UCART19, a first-in-class allogeneic anti-CD19 chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia (CALM): a phase 1, dose-escalation trial.

BACKGROUND: The prognosis for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia remains poor. UCART19, an allogeneic genome-edited anti-CD19 chimeric antigen receptor (CAR) T-cell product derived from healthy donors and available for immediate clinical use, offers a potential therapeutic option for such patients. The CALM trial is a first-in-human study evaluating the safety and antileukaemic activity of UCART19 in adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. METHODS: This phase 1, open-label study was conducted at eight centres across France, the UK, the USA, and Japan. Adult patients aged 16-70 years with CD19-positive relapsed or refractory B-cell acute lymphoblastic leukaemia who had morphological relapse or a minimal residual disease level of at least 1 × 10-3 and had exhausted standard treatment options were enrolled in the study, which comprised a dose-escalation phase of up to three UCART19 doses followed by a safety expansion phase. Patients underwent lymphodepletion with fludarabine (30 mg/m2 per day intravenously for 3 days) and cyclophosphamide (500 mg/m2 per day intravenously for 3 days) with or without alemtuzumab (1 mg/kg or 40 mg or 60 mg over 5 days) and received UCART19 doses of 6 × 106, 6-8 × 107, or 1·8-2·4 × 108 total CAR T cells intravenously, followed by safety evaluation and disease response assessments. The primary endpoint was incidence and severity of adverse events. Secondary endpoints were the overall response rate, duration of response, relapse-free survival, progression-free survival, and overall survival. This trial is registered with ClinicalTrials.gov (NCT02746952) and is complete. FINDINGS: Between Aug 1, 2016, and June 30, 2020, 25 patients were enrolled in the study and treated with UCART19. Median duration of follow-up was 12·8 months (IQR 2·8-24·8). Median age was 37 years (IQR 28-45). 14 (56%) patients were male and 11 (44%) female. 17 (68%) patients were White, two (8%) Black, two (8%) Asian, and four (16%) from other racial or ethnic groups. Three patients developed dose-limiting toxicities (one at each dose level); one had grade 4 cytokine release syndrome and two had grade 4 prolonged cytopenias. Grade 3 or higher cytokine release syndrome was reported in six (24%) patients and grade 3 or higher neurological toxicity in one (4%) patient. Grade 3 or higher infections occurred in seven (28%) patients, and grade 4 prolonged cytopenia in four (16%) patients. Two (8%) patients developed grade 1 acute cutaneous graft-versus-host disease. 14 patients died, nine from progressive disease and five from infections or other complications, of which four were considered to be related to UCART19 or lymphodepletion, or both. After a median of follow-up of 12·8 months (IQR 2·8-24·8), overall response rate was 48% (95% CI 28-69; 12 of 25 patients), duration of response and median relapse-free survival were 7·4 months (95% CI 1·8 to not calculable), progression-free survival was 2·1 months (95% CI 1·2-2·8), and overall survival was 13·4 months (95% CI 4·8-23·0). INTERPRETATION: UCART19 had a manageable safety profile, and showed evidence of antileukaemic activity in heavily pretreated adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. This study shows that allogeneic off-the-shelf CAR T cells can be used safely to treat patients with relapsed B-cell acute lymphoblastic leukaemia. FUNDING: Servier.

Genome-edited, donor-derived allogeneic anti-CD19 chimeric antigen receptor T cells in paediatric and adult B-cell acute lymphoblastic leukaemia: results of two phase 1 studies.

