ABSTRACT
AVENuE - Avelumab in the frontline treatment of advanced classic Hodgkin lymphoma - a window study Background Response adapted ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) has become a standard of care in many countries for advanced stage classic Hodgkin Lymphoma (cHL), as investigated in the RATHL study: following 2 cycles of ABVD patients with negative (Deauville 1-3) interim PET (iPET2) proceeded to 4 cycles of AVD;those with positive (Deauville 4-5) iPET2 intensified therapy to escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone (escBEACOPP) or BEACOPP every 14 days. Overall this strategy was associated with a 3-year progression free survival (PFS) of 82.6%, and outcomes for patients with positive iPET2 were disappointing with 3y progression-free survival (PFS) of 67.5%. More intensive treatment such as upfront use of escBEACOPP has been reported to produce higher PFS (89% at 5 years), but it is unclear whether overall survival (OS) is improved. More intensive treatment is, however, associated with higher risk of toxicity. Inhibitors of programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) have established efficacy in relapsed / refractory cHL with response rates of 55-87%. In the front line setting PD-1 inhibitors have a reported complete metabolic response (CMR) rate of 18-37%. Response to PD-L1 inhibitors in the frontline setting has not been explored. Serial serum TARC (thymus and activation-regulated chemokine) is reported to be prognostic in the frontline treatment of cHL and may aid response assessment because PET interpretation with checkpoint inhibitors is often complex. In the context of PD-1 inhibition, PD-1 expression by immunohistochemistry (IHC) and 9p24.1 copy gain by fluorescence in situ hybridisation (FISH) are reported to correlate with response. Methods AVENuE is a Phase II single-arm multicentre study with sites in the UK and Australia assessing the safety and efficacy of 2 cycles (4 doses) of the PD-L1 inhibitor avelumab for untreated high-risk stage II-IV cHL prior to the iPET2 response adapted approach described above. Eligible patients must be 16-60 years, ECOG 0-1, and have adequate organ function. Patients with;compressive symptoms from lymphoma, autoimmune disorders or immunosuppressive treatment within 2 months are excluded. The primary endpoint is the centrally reviewed PET CMR rate to avelumab. Secondary endpoints are: the safety and tolerability of sequential avelumab and combination chemotherapy as assessed by CTCAE v 5.0;the iPET2 CMR rate after avelumab and 2 cycles of ABVD;PFS and OS at one year. Using a single stage A'hern design, target recruitment is 47 patients to give 90% power at a 0.05% one sided alpha to exclude an overall response rate (ORR) to 2 cycles of avelumab of < 20%;an ORR of 40% would be considered worthy of further study. Recruitment has continued during the COVID-19 pandemic. 29 patients have been enrolled. Exploratory endpoints include correlating disease response with baseline PD-1 copy number by FISH and PD-1 expression by IHC. Serial serum TARC is being explored as an aid to response assessment and changes in peripheral blood immune cell subset are being investigated as possible biomarkers of response. Trial funder: Pfizer Ltd in alliance with Merck KGaA Pfizer Ltd is providing funding as part of an Alliance between Pfizer and Merck KGaA Clinical trials.gov NCT03617666 EUDRACT No.: 2018-002227-42 Disclosures: Hawkes: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau;Regeneron: Speakers Bureau;Merck KgA: Research Funding;Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Janssen: Speakers Bureau;Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees;Gilead: Membership on an entity's Boa d of Directors or advisory committees;Antigene: Membership on an entity's Board of Directors or advisory committees;Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding;Specialised Therapeutics: Consultancy. Barrington: Bristol Myers Squibb international corporation: Research Funding;Pfizer Inc: Research Funding;Amgen Ltd: Research Funding;Takeda Speakers Bureau: Honoraria. McKay: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees;Gilead: Honoraria, Other: Travel Support;KITE: Honoraria, Membership on an entity's Board of Directors or advisory committees;Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support;Janssen: Honoraria, Other: Travel Support;Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees;BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Iyengar: Janssen: Other: conference support, Speakers Bureau;Abbvie: Other: conference support;Beigene: Membership on an entity's Board of Directors or advisory committees;Gilead: Membership on an entity's Board of Directors or advisory committees, Other: conference support, Speakers Bureau;Takeda: Membership on an entity's Board of Directors or advisory committees, Other: conference support, Speakers Bureau. Radford: Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau;AstraZeneca: Current holder of individual stocks in a privately-held company;ADC Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Speakers Bureau;BMS: Honoraria. Shah: Abbvie, Janssen and Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Clifton-Hadley: Bristol-Myers Squibb Pharmaceuticals Ltd.: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.;Amgen: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.;Celgene: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.;Merck Sharp and Dohme: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.;Janssen-Cilag: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.;Pfizer: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.;Millennium pharmaceutics inc.: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials. Collins: Beigene: Membership on an entity's Board of Directors or advisory committees;Novartis: Honoraria, Speakers Bureau;Pfizer: Honoraria;Celgene: Research Funding;Amgen: Research Funding;AstraZeneca: Honoraria, Research Funding;ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees;Celleron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau. OffLabel Disclosure: Avelumab prior to frontline chemotherapy in advanced stage classic Hodgkin lymphoma.
