Matulane (procarbazine hydrochloride)

P2, N=208, Recruiting, International Extranodal Lymphoma Study Group (IELSG) | Trial completion date: Oct 2023 --> Dec 2024 | Trial primary completion date: Oct 2023 --> Dec 2024

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.

P1/2, N=41, Active, not recruiting, Grupo Español de Linfomas y Transplante Autólogo de Médula Ósea | Trial completion date: Oct 2023 --> Oct 2024

P2, N=146, Active, not recruiting, Merck Sharp & Dohme LLC | Trial completion date: Jun 2026 --> May 2024

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.

Radiation therapy and PCV (procarbazine, CCNU, and vincristine) was received by 85 patients, while radiation therapy and temozolomide were administered to 15 patients. Conclusions  Isocitrate dehydrogenase (IDH) wild-type LGG had a lower survival time, while improved survival times were seen for alpha-thalassemia X-linked intellectual disability syndrome (ATRX) retained and 1p19q co-deleted LGGs. Further studies are required to gain a better understanding of lower-grade glial tumor treatment and survival in Pakistan.

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.

P1/2, N=118, Recruiting, Institut Curie | Phase classification: P2 --> P1/2

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.

In terms of frontline-treatment, 21 patients (95%) had received HDMTX + procarbazine + vincristine, and rituximab was administered in 73% (16/22) of patients...CONCLUSION Given that only restricted treatment strategies are available for relapse PCNSL patients, our study suggests that nivolumab can be a suitable option for the disease. Further studies are warranted to determine predictive biomarkers for nivolumab treatment given the excellent survival duration in responders.

Chemoradiotherapy with procarbazine, CCNU, and vincristine is recommended for both grade 2 and 3 oligodendrogliomas. However, the risk of radiation-induced neurotoxicity is a concern in long-term survivors, and several clinical trials have tested the efficacy of chemotherapy alone in terms of cognitive function. Since CCNU is not approved in Japan, ACNU-containing regimen as PAV, or temozolomide are commonly used for the tumor.

Eight patients received a third line of treatment: 2 radiotherapy, 4 Bevacizumab, 1 Procarbazine and 1 TMZ. While our patients were older and with lower KPS than the patients in the RCTs the efficacy of TMZ only treatment was comparable with the clinical trials results with mOS of 11/11. 9/8. 3 month in Sheba/NOA08/Nordic patients, PFS of 5/8.

This study revealed that both the S + RT + TMZ and S + RT + PCV regimens might be effective therapies for treating patients with low-grade gliomas. Among these, the S + RT + TMZ regimen seemed to be safer, but might lead to tumor deterioration. In the IDHmt/coder type, the S + RT + TMZ scheme might have a significant advantage. In the IDHmt/noncoder type, the S + RT + PCV scheme might be more dominant, while in the IDHwt type, the S + H - RT and S + TMZ schemes also might be good treatment options.

Case Study: A 54-year-old man was diagnosed with HL mixed-cellularity 202 months ago and was treated with chemotherapy, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for 8 cycles...The patient had another disease progression with a positive Pet-CT 13 months after the second remission, and it was proposed that the treatment be switched to escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), in which he had received 6 cycles... Data supports using pembrolizumab as monotherapy in cases of relapsed HL; nevertheless, in our case, we do not have a sustained response to the therapeutic impact to draw a firm judgment.

The best treatment strategy for elderly PCNSL patients remains unknown. Treatments range from palliative to curative but more toxic therapies, and there is no standardized measure to select patients for the right treatment. This randomized controlled trial will create evidence for the best treatment strategy with the focus on developing a standardized GA to help define eligibility for an intensive treatment approach.

We modified the BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisolone), whereby bleomycin and etoposide were removed and cyclophosphamide dose was reduced, for older patients with co-morbidities. Here we present data from the first 41 patients treated with 'ACOPP' across 3 centres, demonstrating that it can be delivered, with a favourable toxicity profile (TRM 2%) and promising efficacy (2-year PFS and OS, 73% (95% CI: 52-94) and 93% (95% CI: 80-100) respectively).

Long-term follow-up demonstrated that treatment was well tolerated in most patients enrolled in this study, with stable leukoencephalopathy on imaging and stable clinical performance status. Disease recurrence was not observed beyond 2 years after HDC-ASCT consolidation.

MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) is an effective rescue protocol used to re-induce remission, but is associated with gastrointestinal toxicity and can be a less desirable option for patients that previously failed vincristine-containing protocols. MVPP at the prescribed doses resulted in modest and transient clinical benefit, but was well tolerated with no treatment delays or hospitalizations secondary to side effects. Given the minimal toxicity, dose intensification could be considered to improve clinical responses.

We aimed to evaluate the outcome of rituximab, methotrexate, procarbazine, and vincristine (RMPV) chemotherapy in elderly patients with new-onset PCNSL...Patients received five to seven cycles of RMPV plus response-adapted whole-brain radiotherapy (WBRT) and cytarabine...Initial treatment with RMPV chemotherapy was effective in elderly patients with PCNSL. Adjusting the number of courses of RMPV may improve the prognosis of elderly patients with PCNSL, but further verification is necessary.

