Ocifisertib Receives Orphan Drug Designation From FDA for AML


An orphan drug designation has been granted by the FDA to ocifisertib as a potential treatment option in acute myeloid leukemia.

Ocifisertib Receives Orphan Drug Designation From FDA for AML

Ocifisertib Receives Orphan Drug Designation From FDA for AML

Ocifisertib (CFI-400945 fumarate) received an orphan drug designation from the FDA as a potential treatment option for patients with acute myeloid leukemia (AML), according to an announcement from Treadwell Therapeutics.1

The safety and tolerability of the PLK4 inhibitor in patients with relapsed or refractory AML or myelodysplastic syndrome (MDS) is being explored in a phase 1 study (NCT03187288).2 The safety, efficacy, pharmacokinetics, and pharmacodynamics of the agent are also being evaluated with and without azacitidine (Vidaza) in patients with AML, MDS, and chronic myelomonocytic leukemia (CMML) in another phase 1/2 study (NCT04730258; TWT-202).3

“The FDA’s decision to grant orphan drug designation, along with the previous FDA fast track designation for ocifisertib underscores Treadwell’s dedication to addressing this patient population with few treatment options. Patients with relapsed and/or refractory AML, in particular, TP53-mutated disease suffer poor overall survival and represent a high unmet clinical need,” Roger Sidhu, MD, acting chief executive officer of Treadwell, stated in a press release.1 “We look forward to advancing ocifisertib in partnership with investigators, regulators, patients, and their families for those with limited treatment options in tough-to-treat AML.

PLK4 is an enzyme that is needed for cancer cells to divide and multiply in the presence of increased chromosome count; it also regulates centriole duplication.4 The enzyme is commonly overexpressed in cancer cells and is linked with poor survival outcomes. PLK4 inhibition intensifies genomic instability in cancer cells which leads to their death. Ocifisertib has demonstrated single-agent activity in both solid and liquid tumors.

The early-phase, open-label, dose-escalation study sponsored by the University Health Network, Toronto, enrolled patients with relapsed or refractory AML or MDS who met select criteria for previous treatments.2 Patients needed be at least 18 years of age, have an ECOG performance status of 0 to 2, and a life expectancy of 3 months or more. They also needed to have an acceptable circulating blasts count and laboratory blood and urine test results.

If they received anticancer treatment within 2 weeks or 5 half-lives before study drug initiation or they had not recovered from adverse effects (AEs) linked with prior therapies, they were excluded. Patients also could not have known active extramedullary central nervous system AML, a secondary cancer requiring therapy, or known active human immunodeficiency virus, hepatitis B virus, or hepatitis C virus.

Study participants were given oral ocifisertib at daily doses of 64 mg/kg, 96 mg/kg, 128 mg/kg, 160 mg/kg, 192 mg/kg, or 224 mg/kg. Treatment continued until unacceptable tolerability or progressive disease.

The key primary outcome measures comprise examinations of the frequency and severity of treatment-emergent AEs, the highest tolerated dose of the agent, and the recommended phase 2 dose of the agent. A key secondary outcome measure is identifying the number of patients who respond to the agent utilizing International Working Group response criteria.

The phase 1b/2 TWT-202 study utilizes a 3+3 dose-escalation design and Simon 2 stage expansion.3,5 The first part of the trial includes patients with relapsed and/or refractory AML, MDS, or CMML following more than 1 prior therapy. Those with MDS or CMML are required to have progressed or not have responded following 4 cycles of hypomethylating agents. To participate in the second part of the trial, patients needed to have relapsed and/or refractory AML, or untreated MDS or CMML. Notably, those with treatment-naive disease who are not candidates for intensive therapy were permitted.

Preliminary data from the study were presented during the 2023 ASH Annual Meeting. At a data cutoff date of May 2, 2023, a total of 26 patients had been enrolled to part 1 of the study. The median patient age was 68 years (range, 22-85), and 77% were male. Sixty-nine percent of patients had AML, 15% had MDS, and 15% had CMML.

The median number of prior therapies received was 3, with a range of 1 to 8 lines. Twenty-seven percent of patients previously underwent stem cell transplant. Most patients with AML were adverse risk by European LeukemiaNet 2022 criteria (~80%), and 6 patients had tumors harboring TP53 mutations.

Treatment was given on a 21-days-on/7-days-off schedule where patients received ocifisertib at daily doses of 32 mg (n = 5), 48 mg (n = 4), 64 mg (n = 3), 80 mg (n = 5), or 96 mg (n = 9). One dose-limiting toxicity (DLT) was reported at the 96-mg dose in the form of fungemia, gastroparesis, septic shock, and enteritis. The 28-days-on/0-days-off schedule was introduced at 96 mg, and 3 patients have been enrolled with no DLTs reported at the time of abstract publication.

In terms of efficacy, 50% of 6 response-evaluable patients with AML who received the agent at 96 mg experienced a response to the agent after 1 cycle of treatment. Moreover, 1 patient with adverse genetics in the form of complex karyotype and a TP53 mutation, achieved a complete remission with incomplete count recovery and continued to be in remission after 3 treatment cycles. Another patient with AML and adverse genetics, complex cytogenetics, and TP53 mutations who had previously received 2 regimens achieved a morphologic leukemia-free state (MLFS) and is pending count recovery. A third patient who had AML and normal cytogenetics, adverse genetics, and relapsed or refractory disease following 5 regimens and achieved an MLFS. However, complications that were not determined to be associated with ocifisertib led to dose reduction and treatment hold, and the patient relapsed.

Regarding safety, 23 serious AEs were reported and included febrile neutropenia (n = 13), sepsis (n = 5), diarrhea (n = 4), and pneumonia (n = 4). The most common treatment-emergent AEs included febrile neutropenia (n = 15), nausea (n = 11), diarrhea (n = 10), vomiting (n = 10), hypokalemia (n = 9), dyspnea (n = 8), hypophosphatemia (n = 8), anemia (n = 7), abdominal pain (n = 6), fatigue (n = 6), hypomagnesemia (n = 6), and pneumonia (n = 6). Grade 3 or higher TEAEs were experienced by 31% of patients.


  1. Treadwell announces ocifisertib, a first-in-class PLK4 inhibitor, has received orphan drug designation from US FDA for the treatment of acute myeloid leukemia. News release. February 20, 2024. Accessed February 21, 2024. https://treadwelltx.com/news/treadwell-announces-ocifisertib-a-first-in-class-plk4-inhibitor-has-received-orphan-designation-from-u-s-fda-for-the-treatment-of-acute-myeloid-leukemia/
  2. Study of CFI-400945 fumarate in patients with relapsed or refractory AML or MDS. ClinicalTrials.gov. Updated January 17, 2024. Accessed February 21, 2024. https://clinicaltrials.gov/study/NCT03187288
  3. A study of CFI-400945 with or without azacitidine in patients with AML, MDS or CMML (TWT-202). ClinicalTrials.gov. Updated February 5, 2024. Accessed February 21, 2024. https://clinicaltrials.gov/study/NCT04730258
  4. Novel targets. Treadwell Therapeutics website. Accessed February 21, 2024. https://treadwelltx.com/science/#our-toolbox
  5. Jonas BA, Yee K, Mims A, et al. Preliminary results from a phase 1b/2 open-label, multicenter, dose optimization clinical study of the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) profiles of Cfi-400945 as a single agent or in combination with azacitidine in patients (pts) with acute myeloid leukemia, myelodysplastic syndrome or chronic myelomonocytic leukemia (TWT-202). Blood. 2023;142(suppl 1):4294. doi:10.1182/blood-2023-182027
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