OptiMATe: De-escalated Induction Treatment in Primary CNS Lymphoma (OptiMATe)

Optimizing MATRix as Remission Induction in PCNSL: De-escalated Induction Treatment in Newly Diagnosed Primary CNS Lymphoma - a Randomized Phase III Trial

This phase III study investigates if a de-escalated induction treatment in newly diagnosed primary CNS lymphoma is superior to the standard MATRix protocol in terms of event free survival.

Study Overview

• Status: Recruiting
• Conditions: Primary Central Nervous System Lymphoma
• Intervention / Treatment: Drug: Control intervention: four courses of MATRix; Drug: Experimental Treatment: one course Rituximab/HD-Methotrexate, two courses of MATRix

Detailed Description

This phase III study investigates if a de-escalated induction treatment in newly diagnosed primary CNS lymphoma is superior to the standard MATRix protocol in terms of event free survival. Two arms are compared, in the experimental treatment group, participants receive one course of R/HD-MTX, followed by two courses of MATRix and autologous stem cell transplantation. In the control treatment, participants receive four coourses of MATRix followed by autologous stem cell transplantation.

• Study Type: Interventional
• Enrollment (Estimated): 326
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Gerald Illerhaus, Prof; Phone Number: +4971127830400; Email: g.illerhaus@klinikum-stuttgart.de
• Study Contact Backup: Name: Elisabeth Schorb, MD; Phone Number: +4976127035360; Email: elisabeth.schorb@uniklinik-freiburg.de

Study Locations

• Germany
  • Baden-Württemberg
    • Stuttgart, Baden-Württemberg, Germany, 70174
      • Recruiting
      • Klinikum Stuttgart
      • Contact: Illerhaus Gerald, Prof.
      • Contact: Phone Number: +49711 278-30401; Email: g.illerhaus@klinikum-stuttgart.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Immunocompetent patients with newly diagnosed primary diffuse large B-cell lymphoma of the central nervous system (PCNSL).
2. Male or female patients aged 18-65 years irrespective of ECOG or 66-70 years with ECOG Performance Status ≤2.
3. Histologically or cytologically assessed diagnosis of B-cell lymphoma by local pathologist. Diagnostic sample obtained by stereotactic or surgical biopsy, CSF cytology examination or vitrectomy.
4. Disease exclusively located in the CNS.
5. At least one measurable lesion.
6. Previously untreated patients (previous or ongoing steroid treatment admitted)
7. Negative pregnancy test
8. 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.
9. Ability to understand the nature of the trial and the trial related procedures and to comply with them.

Exclusion Criteria:

1. Congenital or acquired immunodeficiency including HIV infection and previous organ transplantation.
2. Systemic lymphoma manifestation (outside the CNS).
3. Primary vitreoretinal lymphoma without manifestation in the brain parenchyma or spinal cord
4. Previous or concurrent malignancies with the exception of surgically cured carcinoma in situ of the cervix, carcinoma of the skin or other kinds of cancer without evidence of disease for at least 5 years.
5. Previous Non-Hodgkin lymphoma at any time.
6. Inadequate renal function (clearance < 60 ml/min).
7. Inadequate bone marrow, cardiac, pulmonary or hepatic function according to investigator´s decision
8. Active hepatitis B or C disease.
9. Concurrent treatment with other experimental drugs or participation in an interventional clinical trial with study medication being administered within the last 30 days before the start of this study.
10. Third space fluid accumulation > 500 ml.
11. Hypersensitivity to study treatment or any component of the formulation.
12. Taking any medications that are likely to cause interactions with the study medication
13. Known or persistent abuse of medication, drugs or alcohol.
14. Active COVID-19-infection or non-compliance with the prevailing hygiene measures regarding the COVID-19 pandemic
15. Patients without legal capacity who are unable to understand the nature, significance and consequences of the trial and without designated legal representative.
16. Previous participation in this trial.
17. Persons who are in a relationship of dependency/employment with the sponsor and/or the investigator.
18. Any familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
19. Current or planned pregnancy, nursing period
20. For fertile patients: Failure to use one of the following safe methods of contraception: intra-uterine device or hormonal contraception in combination with a mechanical method of contraception.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control treatment (Arm A); Patients receive four courses of MATRix (Rituximab 2 x 375 mg/m2, HD-Methotrexate 3.5 g/m2, HD-Cytarabine 2 x 2 g/m2, Thiotepa 30 mg/m2; i.v.) as induction treatment. Response assessment with gadolinium-enhanced brain MRI (centrally reviewed) takes place after course two and four. Patient with at least PR proceed to 3rd course of MATRix after first response assessment and to HCT-ASCT (BCNU 400 mg/m2, Thiotepa 4 x 5 mg/kg; i.v.) after second response assessment. Collection of autologous stem cells is planed after the second course of MATRix.	Drug: Control intervention: four courses of MATRix; Patients receive four courses of MATRix as induction treatment.
Experimental: Experimental treatment (Arm B); As induction treatment, patients receive one course of Rituximab/HD-Methotrexate (Rituximab 375 mg/m2, HD-Methotrexate 3.5 g/m2; i.v.). In the absence of clinical signs of progression, patients proceed to two courses of MATRix (Rituximab 2 x 375 mg/m2, HD-Methotrexate 3.5 g/m2, HD-Cytarabine 2 x 2 g/m2, Thiotepa 30 mg/m2; i.v.) followed by a response assessment with gadolinium-enhanced brain MRI (centrally reviewed). Patients with at least PR will proceed to HCT-ASCT (BCNU 400 mg/m2, thiotepa 4 x 5 mg/kg; i.v.). Collection of autologous stem cells is planed after the first course of MATRix	Drug: Experimental Treatment: one course Rituximab/HD-Methotrexate, two courses of MATRix; De-escalated induction treatment with R/HD-MTX and two courses of MATRix

