lomustine

P1, N=0, Withdrawn, Philogen S.p.A. | N=24 --> 0 | Not yet recruiting --> Withdrawn

P1/2, N=142, Recruiting, Philogen S.p.A. | Trial primary completion date: Nov 2023 --> Mar 2025

While recommendations are nuanced and reflect the complexity of the disease, maximum safe resection is typically the first step in treatment, followed by radiotherapy and/or chemotherapy using temozolomide or procarbazine, lomustine, and vincristine. The lack of treatment options is compounded by frequently suboptimal clinical practice, in which patients do not receive adequate therapy after resection, including delayed, shortened, or discontinued radiotherapy and chemotherapy courses due to treatment side effects. These unmet needs will require significant efforts to address, including a continued search for novel treatment options, increased awareness of clinical guidelines, improved toxicity management for chemotherapy, and the generation of additional and more robust clinical and health economic evidence.

P3, N=411, Recruiting, European Organisation for Research and Treatment of Cancer - EORTC | Not yet recruiting --> Recruiting

P2, N=90, Not yet recruiting, Philogen S.p.A.

P2, N=178, Not yet recruiting, National Cancer Institute (NCI)

P3, N=225, Suspended, Children's Oncology Group | Active, not recruiting --> Suspended

P2, N=45, Active, not recruiting, Children's Oncology Group | Trial completion date: May 2025 --> Jun 2027 | Trial primary completion date: May 2025 --> Jun 2027

P=N/A, N=464, Recruiting, Jasper Gerritsen

P2, N=92, Not yet recruiting, Darell Bigner | Initiation date: Dec 2023 --> Apr 2024

P2, N=350, Active, not recruiting, Actuate Therapeutics Inc. | Recruiting --> Active, not recruiting

265 patients within the cohort completed postoperative radiotherapy, while 141 patients underwent chemotherapy (procarbazine, lomustine, and vincristine, or temozolomide). Of particular importance, molecular sub-classification significantly predicted survival outcomes for IDH, ATRX, and 1p19 co-deletion mutations. Expanding brain tumor epidemiology will benefit assessing the efficacy of regional oncological centers and establishing standards of care.

P3, N=225, Active, not recruiting, Children's Oncology Group | Recruiting --> Active, not recruiting

P2, N=45, Active, not recruiting, Children's Oncology Group | Recruiting --> Active, not recruiting

P3, N=560, Recruiting, CarThera | Not yet recruiting --> Recruiting

P1/2, N=142, Recruiting, Philogen S.p.A.

Artesunate administered at a dose of 2 × 100 mg/day was without harmful side effects, even if combined with alkylating agents used in glioma therapy. Thus, the phytochemical, which is also utilized as food supplement, is an interesting, well tolerated supportive agent useful for long-term maintenance treatment. Being itself cytotoxic on glioblastoma cells and enhancing the cytotoxicity of temozolomide as well as in view of its senolytic activity, artesunate has clearly a potential to enhance the efficacy of malignant brain cancer therapy.

P2, N=92, Not yet recruiting, Darell Bigner

P2, N=350, Recruiting, Actuate Therapeutics Inc.

The genotoxic methylating agents temozolomide (TMZ) and procarbazine and the chloroethylating nitrosourea lomustine (CCNU) are part of the standard repertoire in the therapy of malignant gliomas (CNS WHO grade 3 and 4)...Cyclin-dependent kinase inhibitors such as regorafenib, synthetic lethality using PARP inhibitors, and alternative therapies including tumor-treating fields (TTF) and CUSP9v3 are discussed in the context of alkylating drug therapy and overcoming glioblastoma chemoresistance. Recent studies have revealed that senescence is the main trait induced by TMZ in glioblastoma cells, exhibiting hereupon the senescence-associated secretory phenotype (SASP). Strategies to eradicate therapy-induced senescence by means of senolytics as well as attenuating SASP by senomorphics are receiving increasing attention, with therapeutic implications to be discussed.

P2, N=180, Active, not recruiting, Eli Lilly and Company | Trial completion date: Dec 2023 --> Sep 2024

P2/3, N=1030, Recruiting, Global Coalition for Adaptive Research

The bifunctional alkylator lomustine (CCNU) remains widely but heterogeneously used as one of the few effective treatments in glioblastoma (GBM) and IDH mutant gliomas...Shared targets were also identified in a CRISPR-activator screen performed on a CCNU sensitive cell line in the presence and absence of CCNU and converged on multiple mTOR pathway genes as top enriched targets and biomarkers of resistance in CCNU-resistant models. These druggable targets are currently being investigated for combination therapies with CCNU and potential to overcome resistance.

Bevacizumab was added for presumed pseudo-progression; followed by chemotherapy with procarbazine and lomustine (PC)...Despite early introduction of 2nd-line chemotherapy with temozolomide, his disease continued to progress and he succumbed 1.5 years after initial diagnosis...Both IDH mutation and 1p19q co-deletion were lost in the gliosarcomatous transformation. This tumor did not respond to alkylating agents despite the MGMT promoter-methylated status.

Salvage therapy comprised re-irradiation (n=52, 43%), temozolomide (TMZ) (n=39, 32%), lomustine (n=47, 39%), and/or bevacizumab (n=22, 18%). Our study outlines the molecular factors associated with survival and response to re-irradiation in rGBM as well as, the molecular differences between primary/recurrent samples.

Berubicin is an analog of doxorubicin (Dox) that appears to cross the BBB with significant central nervous system (CNS) uptake. The review will also include safety and secondary efficacy endpoint summaries. Results of this interim analysis will be available for the SNO annual meeting and an evaluation of its outcome will be performed, with conclusions and recommendations for the further development of Berubicin as a therapeutic option for patients with recurrent GBM.

