Adjusted High-dose Chemotherapy With Autologous Stem Cell Transplant vs. Conventional Immunochemotherapy in Elderly PCNSL Patients

Официальное название

Age-adjusted High-dose Chemotherapy Followed by Autologous Stem Cell Transplantation or Conventional Chemotherapy With R-MP as First-line Treatment in Elderly Primary CNS Lymphoma Patients - a Randomized Phase III Trial

Обзор

Most patients being diagnosed with primary diffuse large B-cell lymphoma of the central nervous system (PCNSL) are 60 years or older. Elderly patients with PCNSL have a poor prognosis and there is a great medical need to improve outcome for this vulnerable population. In Germany and many international centres, there are currently two widely used strategies to treat elderly PCNSL patients who are eligible for high-dose methotrexate (HD-MTX) treatment, which have not yet been compared head-to-head. The R-MP regimen has been established by the Cooperative PCNSL Study Group as a "conventional" immunochemotherapy standard treatment for elderly patients with newly diagnosed disease and consists of Rituximab, HD-MTX and Procarbazine followed by maintenance therapy with Procarbazine. In contrast, another recently established protocol also includes HD-MTX-based induction therapy, but followed by consolidating high-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT). This is an overall more intensive, but substantially shorter treatment approach, feasible for elderly patients being considered eligible for a more intensive treatment. The PRIMA-CNS trial aims to compare these two treatment approaches with respect to survival, response rates and toxicity.

Подробное описание

Primary diffuse large B-cell lymphoma of the central nervous system (PCNSL) is a rare lymphoma affecting only the central nervous system compartment. PCNSL patients are typically 60 years or older and have poor prognoses. However, there are alternative treatment approaches to consider with the potential to improve medical outcomes for this patient population. The current standard of care in Germany and many international centres for patients 65 and older is treatment with R-MP, comprising rituximab, high-dose methotrexate (HD-MTX) and procarbazine followed by maintenance therapy with procarbazine. An alternative approach comprised of a shorter induction treatment with rituximab, HD-MTX and cytarabine (MARTA) followed by age-adjusted high-dose chemotherapy and autologous stem cell transplantation (HCT-ASCT) was recently shown to be feasible and effective in elderly PCNSL patients considered eligible for high-dose chemotherapy requiring autologous stem cell transplantation. Nevertheless, data evaluating this short duration treatment approach remains scarce, and randomized trials have not yet been published. The objective of the PRIMA-CNS trial is to demonstrate that intensified chemotherapy followed by consolidating HCT-ASCT is superior to conventional chemotherapy with R-MP followed by maintenance with procarbazine in elderly patients with newly diagnosed PCNSL; not only regarding survival and remission after treatment but also regarding standards like quality of life (QOL) and treatment related morbidities. Results of this randomized trial will either change the standard of care to an intense and shorter treatment approach or re-define R-MP as a proven treatment standard. In addition, a geriatric assessement is implemented in this trial with the goal to better define transplant eligibility. If this trial shows the superiority of HCT-ASCT, the investigators will establish an improved treatment standard with increased chances for long-term remission and cure and reduced frequency and length of chemotherapy treatment. Considering the poor prognosis of this patient population, this randomized phase III trial is of great clinical importance to provide patients, the patients' families and care takers with optimal treatment.

Вмешательства

• Препарат R-MP and Procarbazine maintenance
  Firstline systemic treatment with conventinal immunochemotherapy (3 cycles of Rituximab-MTX-Procarbazine) followed by Procarbazine maintenance
• Препарат R-MTX/AraC (MARTA) induction followed by consolidating HCT-ASCT
  Firstline systemic treatment with age-adjusted MTX based induction (2 cycles of Rituximab-Methotrexate-Cytarabin) followed by consolidating aged-adapted high-dose chemotherapy and autologous stem cell transplantation

Первичные конечные точки

• Progression free survival (PFS) between the 2 arms [Срок оценки: up to 6 years]

Вторичные конечные точки (7)

