FDA Issues Complete Response Letter to Denileukin Diftitox for R/R Cutaneous T-cell Lymphoma

July 31, 2023

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The FDA has issued a complete response letter to the biologics license application seeking approval of denileukin diftitox for use in patients with relapsed or refractory cutaneous T-cell lymphoma following at least 1 previous systemic therapy.

Leonard Mazur

The FDA has issued a complete response letter to the biologics license application (BLA) seeking approval of denileukin diftitox (Lymphir; I/ONTAK) for use in patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL) following at least 1 previous systemic therapy.¹

The BLA is supported by findings from the phase 3 Study 302 trial (E777-G000-302; NCT01871727) in which the agent elicited a 36.2% (95% CI, 25.0%-48.7%) objective response rate (ORR) by independent review committee (IRC) assessment in the efficacy analysis set (n = 69).² Moreover, the median time to response (TTR) was 1.41 months, and the median duration of response (DOR) was 6.5 months (range, 3.0+ to 23.5+). The clinical benefit rate (CBR) observed with denileukin diftitox was 49.3% (95% CI, 37.0%-61.6%) in this population.²

Additionally, the investigator-assessed ORR achieved with the agent was 42.3% (95% CI, 30.6%-54.6%) in the efficacy analysis set (n = 71), with a median TTR of 1.41 months and a median DOR of 5.7 months (range, 0.7+ to 26.1+). Here, the CBR reported with the agent was slightly higher, at 53.5% (95% CI, 41.3%-65.5%).²

The regulatory agency has requested that the drug developer, Citius Pharmaceuticals, Inc., include stronger product testing, and additional controls that had been agreed on during the review of the market application.¹

No concerns regarding the safety or efficacy of the agent were cited.

“We appreciate the FDA’s expeditious review of our application. We intend to provide additional data and remain fully engaged with the FDA as we continue to work toward approval,” Leonard Mazur, chairman and chief executive officer of Citius Pharmaceuticals, Inc., stated in a press release. “We remain confident in the potential of [denileukin diftitox] to become an important addition to the treatment landscape for patients with relapsed or refractory CTCL and make a meaningful difference in their lives.”

Denileukin diftitox is a recombinant fusion protein that is comprised of the interleukin-2 (IL-2) receptor binding domain and diphtheria toxin fragments. By binding to IL-2 receptors on the cell surface, the agent causes diphtheria toxin fragments that have entered cells to hinder protein synthesis. I/ONTAK is a purified version of denileukin diftitox and a reformulation of ONTAK, which received full FDA approval in October 2008 for use in this population.³ In 2014, the original formulation was voluntarily withdrawn from the US market.

Patients who had a histopathologic diagnosis of CTCL and CD25 positivity were enrolled to the multicenter, open-label, single-arm Study 302 trial.⁴ They were required to be at least 18 years of age, to have previously received treatment for their disease, and have had a washout period of at least weeks 4 before starting treatment on the trial. They also needed to have an ECOG performance status ranging from 0 to 2 for the lead-in portion of the research, and 0 or 1 for the main study; acceptable bone marrow function; and a life expectancy of at least 3 months.

For lead-in portion of the research, investigators set out to determine the optimal dose of the agent in 21 patients who received the drug at daily doses ranging from 6 µg/kg to 15 µg/kg. A dose of 9 µg/kg daily was identified for use in the main study per the trial’s Protocol Steering Committee. In the second part of the study, 91 patients with stage I to IV CTCL received the agent at a daily dose of 9 µg/kg intravenously over the course of 1 hour for 5 consecutive days of every 21-day cycle.

The primary end point was ORR based on the global response score. Per trial protocol, if the lower limit of the 2-sided 95% confidence interval of the observed ORR exceeded 25% per IRC assessment, the drug would be determined to be efficacious and have clinical benefit in this population. Secondary and exploratory end points included progression-free survival, DOR, TTR, ORR, and safety.

Safety data proved to be consistent with what was previously observed with the original formulation of denileukin diftitox. The most common toxicities observed with the agent included nausea, fatigue, increased alanine aminotransferase, chills, and peripheral edema. No new safety signals were reported.