Regulatory Decision Summary for Trecondyv

The MC-FludT.14/L trial II study was the pivotal study included in this NDS-priority review. It was a randomized, parallel-group, open label, multicenter, international, group-sequential phase 3 non-inferiority trial to evaluate efficacy and safety of treosulfan-based conditioning versus a busulfan-based reduced intensity conditioning (RIC) treatment prior to allogeneic HSCT.

Adult patients were initially exposed to a dose of treosulfan of 14g/ m²/d x 3 days (study MC-FludT.14/L Trial I). The selection of the 14g/ m²/d dose was supported by data obtained during the MC-FludT.6/L study (a phase 2, single arm supportive study). It showed that treosulfan, as conditioning regimen, was similarly well tolerated and effective at either 10, 12 or 14 g/m²/d in patients with hematologic malignancy not eligible for standard conditioning therapies.

The sponsor had to stop study MC-FludT.14/L Trial I due to a higher incidence of severe infectious complications within 100 days after transplantation caused by a significant prolonged neutropenia. Study MC-FludT.14/L Trial II was started using a reduced dose for the test arm of 10 g/ m²/d instead of the 14 g/m²/d initially used. It should be noted that patients included in the pivotal MC-FludT.14/L trial II were adults patients diagnosed with AML or MDS that were not eligible to standard conditioning therapies. Adults with other malignancies or with non-malignant diseases as well as children were not included in this trial.

The primary end-point of study MC-FludT.14/L trial II was event free survival (EFS). Events were defined as disease progression, graft failure or death. Key secondary end-points include engraftment, chimerism, non-relapse mortality (NRM), transplant-related mortality (TRM), GvHD-free and Relapse/Progression-free Survival (GRFS), chronic GvHD-free and relapse/progression-free survival (CRFS).

Following the second pre-specified interim analysis of study MC-FludT.14/L Trial II, recommendation was made to stop recruiting patients since the primary objective of the trial, the proof of non-inferiority in 2-year EFS of treosulfan compared to busulfan, had been achieved. Recruitment was stopped and a total of 570 patients had been included in the final report.

Event free survival 24 months after HSCT was estimated at 51.2% (95% confidence interval [CI]: 45.0, 57.0) for the busulfan treatment group, and 65.7% (95% CI: 59.5, 71.2) for the treosulfan treatment group for the full analysis set of patients (FAS). The hazard ratio (HR) was 0.64 with an adjusted event-driven CI of (0.42, 0.97) and was in favour of the treosulfan treatment group. Similar results were obtained with the per protocol set of patients (PPS).

NRM and TRM at 24 months favored treosulfan versus busulfan and were statistically significant. NRM was estimated at 20.4% for busulfan and 12.0% for treosulfan. TRM was estimated at 24.1% for busulfan and 12.8% for treosulfan.

Chimerism was estimated at day +28 and day +100. In both cases, the incidence of complete donor-type chimerism was higher and statistically significant in the treosulfan arm compare to the busulfan arm (83.3% busulfan vs 93.2% treosulfan at day +28 and 80.2% vs 86.1% at day +100).

Other secondary end-points such as GRFS and CRFS at 24 months were also favorable for the Trecondyv group.

The most frequently reported treatment emergent adverse event (TEAE) preferred terms (> 20% in the Trecondyv group) were mucositis oral, nausea, vomiting, fever, edema limbs, and infections.

TEAE preferred terms for which the incidence differed by > 2% between treatment groups were vomiting, pain, bone pain, arthralgia, rash maculo-papular, blood bilirubin increased, AST increased, ALT increased, hypotension, hypomagnesemia, febrile neutropenia, and cardiac events.

Treatment-related Grade 3 or 4 TEAE preferred terms for which the incidence differed by > 2% between treatment groups were ALT increased, febrile neutropenia, infections, and metabolism and nutrition disorders. Dose modifications were not performed during the trial.

Risk mitigation to address the identified risks associated with the use of Trecondyv for the cardiovascular, respiratory, neurologic, and hepatic function were added to the proposed product monograph (PM) for Trecondyv. In addition, the PM outlines that administration of Trecondyv should be supervised by a physician experienced in conditioning treatment followed by alloHSCT.

Two single arm studies with treosulfan as conditioning regimen in pediatric patients with malignant and nonmalignant diseases, respectively, were conducted. However, due to major limitations such as interim nature of one study, lack of proper comparator and lack of adequate optimal dose determination, the safety and efficacy based on those studies could not be established. Although no pediatric study was included in the Trecondyv product monograph, a pediatric indication at a dosage of 10 g/ m²/d for pediatric patients older than 1 year old with AML or MDS was granted based on the pivotal study MC-FludT.14/L and similar pharmacokinetics data noted between adults and children. On the other hand, children of less than 1 year old should not be exposed to treosulfan even at a dose of 10 g/ m²/d since it would correspond approximatively to a dose of 14 g/ m²/d in term of AUC.

Overall, the MC-FludT.14/L trial II study has reached its primary end-point, EFS. Secondary end-points also favored Trecondyv over the busulfan treatment. The safety profile of Trecondyv is consistent with its cytotoxic and myelosuppressive characteristics. Most of the TEAEs related to the treatment with Trecondyv could be mitigated by supportive care. Therefore, the benefit harm uncertainty profile of treosulfan is considered acceptable in adult patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) at increased risk for standard conditioning therapies.