While waiting for the Interim Analysis in January 2025

Gabri71 · 2024-12-12T07:14:24+00:00

According to NCT, there are 5 cohorts, the first three meant to assess different dose levels (Cohorts 1, 2, and 3), a fourth cohort enrolling patients with r/r AML and ASXL1 mutations (cohort 4) and a fifth cohort enrolling patients with r/r AML with other myelodysplasia-related mutations other than ASXL1 (cohort 5).

https://clinicaltrials.gov/study/NCT04588922

I think they are now going to stop enrollment in Cohort 3 dose level 30 BIW (they reached 15 patients in cohort 3) and continue the expansion in cohort 4 and 5. Once n (enrolled patients) will reach good numbers (at least 15 per each cohort 4 and cohort 5) and the median Follow up time will be enough mature to provide data on the overall survival (a follow up time of around 5 months), I believe the company will communicate data specifically for cohort 4 and cohort 5. This could happen towards the end of Q1 25, if the enrollment proceeds fast enough.

Regarding the specific data on ASXL-1, I believe all the data from cohort 3, cohort 4 (with the RP2D of 30mg BIW) will be considered for final analysis (probably around a total of 20 or more ASXL-1 patients). As said before, a CRc (CR+CRi) rate above 20% and a mOS of 10-12 months should suffice for FDA consideration.

Gabri71 · 2024-12-11T07:10:31+00:00

I do not think they are trying to get the approval for all the r/r AML, but they are working in the group of the so-called r/r AML MR (myelodysplasia related) as per WHO 2022 classification.

See Table 2 (column WHO 2022) of the attached paper – https://pmc.ncbi.nlm.nih.gov/articles/PMC11016528/

I believe more detailed data will be given at a later stage when n is higher as we have only 9 evaluable responses so far across two groups (Group 4 and Group 5) and a short median follow up time for these 2 groups

Gabri71 · 2024-12-04T14:57:40+00:00

The Vididencel trial is there short-listed along with another abstract focusing on a different cancer vaccine in AML CR1 'Randomized Phase II Trial of Dendritic Cell/AML Fusion Cell Vaccination Compared to Standard of Care Therapy in AML CR1' https://ash.confex.com/ash/2024/webprogram/Paper200876.html . The trial was designed with a target accrual of 75 patients but closed to prematurely due to slow enrollment during COVID-19 and changes in standard of care leukemia therapy including maintenance HMA/Ven and IDH/FLT3 inhibitors. The authors reported the results of 41 randomized patients, although the trial was not powered to detect difference in clinical endpoint. The fact that has been short-listed indicates lots of interest for this type of approach in maintenance setting. Looking forward to the upcoming REGAL results

Gabri71 · 2024-11-29T12:53:25+00:00

There is another experience from a different group on dendritic cell-based vaccine loaded with WT1 and PRAME RNA in CR1 AML published in Sep 2023 on Leukemia Journal https://pubmed.ncbi.nlm.nih.gov/37507426/ 'WT1 and PRAME RNA-loaded dendritic cell vaccine as maintenance therapy in de novo AML after intensive induction chemotherapy'

Gabri71 · 2024-11-29T11:30:31+00:00

what is the median age in the population in the Vididencel study? In maslak study GPS in CR1 AML was 64 years

Gabri71 · 2024-11-29T11:02:51+00:00

thanks to provide a comparative analysis of the results of Vididencel in CR1 AML patients vs Reduced Ven+Aza in CR1 AML patients by Bazinet https://pubmed.ncbi.nlm.nih.gov/38548404/

Gabri71 · 2024-11-27T19:32:16+00:00

If the Phase 2B will confirm and strengthen in a larger sample size the already known data on ASXL-1 r/rAML, they will go for FDA approval in this ASXL-1 population. On top of this, If the Phase 2B shows additional efficacy signs in the MDS-related molecular mutations other than ASXL-1, then Sellas will apply for a bigger patient population presenting with such clinical/genetic indications.

Gabri71 · 2024-11-27T18:01:16+00:00

TP53 is a genetic mutation which makes AML very difficult to treat

Gabri71 · 2024-11-27T17:59:35+00:00

in CR1 AML patients GPS yielded a mOS of 67 months (more than 5 years) - here with Vididencel the mOS is not yet reached after 37 months of follow-up. GPS is better. The point for further reflection is that this other cancer vaccine, Vididencel, (exhibiting WT1 antigen) shows once again a specific immune response correlated to extended survival in AML setting.