These studies investigated the omission of consolidation radiotherapy (RT) in patients with a negative interim positron emission tomography (iPET) (ie, Deauville score <3) after chemotherapy (HD16: 2× doxorubicin, bleomycin, vinblastine, and dacarbazine [ABVD]; HD17: 2× escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [BEACOPP] plus 2× ABVD). Taken together, contemporary HL-directed treatment approaches result in excellent outcomes for patients with newly diagnosed early-stage NLPHL and thus represent valid treatment options. In patients with early-stage favorable NLPHL, consolidation RT appears necessary after 2xABVD to achieve the optimal disease control irrespective of the iPET result.

Anaplastic oligodendroglioma patients treated with postoperative PCV chemotherapy alone occasionally develop T2/FLAIR hyperintensities around the surgical cavity that can wrongly suggest tumour progression. Multimodal imaging and close follow-up should be considered in this situation.

HL survivors appear to have an impaired ovarian reserve. However, chance to achieve pregnancy seems reassuring at a young age. Additional follow-up studies are needed to assess fertile life span and reproductive potential of HL survivors, in particular for current HL treatments that are hypothesized to be less gonadotoxic.

Upfront first-line chemotherapy is indicated for all features of classical Hodgkin's lymphoma, followed by involved node radiotherapy in early stages; the ABVD protocol (doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine) is the international standard of care. The 7-agent BEACOPP protocol (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine (Oncovin), procarbazine, prednisone) is used in advanced stages in its «escalated» version (BEAesc)...Thus, early PET response evaluation is now essential to adapt the treatment intensity. Despite these major advances, several issues remain, including the management of acute and long-term side effects of first-line treatments, the better options for refractory patients, the place and optimization of radiotherapy, and the place for new therapeutic agents such as the anti-CD30 conjugate antibody (brentuximab vedotin) and PD-1 inhibitors in the first-line treatment setting.

To our knowledge, we demonstrate-for the first time-that the risk of bone cancer is increased 5- to 10-fold after exposure of bone tissue to cumulative radiation doses of 1-9 Gy. Alkylating agents exceeding 10,000 mg/m increase the risk 7- to 8-fold, particularly following procarbazine, ifosfamide, and cyclophosphamide. These substantially elevated risks should be used to develop/update clinical follow-up guidelines and survivorship care plans.

The vast majority of patients are PET 2 negative (Deauville scores of 1–3) after 2 cycles of ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine). Adult trials have studied various approaches, and in general, 2–4 additional cycles of ABVD or 4 cycles of AVD result in more than 90% of patients being disease free at 3 years.4–6 Outcomes in patients who are PET2 positive (Deauville 4–5) are less favorable, though escalation to BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) with the addition of radiotherapy results in improved progression free survival (PFS) compared to continuation of ABVD plus RT.4 A US and Canadian Intergroup trial led by the Children's Oncology Group using a PET adapted approach after 2 cycles of ABVD recently opened and will randomize patients to standard therapy versus BV plus nivolumab...For patients who are BV naïve, brentuximab plus nivolumab is highly active with high overall and complete response rates.11 More recently, a phase 2 study demonstrated excellent outcomes in patients treated with pembrolizumab plus gemcitabine/vinorelbine/doxil.12 S9 The current standard of care is consolidation with high dose chemotherapy with stem cell rescue (ASCT) in responding patients...Single center studies using intensified regimens showed better outcomes compared to CHOP.13 The introduction of rituximab led to improved PFS of RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) compared to CHOP alone...In addition, survivorship issues are paramount. Integrated care with psychosocial support, discussion of fertility preservation and monitoring for late effects are crucial for optimal outcomes both medically and with respect to quality of life.

TEPIP is a locally developed, all-oral low-dose regimen comprising trofosfamide, etoposide, procarbazine, idarubicin, and prednisolone. TEPIP demonstrated competitive efficacy with a tolerable safety profile in a highly palliative cohort of patients with difficult-to-treat PTCL. The all-oral application, which makes outpatient treatment possible, is particularly noteworthy.

P1/2, N=109, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Dec 2023 --> Dec 2026 | Trial primary completion date: Dec 2023 --> Dec 2026

P3, N=1875, Recruiting, National Cancer Institute (NCI) | Trial completion date: Jun 2030 --> Apr 2031 | Trial primary completion date: Jun 2030 --> Apr 2031

The research was funded by: Takeda Oncology Introduction: Individualized, PET2-guided first-line treatment of patients with advanced-stage classical Hodgkin Lymphoma (AS-cHL) with eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) achieves outstanding survival outcomes, but also causes relevant treatment-related morbidity (TRMB). We hypothesized that remodeling the eBEACOPP regimen with brentuximab vedotin (BV) could decrease TRMB while maintaining its high efficacy. Here, we report the results of the HD21 study regarding non-inferiority of BrECADD (BV, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) as compared to eBEACOPP in terms of progression-free survival (PFS)... This interim analysis of the GHSG HD21 trial fully establishes non-inferiority of BrECADD compared to eBEACOPP. Importantly, we observed a relevant reduction in early PFS events with BrECADD resulting in a 3-year PFS rate of 94.9%. This mature and unparalleled PFS rate suggests that individualized treatment with PET2-directed BrECADD is currently the most effective therapy for adult patients with AS-cHL.

