Australasian Leukaemia & Lymphoma Group NHL32 Block PCNSL: An Open Label Phase II Study of Pembrolizumab Following Chemoimmunotherapy for Newly Diagnosed Primary Central Nervous System Lymphoma - Trial in Progress

Background:

Diffuse Large B-cell lymphoma of the Central Nervous System (DLBCL of the CNS), or Primary CNS Lymphoma (PCNSL), is an aggressive disease of predominantly older patients with a median age at diagnosis of 67 and increasing incidence in those over 70. The current standard of care is intensive chemoimmunotherapy (CIT) containing high-dose methotrexate (MTX) and cytarabine (Ara-C), such as MATRix (MTX, Ara-C, thiotepa, rituximab) or R-MPV/Ara-C (rituximab, MTX, procarbazine, vincristine followed by Ara-C), followed by consolidation with either autologous stem cell transplantation (ASCT) or whole brain radiotherapy (WBRT) for suitable patients. While favorable responses can be achieved (2-year PFS: 57-69%, 2-year OS: 71-81%), questions remain regarding the benefit of either consolidative strategy, particularly in patients who achieve a complete response to induction CIT. Sparing patients from WBRT-related cognitive impairment and the well-described morbidity and mortality of ASCT continues to be a priority, as are novel approaches for those not eligible for either strategy due to age or comorbidities. Genomic interrogation of PCNSL has demonstrated copy number alterations and translocations affecting chromosome 9p24.1 (encoding loci for PD-L1 and PD-L2), providing therapeutic rationale for treatment with PD-1 inhibition. Furthermore, case series and phase 2 studies have demonstrated that PD-1 inhibition can lead to clinical and radiological responses in the relapsed setting. NHL32 is a national cooperative group trial in progress examining an alternative consolidation strategy with PD-1 blockade with the anticipated outcome of improved long-term disease control and reduction in late neurocognitive complications or morbidity associated with WBRT and ASCT respectively.

Method:

ALLG NHL32 (BLOCK PCNSL) [ACTRN12619000518167] is a phase II, single arm, open-label trial of CIT followed by pembrolizumab maintenance, which has been designed using Fleming-A'Hern early phase principles. The trial is open to recruitment across Australia. Approximately 45 patients with newly diagnosed PCNSL will be enrolled. Eligible patients receive induction CIT, either R-MPV/Ara-C or MATRix as per investigator choice. Patients who achieve stable disease or better and adequate resolution of toxicity (i.e. grade <3) after induction CIT will proceed to maintenance pembrolizumab (200mg) administered intravenously every 21 days for 35 cycles or until disease progression. Eligible patients are adults (>18 years) with treatment-naïve histologically confirmed DLBCL of the CNS, ECOG performance status 0-1 (or 2 if due to neurological deficit), and adequate organ function to receive induction CIT. Key exclusion criteria include presence of active autoimmune disease and previous treatment with checkpoint blockade or CAR-T therapy.

The primary endpoint is 1-year progression free-survival (PFS) from cycle 1, day 1 of CIT (intent-to-treat population) as estimated using the Kaplan-Meier method. The secondary endpoints include 2-year PFS, 2-year OS, PFS with subgroup analysis according to induction CIT and response endpoints. Adverse event reporting during CIT phase will be limited to grade >3 events. The safety analysis of adverse events occurring during the pembrolizumab phase will be descriptive, with the number of patients experiencing the event and percentage presented. Exploratory endpoints include describing the utility of PET/MRI assessment for treatment response and biomarkers such as molecular profiling of tumour-tissue, gene expression profiling for immune gene signatures and cell-of-origin, PD-1/PD-L1 immunohistochemistry, 9p24 FISH and circulating tumour DNA (plasma and CSF).

Keane:Gilead: Consultancy; Merck: Consultancy, Speakers Bureau; Roche: Consultancy; Takeda: Speakers Bureau; Astra Zeneca: Speakers Bureau. Giri:Royal Adelaide Hospital: Current Employment. Cull:BeiGene: Research Funding; AstraZeneca: Research Funding; Glycomimetics: Research Funding. Lasica:Celgene: Other: Travel, accommodations, expenses. Wight:Sobi: Membership on an entity's Board of Directors or advisory committees. Hawkes:Merck KGaA: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Regeneron Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Trial Steering Committee, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Antengene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck Sharpe and Dohme: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Other: Trial Steering Committee, Research Funding, Speakers Bureau; Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Trial Steering Committee, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gregory:Merck, Amgen, Roche, Novartis, BMS, Clinigen, Gilead, Prelude Therapeutics: Membership on an entity's Board of Directors or advisory committees; Roche, Merck: Speakers Bureau; Merck, BeiGene (to institute, not individual): Research Funding.

PD-1 (encoded by the Pdcd1 gene, located on chromosome 2) is an Ig superfamily member related to CD28 and CTLA-4 and is expressed on activated CD4+ and CD8+ T-cells, the latter which have a particularly important role in preventing the evolution of cancer. Tumours can evade immune surveillance by upregulating the expression of PD-1 ligands (PD-L1 and PD-L2). Pembrolizumab is a highly selective humanized monoclonal antibody designed to block the PD-1/PD-L1 interaction which results in CD8+ T-cell driven tumour rejection. Pembrolizumab is administered intravenously and dosed at 200mg on a 3-weekly schedule, irrespective of tumour type or patient weight. Pembrolizumab has proven safety and efficacy in relapsed/refractory classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma, diseases with molecular similarity to PCNSL as characterised by frequent copy number alterations and translocations affecting chromosome 9p24.1 which encode PD-L1 and PD-L2.