• Overall survival (OS) between the 2 arms [Срок оценки: up to 6 years]
• Event free survival (EFS) between the 2 arms [Срок оценки: up to 6 years]
• Remission status after 2 cycles of rituximab-methotrexate-procarbazine (R-MP) (arm A)/2 cycles of R-MTX/cytarabine (AraC) [Срок оценки: at RA I: after 8 weeks (Arm A), after 6 weeks (Arm B)]
• Remission status after 3 cycles of R-MP (arm A)/consolidating HCT-ASCT (arm B) [Срок оценки: at RA II: after 12 weeks]
• Remission status after completion of maintenance treatment (arm A)/6 months follow-up (arm B) [Срок оценки: 6 months after RA II]
• Quality of life (EORTC QLQ-C30) [Срок оценки: from date of informed consent form (ICF) signature up to 6 years]
• Quality of Life (EORTC-QLQ BN 20) [Срок оценки: from date of informed consent form (ICF) signature up to 6 years]

Критерии участия

Критерии включения

• Immunocompetent patients with newly-diagnosed primary DLBCL of the central nervous system.
• Age > 70 years or age 65-70 years if not eligible for more intensive treatment (e.g. OptiMATe trial).
• Histologically or cytologically assessed diagnosis of B-cell lymphoma by local pathologist.
• Diagnostic sample obtained by stereotactic or surgical biopsy, cerebrospinal fluid (CSF) cytology examination or vitrectomy.
• Disease exclusively located in the CNS.
• At least 1 measurable lesion.
• Eastern Cooperative Oncology Group (ECOG)-Performance Status (PS) ≤ 2. ECOG PS > 2 accepted if due to PCNSL symptoms.
• Patients possibly eligible for HCT-ASCT as judged by the treating physician.
• Written informed consent obtained according to international guidelines and local laws by patient or authorized legal representative in case patient is temporarily legally not competent due to his or her disease.

Additional randomization criteria:

• Patients eligible for HCT-ASCT defined by the EBL score (at most one of the 3 following conditions may apply: ECOG PS > 1, Barthel Index of activities of daily living (ADL) < 20 and Lachs geriatric screening > 3), improvement of PS after pre-phase treatment or clinical judgement by the treating physician after discussion with the study expert team.
• No evidence of disease progression after pre-phase treatment.

Критерии исключения

• Congenital or acquired immunodeficiency including HIV infection and previous organ transplantation.
• Systemic lymphoma manifestation (outside the CNS).
• Primary vitreoretinal lymphoma or primary leptomeningeal lymphoma without manifestation in the brain parenchyma or spinal cord.
• Previous or concurrent malignancies with the exception of surgically cured carcinoma in situ or other kinds of cancer without evidence of disease for at least 5 years.
• Previous systemic Non-Hodgkin lymphoma at any time.
• Inadequate renal function (creatinine clearance <60 ml/min).
• Inadequate bone marrow, cardiac, pulmonary or hepatic function according to investigator´s decision.
• Active hepatitis B or C disease.
• Concurrent treatment with other experimental drugs or participation in an interventional clinical trial with administration of study medication within the last thirty days before the start of this study.
• Third space fluid accumulation >500 ml.
• Hypersensitivity to study treatment or any component of the formulation.
• Taking any medications likely to cause interactions with the study medication.
• Known or persistent abuse of medication, drugs or alcohol.
• Active COVID-19-infection or non-compliance with the prevailing hygiene measures regarding the COVID-19 pandemic.
• Patients without legal capacity and who are unable to understand the nature, significance and consequences of the study and without designated legal representative.
• Previous participation in this trial.
• Persons who are in a relationship of dependency/employment to the sponsor and/ or investigator.
• Any familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
• Fertile patients refusing to use safe contraceptive methods during the study.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Германия · 35 центров

• University Hospital Freiburg, Department Medicine I, Hematology, oncology and stem cell tr — Freiburg im Breisgau
• Klinikum Stuttgart, Clinic of Hematology, Oncology and Palliative Care, Stuttgart Cancer C — Stuttgart
• University Hospital Aachen — Aachen
• University Hospital Augsburg — Augsburg
• Helios Klinikum Berlin-Buch — Berlin
• University Hospital Berlin — Berlin
• Evangelisches Klinikum Bethel — Bielefeld
• Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH — Bochum
• … и ещё 27 центров