Most RCT patients received temozolomide (TMZ) instead of procarbazine, lomustine, and vincristine. Whereas previous studies often comprise tumors with IDH wild type status and without 1p/19q-codeletion, this homogeneous ODG cohort, as defined by the current WHO classification, demonstrated PFS benefits for various therapies, especially concerning RCT. While this is generally in accordance with comparable studies, more prospective work on homogeneous patient cohorts is required to refine treatment guidelines and to determine the role of TMZ in ODG.

The most common induction regimens were high-dose methotrexate (HD-MTX) ± rituximab; methotrexate, temozolomide, rituximab (MTR); and rituximab, methotrexate, procarbazine, vincristine (R-MPV)...Altogether, outcomes in older PCNSL patients appeared optimized with high-dose methotrexate combination induction as well as maintenance. Furthermore, several prognostic factors, including geriatric measures, were associated with divergent outcomes.

P3, N=1875, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

Aims: We aim to report our data on the use of the R-MPV protocole (Rituximab, Methotrexate, Procarbazine, Vincristine) followed by a reduced dose whole-brain radiotherapy in the treatment of PCNSL in real word settings. Following our experience, an advanced age at diagnosis, low PS score and late diagnosis are poor prognosis factors. The R-MPV protocol associated to consolidation rdWBRT and Cytarabine was associated with high response rate and minimal neurotoxicity, even in elderly patients.

This retrospective study aimed to evaluate the clinical outcomes of patients with PCNSL treated with DeAngelis (MTX, intrathecal MTX, vincristine, procarbazine, dexamethasone, high-dose cytarabine, and whole brain radiotherapy), MATRix (HD- MTX, Ara-C, Thiotepa, Rituximab), or PRIMAIN (Rituximab, HD-MTX, Procarbazine) protocols and to determine the impact of age and treatment on overall survival (OS) and progression-free survival (PFS)... Our study highlights the importance of age and treatment selection in the management of PCNSL. The MATRix protocol demonstrated better clinical outcomes compared to DeAngelis and RMP. Compounding factors including age, perfromanace status and associated co-morbidities also influenced the outcome.

In effort to reduce late effects, treatment protocols were adapted and gonadotoxic procarbazine was successfully omitted...Effectivity of HL treatment with OEPA-COPDAC (OEPA: vincristine , etoposide, prednisolone and doxorubicin; COPDAC: cyclophosphamide, vincristine , prednisone and dacarbazine) is compared to intensified OEPA-DECOPDAC chemotherapy ( COPDAC with higher cumulative dose of cyclophosphamide and additional doxorubicin and etoposide ) in a randomized setting... 45% of boys had impaired semen quality at 2 years post HL diagnosis. Treatment-induced amenorrhea (72%) persisted in >10% of girls. Serum FSH, inhibin B and AMH are available by Apr '23.

Cyclophosphamideequivalent dose(CED-score) exceeded 6000mg/m2 in 56 (67%) femalesurvivors and 14 (17%) survivors received pelvic irradiation...Gonadotoxicity was specifically presentafter treatment with procarbazineand higher CED-score... HL survivors areat risk of impaired ovarian reservestatus. However chanceto conceiveand pregnancy outcomes appear to bereassuring when attempting pregnancy ata relatively young age. Newly diagnosed patients and survivors should becounselled individually with respect to family planning and potential use of fertility preservation methods in survivorship.

P3, N=1202, Active, not recruiting, University College, London | Trial completion date: Jan 2022 --> May 2023

The patient we give induction therapy with RMP Regimens (Rituximab 375 mg/m2, day 1, 15 and 29, High Dose Methotrexate (HDMTX) 3000mg/m2 day 2, 16 and 30, and Procarbazine 60mg/m2 day 3-12) because Procarbazine in not available in Palembang we change to Dacarbazine 375mg/m2 days 3,17 and 31), Dexamethasone 5mg/6 hours, and has finished  Low Dose Whole Brain Radiotherapy for consolation therapy. PCNSL is rare form aggressive extra nodal NHL, especially in Immunocompetent patient. In this particular case of patients High Dose Methotrexate Chemotherapy has achieved high respond especially for this patient that showed GCS E4M5V6 and recovery neurological deficit after 2 cycle chemotherapy.

CH in survivors is associated with exposures to alkylating agents, radiation, and bleomycin...Single-cell profiling of peripheral blood samples revealed STAT3 mutations predominantly present in T cells and contributed by SBS25, a mutational signature associated with procarbazine exposure...Serial-sample tracking reveals that larger clone size is a predictor for future expansion of age-related CH clones, while therapy-related CH remains stable decades post-treatment. These data depict the distinct dynamics of these CH subtypes and support the need for longitudinal monitoring to determine the potential contribution to late effects.