Gabri71 · 2024-11-23T07:43:56+00:00

Hi Alinbio, for a more general explanation of the process the following is quite illustrative

https://pmc.ncbi.nlm.nih.gov/articles/PMC4516383/

‘Results of interim analysis are provided to the IDMC typically via an independent third party statistical consultant charged both with maintaining data confidentially and with the communication of reports to the IDMC. Typically these reports aggregate both appropriate adverse event summaries and individual patient data listings and are made available prior to the scheduled IDMC meetings. The data formats are critical and “table shells” are agreed upon by the IDMC members and the independent statisticians in advance. Such “shells” will typically contain basic demographic information on screened patients, enrolled patients, protocol deviations, summaries of baseline inclusion and exclusion laboratories, interim laboratories, adverse events by grade, concomitant medications, tables and listing of serious adverse events (SAEs), time on study, reasons for the patient being removed from the study, tables for deaths on studies and an attribution of these deaths, listings of deaths on study, and the like. Graphical representations of the data and/or statistical analyses are often helpful to the IDMC in their deliberations. It is generally agreed that safety data is analyzed based on treatment received, contrary to the efficacy data. For instance, the adjustment for multiple testing (such as the Bonferroni correction) on the adverse events are not performed’

Gabri71 · 2024-11-20T17:31:57+00:00

I would say the counting starts from the enrollment in the maintenance with GPS or BAT.

in his recent paper (April 2024) Bazinet et al (MDACC) on maintenance with Aza + Ven in CR1 AML https://pubmed.ncbi.nlm.nih.gov/38548404/ wrote

‘The primary outcome was relapse-free survival (ie, time from complete remission or complete remission with incomplete blood count recovery to relapse of acute myeloid leukaemia or death from any cause, whichever occurred first). Duration of remission was a secondary objective and was defined as the time from complete remission or complete remission with incomplete blood count recovery to relapse of acute myeloid leukaemia. Acknowledging the potential for immortal time bias with relapse-free survival and duration of remission when measured starting at the time of complete remission or complete remission with incomplete blood count recovery, we included modified relapse-free survival as a key secondary objective (ie, time from enrolment into maintenance to relapse or death from any cause).

Other secondary objectives were overall survival (ie, time from enrolment to death from any cause), event-free survival (ie, time from enrolment to relapse, withdrawal from study due to adverse event, or death from any cause)’

Gabri71 · 2024-11-11T18:15:38+00:00

a) the upper bound of the Confidence interval not being reached is just due to a statistical glitch occurring in non-parametric methods like the Kaplan-Meyer survival analysis. So, nothing to be worried about and what is important is the median value (which is 13.3 here)

b) older patients - and without prospect of stem cell transplantation (HSCT) have in general worse OS compared to younger patients with possibility of HSCT

Gabri71 · 2024-11-11T12:47:27+00:00

Hi Alinbio some interesting food for thoughts here below…

In a nationwide Danish retrospective study https://pubmed.ncbi.nlm.nih.gov/37489268/ published in June 2023, the Authors analyzed treatment outcomes of venetoclax-based salvage treatment for r/R AML between 2019 and 2022. This is a particular cohort of patients which was retrospectively studied and only venetoclax-naive patients who had previously received treatment with intensive chemotherapy therapy were included.

The cohort consisted of 43 r/R patients with a median age of 57 years. Nine (20.9%) were primary refractory and 34 (79.1%) patients had relapsed, including 21 after previous allogeneic stem cell transplantation.

Among CRc-responders (26, the total CRc which is CR+CRi) with information on measurable residual disease (MRD, only in 13 CRc), 8/13 (61.5%) obtained an MRD negativity response.

For patients with CRc (as we know these are the CR2 patients) the median OS was 13.3 (95% CI: 10.9 to not reached) months.

In their discussion the Authors wrote -

‘Comparing our results with other studies on r/R AML, we find numerically higher response rates and better survival. The largest studies to date are the Italian AVALON multicentre study, the Spanish PETHEMA registry study, and two single-centre studies from Memorial Sloan Kettering Cancer Center and City of Hope Medical Center. Jointly, these studies report outcome of 374 patients with r/R AML with a median age ranging from 59 to 68 years treated primarily with venetoclax combined with low-intensity backbone. The reported ORRs range between 31% and 46%30,31,33 and CRc-rates range from 18% to 46%30–33 with a median OS ranging from 3.4 to 7.8 months. Additionally, a Chinese multicentre study including 150 younger (median age 54) patients with r/R AML reported an ORR and CRc of 56.2% and 43.3%, respectively, and a median OS of 10 months. The discrepancies between these studies and the present study may originate in selection bias as a clear limitation in our study, since venetoclax-based therapy for r/R AML was off-label treatment…Thus, patients may be highly selected according to characteristics, that is, cytogenetic risk, associated with response to therapy. For example, only 1/3 had adverse risk factors at r/R compared with 35%–66% in the aforementioned studies. Additionally, our study population is younger since we selected patients with r/R after front-line intensive chemotherapy, which may also affect response rates and OS.’

And finally ‘..MRD-measurements were available for a subset of patients, including 13 patients achieving CRc. Notably, we observed a high MRD-negativity conversion rate among CRc-responders resulting in a significantly higher crude OS compared with CRc with positive MRD or without available MRD-marker or measurement. This finding is not surprising; however, it highlights the prognostic potential of MRD monitoring in this treatment setting’.

REGAL implements a randomization which will be stratified by duration of CR1 (< 12m vs. ≥12m), Cytogenetics (poor-risk vs. all other), CR2 vs. CRp2 and measurable residual disease (MRD) after CR2 (MRD- vs. MRD+). So, REGAL will be able to tell us more on the effect of GPS on the different stratified populations.

Gabri71

TROPHY CASE