Публикации

• Schorb E, Isbell LK, Kerkhoff A, Mathas S, Braulke F, Egerer G, Roth A, Schliffke S, Borchmann P, Brunnberg U, Kroschinsky F, Mohle R, Rank A, Wellnitz D, Kasenda B, Pospiech L, Wendler J, Scherer F, Deckert M, Henkes E, von Gottberg P, Gmehlin D, Backenstrass M, Jensch A, Burger-Martin E, Grishina O, Fricker H, Malenica N, Orban A, Duyster J, Ihorst G, Finke J, Illerhaus G. High-dose chemotherapy PMID 38301670
• Mendez JS, Ostrom QT, Gittleman H, Kruchko C, DeAngelis LM, Barnholtz-Sloan JS, Grommes C. The elderly left behind-changes in survival trends of primary central nervous system lymphoma over the past 4 decades. Neuro Oncol. 2018 Apr 9;20(5):687-694. doi: 10.1093/neuonc/nox187. PMID 29036697
• Houillier C, Soussain C, Ghesquieres H, Soubeyran P, Chinot O, Taillandier L, Lamy T, Choquet S, Ahle G, Damaj G, Agape P, Molucon-Chabrot C, Amiel A, Delwail V, Fabbro M, Jardin F, Chauchet A, Moles-Moreau MP, Morschhauser F, Casasnovas O, Gressin R, Fornecker LM, Abraham J, Marolleau JP, Tempescul A, Campello C, Colin P, Tamburini J, Laribi K, Serrier C, Haioun C, Chebrek S, Schmitt A, Blonski M PMID 31907289
• Schorb E, Fox CP, Kasenda B, Linton K, Martinez-Calle N, Calimeri T, Ninkovic S, Eyre TA, Cummin T, Smith J, Yallop D, De Marco B, Krampera M, Trefz S, Orsucci L, Fabbri A, Illerhaus G, Cwynarski K, Ferreri AJM. Induction therapy with the MATRix regimen in patients with newly diagnosed primary diffuse large B-cell lymphoma of the central nervous system - an international study of feasibility and e PMID 31997308
• Olivier G, Clavert A, Lacotte-Thierry L, Gardembas M, Escoffre-Barbe M, Brion A, Cumin I, Legouffe E, Solal-Celigny P, Chabin M, Ingrand P, Colombat P, Delwail V. A phase 1 dose escalation study of idarubicin combined with methotrexate, vindesine, and prednisolone for untreated elderly patients with primary central nervous system lymphoma. The GOELAMS LCP 99 trial. Am J Hematol. 2014 Nov;89(11):10 PMID 25052698
• Ferreri AJ, Cwynarski K, Pulczynski E, Ponzoni M, Deckert M, Politi LS, Torri V, Fox CP, Rosee PL, Schorb E, Ambrosetti A, Roth A, Hemmaway C, Ferrari A, Linton KM, Ruda R, Binder M, Pukrop T, Balzarotti M, Fabbri A, Johnson P, Gorlov JS, Hess G, Panse J, Pisani F, Tucci A, Stilgenbauer S, Hertenstein B, Keller U, Krause SW, Levis A, Schmoll HJ, Cavalli F, Finke J, Reni M, Zucca E, Illerhaus G; In PMID 27132696
• Ferreri AJM, Cwynarski K, Pulczynski E, Fox CP, Schorb E, La Rosee P, Binder M, Fabbri A, Torri V, Minacapelli E, Falautano M, Ilariucci F, Ambrosetti A, Roth A, Hemmaway C, Johnson P, Linton KM, Pukrop T, Sonderskov Gorlov J, Balzarotti M, Hess G, Keller U, Stilgenbauer S, Panse J, Tucci A, Orsucci L, Pisani F, Levis A, Krause SW, Schmoll HJ, Hertenstein B, Rummel M, Smith J, Pfreundschuh M, Cabr PMID 29054815
• Fritsch K, Kasenda B, Schorb E, Hau P, Bloehdorn J, Mohle R, Low S, Binder M, Atta J, Keller U, Wolf HH, Krause SW, Hess G, Naumann R, Sasse S, Hirt C, Lamprecht M, Martens U, Morgner A, Panse J, Frickhofen N, Roth A, Hader C, Deckert M, Fricker H, Ihorst G, Finke J, Illerhaus G. High-dose methotrexate-based immuno-chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study). Leukemia. 2 PMID 27843136

Идентификаторы

NCT: NCT06830421 · P003077 · 2020-001181-10 · DRKS00024085

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