BACKGROUND: Genome-edited donor-derived allogeneic anti-CD19 chimeric antigen receptor (CAR) T cells offer a novel form of CAR-T-cell product that is available for immediate clinical use, thereby broadening access and applicability. UCART19 is one such product investigated in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. Two multicentre phase 1 studies aimed to investigate the feasibility, safety, and antileukaemic activity of UCART19 in children and adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. METHODS: We enrolled paediatric or adult patients in two ongoing, multicentre, phase 1 clinical trials to evaluate the safety and antileukaemic activity of UCART19. All patients underwent lymphodepletion with fludarabine and cyclophosphamide with or without alemtuzumab, then children received UCART19 at 1·1-2·3 × 106 cells per kg and adults received UCART19 doses of 6 × 106 cells, 6-8 × 107 cells, or 1·8-2·4 × 108 cells in a dose-escalation study. The primary outcome measure was adverse events in the period between first infusion and data cutoff. These studies were registered at ClinicalTrials.gov, NCT02808442 and NCT02746952. FINDINGS: Between June 3, 2016, and Oct 23, 2018, seven children and 14 adults were enrolled in the two studies and received UCART19. Cytokine release syndrome was the most common adverse event and was observed in 19 patients (91%); three (14%) had grade 3-4 cytokine release syndrome. Other adverse events were grade 1 or 2 neurotoxicity in eight patients (38%), grade 1 acute skin graft-versus-host disease in two patients (10%), and grade 4 prolonged cytopenia in six patients (32%). Two treatment-related deaths occurred; one caused by neutropenic sepsis in a patient with concurrent cytokine release syndrome and one from pulmonary haemorrhage in a patient with persistent cytopenia. 14 (67%) of 21 patients had a complete response or complete response with incomplete haematological recovery 28 days after infusion. Patients not receiving alemtuzumab (n=4) showed no UCART19 expansion or antileukaemic activity. The median duration of response was 4·1 months with ten (71%) of 14 responders proceeding to a subsequent allogeneic stem-cell transplant. Progression-free survival at 6 months was 27%, and overall survival was 55%. INTERPRETATION: These two studies show, for the first time, the feasibility of using allogeneic, genome-edited CAR T cells to treat patients with aggressive leukaemia. UCART19 exhibited in-vivo expansion and antileukaemic activity with a manageable safety profile in heavily pretreated paediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. The results this study are an encouraging step forward for the field of allogeneic CAR T cells, and UCART19 offers the opportunity to treat patients with rapidly progressive disease and where autologous CAR-T-cell therapy is unavailable. FUNDING: Servier.

Paediatric Strategy Forum for medicinal product development for acute myeloid leukaemia in children and adolescents: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

PURPOSE: The current standard-of-care for front-line therapy for acute myeloid leukaemia (AML) results in short-term and long-term toxicity, but still approximately 40% of children relapse. Therefore, there is a major need to accelerate the evaluation of innovative medicines, yet drug development continues to be adult-focused. Furthermore, the large number of competing agents in rare patient populations requires coordinated prioritisation, within the global regulatory framework and cooperative group initiatives. METHODS: The fourth multi-stakeholder Paediatric Strategy Forum focused on AML in children and adolescents. RESULTS: CD123 is a high priority target and the paediatric development should be accelerated as a proof-of-concept. Efforts must be coordinated, however, as there are a limited number of studies that can be delivered. Studies of FLT3 inhibitors in agreed paediatric investigation plans present challenges to be completed because they require enrolment of a larger number of patients than actually exist. A consensus was developed by industry and academia of optimised clinical trials. For AML with rare mutations that are more frequent in adolescents than in children, adult trials should enrol adolescents and when scientifically justified, efficacy data could be extrapolated. Methodologies and definitions of minimal residual disease need to be standardised internationally and validated as a new response criterion. Industry supported, academic sponsored platform trials could identify products to be further developed. The Leukaemia and Lymphoma Society PedAL/EUpAL initiative has the potential to be a major advance in the field. CONCLUSION: These initiatives continue to accelerate drug development for children with AML and ultimately improve clinical outcomes.

From single-arm studies to externally controlled studies. Methodological considerations and guidelines.

Single-arm studies are sometimes used as pivotal studies but they have methodological limitations which prevent them from obtaining the high level of reliability as for a randomised controlled study which remains the gold standard in the evaluation of new treatments. The objective of this roundtable was to discuss the limitations of these single-arm studies, to analyse available and acceptable solutions in order to propose guidelines for their conduct and assessment. Single-arm studies themselves are intrinsically inappropriate for demonstrating the benefit of a new treatment because it is impossible to infer the benefit from a value obtained under treatment without knowing what it would have been in the absence of the new treatment. The implication is that comparison with other data is necessary. However this comparison has limitations due to (1) the post hoc choice of the reference used for comparison, (2) the confusion bias for which an adjustment approach is imperative and, (3) the other biases, measure and attrition among others. When these limitations are taken into account this should, first and foremost, lead to the conduct of externally controlled trials instead of single-arm trials as is proposed by the latest version of ICH E10. Moreover, the external control must be formalised in the study protocol with a priori selection of both the reference control and the formal method of comparison: test in relation to a standard, adjustment on individual data, a synthetic control group or matching-adjusted indirect comparisons (MAIC). Lastly, externally controlled studies must be restricted to situations where randomisation is infeasible. To be acceptable, these studies must be able to guarantee freedom from residual confusion bias, which is only truly acceptable if the observed effect is dramatic and the usual course of the disease is highly predicable.

Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Panobinostat plus bortezomib and dexamethasone significantly increased median progression-free survival compared with placebo plus bortezomib and dexamethasone in the phase 3 PANORAMA 1 trial. Here, we present the final overall survival analysis for this trial. METHODS: PANORAMA 1 is a randomised, placebo-controlled, double-blind, phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma with one to three previous treatments. Patients were randomly assigned (1:1) to receive panobinostat (20 mg orally) or placebo, with bortezomib (1·3 mg/m2 intravenously) and dexamethasone (20 mg orally), over two distinct treatment phases. In treatment phase 1 (eight 3-week cycles), patients received: panobinostat or placebo on days 1, 3, 5, 8, 10, and 12; bortezomib on days 1, 4, 8, and 11; and dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. During treatment phase 2 (four 6-week cycles with a 2 weeks on, 1 week off schedule), panobinostat or placebo was given three times a week, bortezomib was administered once a week, and dexamethasone was given on the days of and following bortezomib administration. The primary endpoint was progression-free survival; overall survival was a key secondary endpoint. This study is registered at ClinicalTrials.gov, NCT01023308. FINDINGS: Between Jan 21, 2010, and Feb 29, 2012, 768 patients were enrolled into the study and randomly assigned to receive either panobinostat (n=387) or placebo (n=381), plus bortezomib and dexamethasone. At data cutoff (June 29, 2015), 415 patients had died. Median overall survival was 40·3 months (95% CI 35·0-44·8) in those who received panobinostat, bortezomib, and dexamethasone versus 35·8 months (29·0-40·6) in those who received placebo, bortezomib, and dexamethasone (hazard ratio [HR] 0·94, 95% CI 0·78-1·14; p=0·54). Of patients who had received at least two previous regimens including bortezomib and an immunomodulatory drug, median overall survival was 25·5 months (95% CI 19·6-34·3) in 73 patients who received panobinostat, bortezomib, and dexamethasone versus 19·5 months (14·1-32·5) in 74 who received placebo (HR 1·01, 95% CI 0·68-1·50). INTERPRETATION: The overall survival benefit with panobinostat over placebo with bortezomib and dexamethasone was modest. However, optimisation of the regimen could potentially prolong treatment duration and improve patients' outcomes, although further trials will be required to confirm this. FUNDING: Novartis Pharmaceuticals.

Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment.

Panobinostat is a potent pan-deacetylase inhibitor that affects the growth and survival of multiple myeloma (MM) cells through alteration of epigenetic mechanisms and protein metabolism. Panobinostat plus bortezomib and dexamethasone (PAN-BTZ-Dex) led to a significant increase in progression-free survival (PFS) vs placebo plus bortezomib and dexamethasone (Pbo-BTZ-Dex) in patients with relapsed or relapsed and refractory MM in the phase 3 PANORAMA 1 trial. This subgroup analysis evaluated outcomes in patients in the PANORAMA 1 trial based on prior treatment: a prior immunomodulatory drug (IMiD; n = 485), prior bortezomib plus an IMiD (n = 193), and ≥2 prior regimens including bortezomib and an IMiD (n = 147). Median PFS with PAN-BTZ-Dex vs Pbo-BTZ-Dex across subgroups was as follows: prior IMiD (12.3 vs 7.4 months; hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.43-0.68), prior bortezomib plus IMiD (10.6 vs 5.8 months; HR, 0.52; 95% CI, 0.36-0.76), and ≥2 prior regimens including bortezomib and an IMiD (12.5 vs 4.7 months; HR, 0.47; 95% CI, 0.31-0.72). Common grade 3/4 adverse events and laboratory abnormalities in patients who received PAN-BTZ-Dex across the prior treatment groups included thrombocytopenia, lymphopenia, neutropenia, diarrhea, and asthenia/fatigue. Incidence of on-treatment deaths among patients who received prior bortezomib and an IMiD (regardless of number of prior regimens) was similar between treatment arms. This analysis demonstrated a clear PFS benefit of 7.8 months with PAN-BTZ-Dex among patients who received ≥2 prior regimens including bortezomib and an IMiD, a population with limited treatment options and poorer prognosis. This trial was registered at www.clinicaltrials.gov as #NCT01023308.

Panobinostat PK/PD profile in combination with bortezomib and dexamethasone in patients with relapsed and relapsed/refractory multiple myeloma.

