A Pilot Study of CPX-351 (Vyxeos ^©) for Transplant Eligible, Higher Risk Patients with Myelodysplastic Syndrome

Introduction: CPX-351 (Vyxeos ^©; daunorubicin and cytarabine liposome for injection) is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar drug ratio that is FDA approved for treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. Secondary AML is clinically and biologically similar to MDS, sharing many of the same genetic mutations. We hypothesize that CPX-351 therapy may result in deeper responses than traditional therapy with hypomethylating agents, with acceptable tolerability, and translate into better outcomes in the MDS population. This is a multicenter, dose-escalation and safety expansion study (NCT03572764) to investigate induction and consolidation therapy with CPX-351 in a transplant eligible, higher risk MDS population.

Methods: Two dose levels were investigated in the dose-escalation portion. Induction Dose Level 1: (daunorubicin 29 mg/m ² and 65 mg/m ² cytarabine) liposome on days 1, 3, 5; and Induction Dose Level 2: (daunorubicin 44 mg/m ² and 100 mg/m ² cytarabine) liposome on Days 1, 3, 5.

The primary objectives were to evaluate safety and to determine the dose-limiting toxicities (DLTs) and recommended Phase 2 dose (RP2D). DLTs were assessed during the induction period (up to day 56 to evaluate for prolonged myelosuppression). Additionally, a dose expansion (for up to 20 treated patients) was performed at the RP2D.

After induction, patients could receive up to two cycles of consolidation per dose level: Dose Level 1, (daunorubicin 14.3 mg/m ² and 32 mg/m ² cytarabine) liposome on Days 1 and 3; or Dose Level 2 (daunorubicin 29 mg/m ² and 65 mg/m ² cytarabine) liposome on Days 1 and 3. After induction, the patient could proceed to alloHCT at any time at the discretion of the treating physician.

Key eligibility criteria included MDS patients who were naïve to hypomethylating agents, aged 18-70 years, an IPSS-R score > 3 (Intermediate, High or Very High Risk), ≥ 5% bone marrow myeloblasts, and suitable candidates for cytotoxic induction therapy and allogeneic hematopoietic cell transplant (alloHCT).

Key secondary endpoints were day 30 and 60 post-induction mortality, the proportion of patients proceeding to alloHCT, and response assessments per IWG 2006 criteria.

Results: As of abstract submission, 19 patients have been treated and dose escalation is complete. The dose escalation portion included 12 patients (Dose Level 1, n=6; Dose Level 2, n=6), and the safety expansion to date includes 7 patients treated at Dose Level 2.

The median age was 64 years (range, 18-68), 67% were female, and the IPSS-R risk categories were as follows: intermediate (n=1, 5%), high (n=10, 53%) and very high (n=8, 42%).

There were no DLTs in either Dose Level 1 or Dose Level 2, and Dose Level 2 was selected for safety expansion. Treatment-emergent adverse events (TEAEs) were evaluated in the 18 patients who had completed induction (Table). The most common TEAEs were hematologic, as expected. The most common non-hematologic TEAEs were febrile neutropenia (n=13, 72.2%), hypertension (n=9, 50%), and sepsis (n=5, 27.8%).

SAEs included febrile neutropenia (n=5), sepsis (n=2), lower GI hemorrhage (n=2, two instances in the same patient), atrial fibrillation (n=1), pneumonitis (n=1), and catheter related infection (n=1).

To date, the 30 and 60 day mortality is 0% and 5% (n=1), respectively, with the 1 death unrelated to therapy and due to progression of disease to AML. Of the 19 patients, 13 have received alloHCT with 4 still potentially alloHCT candidates. Of response evaluable pts (n=18, 1 pt pending response evaluation at data cutoff), the overall response rate was 78% with best overall responses of CR (n=4), mCR (n=10), stable disease (n=2), progressive disease (n=2) and pending (n=1). Of the 10 patients with mCR, 3 also had hematologic improvements.

Conclusions: CPX-351 (daunorubicin 44 mg/m ² and 100 mg/m ² cytarabine) liposome on Days 1, 3, 5, has demonstrated a tolerable safety and promising efficacy profile when used in a transplant eligible, higher risk MDS population, warranting further study. Updated safety and efficacy outcomes will be presented at the meeting.

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