ABSTRACT
Background: The role of upfront ASCT for NDTE MM remains under evaluation with high MRD rates following novel induction and consolidation (cons) strategies. K maintenance represents an alternative strategy to lenalidomide maintenance. The CARDAMON trial investigated K maintenance following KCd induction plus either ASCT or KCd cons. Methods: NDTE pts received 4 x KCd induction (K 20/56 mg/m2 biweekly, C 500 mg D 1,8,15, d 40mg weekly) before 1:1 randomisation to ASCT or 4 x KCd cons followed by 18 cycles K maintenance (56mg/m2 D1,8,15). Flow cytometric MRD (10-5) was assessed post induction, pre-maintenance and at 6 months maintenance. Primary endpoints were ≥VGPR post induction and 2-year PFS from randomisation. Secondary endpoints included improvements in disease response and MRD conversion following ASCT/ cons and maintenance. Results: 281 patients were registered, with 218 randomised to either ASCT or cons. The median PFS for ASCT was not yet reached vs 3.4 years for cons, with cons failing to show non-inferiority (difference in 2-year PFS 6.5%, 70% CI 1.0% to 11.1%). 196 patients received K maintenance (99 ASCT, 97 cons), 17 remain on treatment. A median of 16 cycles (1-18) were given over a median of 15.9 months (0-21.5). COVID-19 led to maintenance treatment interruptions in 41 (8 ASCT, 6 Cons) and treatment discontinuation in 15 (9 ASCT, 6 Cons). The median K dose given was 50.6mg/m2 and was similar across both arms (51.2 vs 49.4mg/m2, p=0.03). K maintenance was discontinued for PD in 14.1% (ASCT) vs 22.7% (cons), and for adverse events (AEs) in 7.1% (ASCT) vs 4.1% (cons). Most common AEs were hypertension and infections and more ≥G3 AEs were noted in ASCT vs cons (p=0.01). Patient/ clinician withdrawals from maintenance were low but occurred more in the ASCT arm (9.1% vs 1%). MRD neg patients post ASCT/ Cons had a longer PFS than MRD pos (p=0.002);with a higher MRD neg rate in the ASCT arm (53.6% vs 35.1% in Cons, p=0.01). MRD neg patients at 6 months post maintenance also had longer PFS (p=0.004 cf MRD pos patients);again with higher MRD neg rates in the ASCT arm (58.1% ASCT vs 40.5% Cons, p=0.02). There was no difference in PFS for MRD neg patients according to treatment arm from PBSCH, post-ASCT/ Cons or 6 months maintenance timepoints. Overall, 27.8% of MRD pos patients converted to MRD neg post ASCT/ Cons with more converting with ASCT (39.1% ASCT vs 16.1%, p=0.004). 23.5% of MRD pos patients converted to neg during maintenance (30.6% ASCT, 17.8%: p=0.2). Maintenance of MRD negativity over the first 6 months was similar between ASCT and Cons arms (p=0.3). There was no evidence that the timing of achievement of MRD negativity impacted PFS. Conclusions: K maintenance at 56mg/m2 weekly was deliverable and tolerable, with continued higher MRD neg rates at 6 months post-ASCT compared to post-Cons. However more ≥G3 AEs and discontinuations for AEs/ patient choice were noted for K maintenance after ASCT.
ABSTRACT
Background: We have previously described AUTO1 (CAT19), a CD19 CAR with a fast off-rate CD19 binding domain, designed to reduce CAR T-cell immune toxicity and improve engraftment. Its clinical activity has been tested in r/r paediatric and adult B-ALL. Cumulatively, this data confirms the intended fucntion of the receptor, with low levels of CRS/ ICANS and long-term engraftment of CAR T-cells observed in both patient groups. Recently, CAR therapy has been explored in indolent lymphomas such as follicluar (FL) and mantle cell lymphoma (MCL), but a high incidence of toxicity inluding Grade 3-4 ICANS has been reported. Aims: We have initiated testing of AUTO1 (CAT19) in the setting of indolent B-cell lymphoma (NCT02935257). Methods: Manufacturing: CAR T-cell products were generated using a semi-automated closed process from non-mobilised leucapheresate. Study design: subjects>/=16y underwent lymhpodepletion with fludarabine (30mg/m2 x3) and cyclophosphamide (60mg/kg x1) followed by a single CAR T-cell infusion of 200 x10