and CTCL subtypes were observed. Correlative studies are aimed at identifying predictors of response and resistance.