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free survival (EFS)	time from randomization to premature end of treatment due to any reason, lymphoma progression or death, whichever occurs first	up to 24 months after end of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	time from randomization to death of any course	up to 24 months after end of treatment
Progression free survival (PFS)	time from randomization until disease progression, relapse or death from any cause	up to 24 months after end of treatment
Remission rate prior to consolidation therapy	Remission prior to consolidation therapy will be determined at RA II and will be divided in CR, uCR, PR, CD, PD according to IPCG criteria	assesed at RA II (Arm B: day 18-20 of cycle 2, each cycle is 21 days. Arm A: day 18-20 of cycle 4, each cycle is 21 days)
Remission rate after consolidation therapy	Remission after consolidation therapy will be determined on day 30 after ASCT and will be divided in CR, uCR, PR, SD, PD according to IPCG criteria	30 days after ASCT
rate of patients reaching consolidation therapy	defined as obtaining at least the first dose of consolidation therapy, will be determined after the response assessment II (following 4 cycles of MATRix in the control arm and following 1 cycle of R/HD-MTX and 2 cycles of MATRix in the experimental arm)	determined up to 4 weeks after response assessment II
Quality of life (QOL), EORTC QLQ-C30,	EORTC (European Organization for research and cancer treatment) QLQ-C30, measured during screening, at response assessment II, and with beginning of RA III every 12 months until end of follow-up	up to 24 months after end of treatment
Quality of life (QOL), QLQ-BN20	EORTC (European Organization for research and cancer treatment) QLQ-BN20; measured during screening, at response assessment II, and with beginning of RA III every 12 months until end of follow-up	up to 24 months after end of treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of de-escalated regimen to standard induction therapy regarding safety	incidence of (Serious) adverse events, laboratory parameters:WBC <2.500/µl and platelets <80.000/μl , vital signs: blood pressure (mmHg), heart rate (bpm)	up to 60 days after ASCT
Comparison of de-escalated regimen to standard induction therapy regarding neurotoxicity	MoCA (Montreal Cognitive Assesment) performed at screening, EOT and every 12 months until end of follow-up	up to 24 months after end of treatment
Comparison of de-escalated regimen to standard induction therapy regarding neurotoxicity	WAIS III (Wechsler Adult Intelligence scale) counting test performed at screening, EOT and every 12 months until end of follow-up	up to 24 months after end of treatment
Comparison of de-escalated regimen to standard induction therapy regarding neurotoxicity	WAIS III (Wechsler Adult Intelligence scale) subtest similarities and verbal fluency test performed at screening, EOT and every 12 months until end of follow-up	up to 24 months after end of treatment
Comparison of de-escalated regimen to standard induction therapy regarding neurotoxicity	Trail Making Test A and B, performed at screening, EOT and every 12 months until end of follow-up	up to 24 months after end of treatment
Comparison of de-escalated regimen to standard induction therapy regarding neurotoxicity	Brief Test of Attention performed at screening, EOT and every 12 months until end of follow-up	up to 24 months after end of treatment
Comparison of de-escalated regimen to standard induction therapy regarding neurotoxicity	Hopkins Verbal Learning Test performed at screening, EOT and every 12 months until end of follow-up	up to 24 months after end of treatment
Comparison of de-escalated regimen to standard induction therapy regarding neurotoxicity	Grooved Pegboard Test, performed at screening, EOT and every 12 months until end of follow-up	up to 24 months after end of treatment
Comparison of de-escalated regimen to standard induction therapy regarding neurotoxicity	Rey-Osterrieth-Complex-Figure-Test performed at screening, EOT and every 12 months until end of follow-up	up to 24 months after end of treatment
Unplanned hospital admissions	Defined as in-patient hospitalization from randomization until 6 months after EOT visit (excluding those for study therapy and/or assessments, placement of an indwelling catheter, social/convenience admissions, respite care, elective or pre-planned treatment/surgery)	up to 6 months after EOT visit
Length of hospital stays	Measured as number of nights in hospital from randomization and until 6 months after EOT. Hospitalization must be in relation to the disease or the administered treatment or due to toxicity	up to 6 months after EOT visit

Collaborators and Investigators

• Sponsor: Klinikum Stuttgart
• Collaborators: German Federal Ministry of Education and Research; University Hospital Freiburg
• Investigators: Principal Investigator: Gerald Illerhaus, Prof, Klinikum Stuttgart

Study record dates

Study Major Dates

• Study Start (Actual): June 7, 2021
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): May 1, 2028

Study Registration Dates

• First Submitted: August 25, 2020
• First Submitted That Met QC Criteria: June 17, 2021
• First Posted (Actual): June 18, 2021

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 11, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Dermatologic Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Rituximab; Methotrexate
• Other Study ID Numbers: SCC215

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: After approval through ethics committee publication of study protocol. Anonymised patient data can be provided upon project related request.
• IPD Sharing Time Frame: Study protocol: 1st quarter 2021 Not before 2nd quarter 2028: Anonymised patient data
• IPD Sharing Access Criteria: To get access to anonymised patient data, a research proposal/project plan is required.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No