Subsequent re-challenge with L19TNF and lomustine again led to a partial response. These encouraging results justify further investigations within the phase II part of the clinical trial that is recruiting patients in four countries.

Following temozolomide he underwent another resection (1.5 years after initial surgery) due to tumor recurrence...Selumetinib was stopped five months after initiation due to increased tumor burden and he began lomustine, followed by bevacizumab and etoposide at next recurrence. About 2.5 years after his initial GBM diagnosis, he had low back pain and imaging showed multiple sites of bony metastases. Pathology confirmed extracranial spread of GBM.

The combination of survival and MRI analyses identified a subgroup of CCNU/TMZ-treated patients with features that sets them apart from other patients in the trial: short first PFS despite long PPS and significant increase in mean ADC values upon mRANO-defined progression. The observed pattern is compatible with the features commonly observed in pseudoprogression suggesting mRANO-undetected pseudoprogressions in the CCNU/TMZ arm of CeTeG/NOA-09.

BACKGROUND The EORTC-26101 study was a randomized phase 2 and 3 clinical trial of bevacizumab in combination with lomustine versus lomustine alone in progressive glioblastoma. MGMT promoter methylation and RTK1 classifier assignment were prognostic in progressive glioblastoma. NF1 mutation may be a predictive biomarker for bevacizumab treatment.

In France, lomustine was added to 7+3 in patients >60 years. The most frequent second-line therapy in the whole IC population was salvage chemotherapy with high-dose or intermediate-dose cytarabine or a combination of either of these with anthracycline (daunorubicin, idarubicin, or amsacrine) in France and decitabine or the combination of cytarabine, etoposide and mitoxantrone in the USA. Azacitidine/venetoclax combination was used in second and third line in France and USA and it was the most frequent third-line therapy (35.8%) in France. Patients received IC in combination with targeted therapies (mainly midostaurin) in 18% of the IC population in France and 12.4% of the IC population in the USA...In the REAL-IDH study we observed that treatment patterns in mIDH1 or wild type patients were similar. More specific data is needed regarding the sequencing of treatment regimens and overall outcomes in mIDH1 AML patients.

Treatment: First line IC was cytarabine 200 mg/m² d1-7 with idarubicin 9mg/m²/d1-5 or daunorubicin 90mg/m²/d1-3 in pts 18-60y or cytarabine 100 mg/m² d1-7 with idarubicin 8mg/m²/d1-5 and lomustine 200 mg/m²/d1 in pts > 60y...Midostaurin was added in FLT3-mutated pts...During first cycle of VEN/AZA, 12, 5 and 5 pts received 14, 21 or 28 days venetoclax, respectively; 19 were treated as out-pts, 4 received posaconazole and GCSF was used in 11 pts... In the setting of molecular relapse, VEN/AZA is safe, prevent overt relapse, and induce a high rate of molecular response before alloHCT. Molecular relapse becomes a major therapeutic challenge. Clinical trial endpoints should include the treatment of molecular relapse as an event for RFS and EFS estimation.

Fit patients >60 years with secondary AML and/or adverse cytogenetics according to the European LeukemiaNet, included in the Rev-5-Aza trial (NCT01301820), received induction therapy with lomustine 200 mg/m2 day 1, idarubicin 8 mg/m2 days 1–5, and cytarabine 100 mg/m2 days 1–7. Patients in complete remission (CR) after one induction cycle received consolidation therapy with 12 cycles of alternating azacitidine 75 mg/m2 days 1–7 and lenalidomide 10 mg days 1–21 every 28 days (Hunault-Berger M, Blood Cancer J 2017)... Together, these data suggest that the clinical history contains limited prognostic value compared to genetics, supporting the most recent approach to use cytogenetic and molecular data to assess disease risk. In this patient population, complex karyotype and TP53 mutations, rather than secondary-type mutations, were associated with outcome. Figure.

Thorough molecular classification is important for brain tumor clinical trial inclusion and evaluation. MGMT promoter methylation and RTK1 classifier assignment were prognostic in progressive glioblastoma. NF1 mutation may be a predictive biomarker for bevacizumab treatment.

Our series provides a report of acute and late side effects of treatment of young adult patients with medulloblastoma. Significant OS and PFS advantage are seen of aCTH completion in this patient population. Since optimal treatment of these patients is still an unmet need, prospective studies for this rare disease entity are needed.

We integrate targeted epigenome editing with unbiased genome-wide approaches to build a novel discovery and therapeutic platform in glioblastoma, a framework that is well suited for targeting diseases with known or suspected epigenetic vulnerabilities.

BACKGROUND In the randomized phase 2 REGOMA trial, regorafenib has shown promising activity in recurrent glioblastoma patients with a significantly longer survival compared to the standard lomustine therapy. MGMT was methylated in 43% and IDH1/2 was wild-type in 92% of patients. The results from this large multicenter Italian study are expected in the second half of 2023.

The results support the clinical benefit demonstrated for concomitant TTFields with TMZ plus CCNU, showing that the efficacy of TMZ and CCNU may be enhanced by TTFields, with synergism seen for the latter case in cells not expressing MGMT. The BRCAness state induced by TTFields rationalizes this, as in the absence of MGMT DNA damage induced by CCNU requires the FA-BRCA pathway for repair.

P2, N=210, Active, not recruiting, CNS Pharmaceuticals, Inc. | Recruiting --> Active, not recruiting