• CARDAMON:Carfilzomib (K) maintenance following Autologous Stem Cell Transplant (ASCT) or carfilzomib-cyclophosphamide-dexamethasone (KCd) consolidation for newly diagnosed (NDTE) multiple myeloma (MM)

      Popat, R.; Wilson, W.; Camilleri, M.; De Tute, R.; Pang, G.; Jenner, R.; Dadaga, T.; Kamora, S.; Streetly, M.; Ramasamy, K.; et al. (2021)
      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.
    • TRIOC-A randomised phase II trial to examine MVA-5T4 vaccine in patients with relapsed asymptomatic epithelial ovarian, fallopian tube or primary peritoneal cancer

      Michael, A.; Wilson, W.; Harrop, R.; McNeish, I.; Lord, R.; Blount, D.; Clamp, Andrew R; Feeney, M.; Farrelly, L.; Hanna, L.; et al. (2020)
      Background: Continued surveillance is often used in patients with ovarian cancer who have asymptomatic relapse. Immunotherapy directed at 5T4, an onco-foetal tumour antigen (TAA) may contain the relapse and delay the need for further chemotherapy. MVA-5T4 (TroVax ) consists of an attenuated Vaccinia Virus (Modified Vaccinia Ankara, MVA) containing the gene encoding for the human TAA, 5T4. We examined whether MVA-5T4 vaccination can delay tumour progression of relapsed ovarian cancer. Methods: The trial started as a double-blind randomised phase II trial with placebo, but an unforeseen interim trial suspension led to limited drug supply, so it later changed to a single arm study. Eligible patients had asymptomatic (CA-125 rise onlyor low volume disease) relapsed ovarian cancer; 6 months since prior chemotherapy and ECOG 0-1. Primary endpoint was progression rate at 25 weeks (PR-25): confirmed progression using RECIST and immune-related response criteria, clinical intervention for symptoms of progression or death. We aimed to detect an improvement in PR from 70% (placebo) to 50% (MVA-5T4). Results: 94 eligible patients were recruited from 12 centres (11/13 to 11/17). There were 69 randomised patients, 25 were added in a single arm study. Median age was 65 years (range 42 to 82), and median time since prior chemotherapy 18 months (7 to 86); median follow up 34 months (2 to 46). 22 patients were withdrawn from trial treatments during the suspension. The PR-25 was similar: 80.0% (MVA-5T4) vs 82.9% (placebo) p-0.74. In the pre-specified per protocol analysis (patients who had 5 treatment injections and were unaffected by trial suspension), the corresponding rates were 78.8% and 90.9%. Median PFS was the same in both arms (3.0 months). Median time to clinical intervention appeared to be improved with MVA-5T4 9.7 (6.7- 14.3) vs 6.1 (5.1-8.6), p-0.14. 27.6% (MVA-5T4) vs 22.9% (placebo) had a grade 3-4 adverse event. QoL was also similar in both arms. Conclusions: MVA-5T4 vaccination in patients with asymptomatic relapse was welltolerated but did not improve the progression rate at 25 weeks. Further immunological analysis to identify subsets of patients who might benefit from MVA-5T4 is ongoing.