PURPOSE: Panobinostat, a potent pan-deacetylase inhibitor, improved progression-free survival (PFS) in patients with relapsed and refractory multiple myeloma when combined with bortezomib and dexamethasone in a phase 3 trial, PANORAMA-1. This study aims to explore exposure-response relationship for panobinostat in this combination in a phase 1 trial, B2207 and contrast with data from historical single-agent studies. METHODS: Panobinostat plasma concentration-time profiles were obtained in patients from PANORAMA-1 (n = 12) and B2207 (n = 12) trials. Overall response rates (ORR) and major adverse events (AE) by panobinostat exposure were investigated in the B2207 trial. Panobinostat PK data from combination trials were contrasted with data from single-agent studies. RESULTS: At maximum tolerated dose (MTD), the geometric mean of panobinostat area under curve from 0 to 24 h (AUC0-24) was 47.5 ng h/mL (77 % CV), and maximum plasma concentration (Cmax) was 8.1 ng/mL (90 % CV). These values were comparable with exposure data obtained in PANORAMA-1, but were 20 % lower than those without dexamethasone, and ∼ 50 % lower from single-agent trials, likely due to enzyme induction by dexamethasone. Higher levels of panobinostat exposure were associated with higher response rates and higher incidences of diarrhea and thrombocytopenia. CONCLUSIONS: Apparent panobinostat exposure-AE and exposure-ORR relationships were observed when combined with bortezomib and dexamethasone in the treatment of patients with relapsed and refractory multiple myeloma. The addition of dexamethasone facilitated best response even though plasma exposure of panobinostat was reduced. Combination with a strong enzyme inducer should be avoided in future trials to prevent further reduction of panobinostat exposure.

Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial.

BACKGROUND: Panobinostat is a potent oral pan-deacetylase inhibitor that in preclinical studies has synergistic anti-myeloma activity when combined with bortezomib and dexamethasone. We aimed to compare panobinostat, bortezomib, and dexamethasone with placebo, bortezomib, and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma. METHODS: PANORAMA1 is a multicentre, randomised, placebo-controlled, double-blind phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma who have received between one and three previous treatment regimens. Patients were randomly assigned (1:1) via an interactive web-based and voice response system, stratified by number of previous treatment lines and by previous use of bortezomib, to receive 21 day cycles of placebo or panobinostat (20 mg; on days 1, 3, 5, 8, 10, 12, orally), both in combination with bortezomib (1·3 mg/m(2) on days 1, 4, 8, 11, intravenously) and dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, 12, orally). Patients, physicians, and the investigators who did the data analysis were masked to treatment allocation; crossover was not permitted. The primary endpoint was progression-free survival (in accordance with modified European Group for Blood and Marrow Transplantation criteria and based on investigators' assessment) and was analysed by intention to treat. The study is ongoing, but no longer recruiting, and is registered at ClinicalTrials.gov, number NCT01023308. FINDINGS: 768 patients were enrolled between Jan 21, 2010, and Feb 29, 2012, with 387 randomly assigned to panobinostat, bortezomib, and dexamethasone and 381 to placebo, bortezomib, and dexamethasone. Median follow-up was 6·47 months (IQR 1·81-13·47) in the panobinostat group and 5·59 months (2·14-11·30) in the placebo group. Median progression-free survival was significantly longer in the panobinostat group than in the placebo group (11·99 months [95% CI 10·33-12·94] vs 8·08 months [7·56-9·23]; hazard ratio [HR] 0·63, 95% CI 0·52-0·76; p<0·0001). Overall survival data are not yet mature, although at the time of this analysis, median overall survival was 33·64 months (95% CI 31·34-not estimable) for the panobinostat group and 30·39 months (26·87-not estimable) for the placebo group (HR 0·87, 95% CI 0·69-1·10; p=0·26). The proportion of patients achieving an overall response did not differ between treatment groups (235 [60·7%, 95% CI 55·7-65·6] for panobinostat vs 208 [54·6%, 49·4-59·7] for placebo; p=0·09); however, the proportion of patients with a complete or near complete response was significantly higher in the panobinostat group than in the placebo group (107 [27·6%, 95% CI 23·2-32·4] vs 60 [15·7%, 12·2-19·8]; p=0·00006). Minimal responses were noted in 23 (6%) patients in the panobinostat group and in 42 (11%) in the placebo group. Median duration of response (partial response or better) was 13·14 months (95% CI 11·76-14·92) in the panobinostat group and 10·87 months (9·23-11·76) in the placebo group, and median time to response (partial response or better) was 1·51 months (1·41-1·64) in the panobinostat group and 2·00 months (1·61-2·79) in the placebo group. Serious adverse events were reported in 228 (60%) of 381 patients in the panobinostat group and 157 (42%) of 377 patients in the placebo group. Common grade 3-4 laboratory abnormalities and adverse events (irrespective of association with study drug) included thrombocytopenia (256 [67%] in the panobinostat group vs 118 [31%] in the placebo group), lymphopenia (202 [53%] vs 150 [40%]), diarrhoea (97 [26%] vs 30 [8%]), asthenia or fatigue (91 [24%] vs 45 [12%]), and peripheral neuropathy (67 [18%] vs 55 [15%]). INTERPRETATION: Our results suggest that panobinostat could be a useful addition to the treatment armamentarium for patients with relapsed or relapsed and refractory multiple myeloma. Longer follow up will be necessary to determine whether there is any effect on overall survival. FUNDING: Novartis Pharmaceuticals.