Safety and Tolerability of E7777 (improved purity Denileukin diftitox [ONTAK]) in Patients with Relapsed or Refractory Cutaneous T-Cell Lymphoma: Results from Pivotal Study 302

Introduction: Denileukin diftitox (Dd), a recombinant fusion protein composed of diphtheria toxin fragments and human interleukin-2 was approved and marketed (as ONTAK) in the US from 1999-2014 for the treatment of relapsed/refractory CTCL. Manufacturing improvements (to decrease the presence of misfolded and aggregated proteins) resulted in a new, more bioactive formulation, E7777. It is considered a new drug by the FDA and required a new registrational clinical trial. Study 302 (NCT01871727) is a multicenter, open-label, single-arm registrational trial in which the primary efficacy and safety of E7777 were assessed. Here, we report the safety results of E7777.

Methods: E7777 was given at 9 mcg/kg/day for 5 days every 21 days up to 8 cycles in patients with relapsed/refractory CTCL. Key inclusion/exclusion criteria: histopathologic diagnosis of CTCL; ECOG PS 0 or 1; no prior exposure to ONTAK. Evaluation of safety included incidence and severity of treatment-emergent AEs (TEAEs), and adverse events of special interest (AESIs). Key AESIs include capillary leak syndrome (CLS), infusion reaction, visual impairment (these three AEs were listed as Box warnings in the ONTAK label); and hepatotoxicity.

Results: The Primary Efficacy endpoint, ORR (95% CI) by IRC, was 36.2% (95% CI: 25.0%, 48.7%), with 8.7% achieving a CR; detailed efficacy data will be presented in a separate abstract. In the subset of patients with Stage I-III disease (n=69), the median age was 64 years and the median number of E7777 cycles received was 6 (range 1 to 42); 66 patients had mycosis fungoides and 3 had Sezary syndrome, and 39 (57%) had disease of stage IIb or worse.

The most common TEAEs were nausea (43.5%); fatigue (31.9%); and increased ALT, chills, and peripheral edema (27.5% each). Thirty patients (43.5%) had a Grade ≥3 TEAE (90% Grade 3; 10% Grade 4)). The most common serious adverse events (≥ 5%) were capillary leak syndrome (10%) and infusion reactions (9%). Overall, the mean numbers of TEAEs per subject were higher in the first 1 to 2 treatment cycles.

Most patients [92.8%] had at least 1 AESI (mostly Grade 1/2). Overall, 22 patients (31.9%) experienced AESIs that were Grade ≥3; (7.2%) had drug discontinuation; (4.3%) had drug dose reduction, and (26.1%) had drug dose interruption.

Fourteen patients (20.3%) had CLS. CLS was defined as the occurrence of at least 2 of the following: hypotension, edema, or serum albumin < 3.0 g/dL. CLS was Grade 1 in 2.9%, Grade 2 in 11.6%, Grade 3 in 4.3%, and Grade 4 in 1.4%. Nine patients (13.0%) underwent drug modification: (4.3%) discontinued E7777; and (10.1%) had either dose reduction or temporary dose interruption. CLS typically occurred in the first 1/2 cycles. Risk/severity of CLS was mitigated by fluid management; confirmation of serum albumin levels (≥ 3.0 g/dl); close monitoring of weight, edema, and BP; early drug interruption; and rapid initiation of diuretic therapy on recovery.

Fifty-one patients (73.9%) had an AESI related to infusion reaction. Grade 1 in 43.5%, Grade 2 in 26.1%, and Grade 3 in 4.3%. One patient (1.4%) had study drug discontinuation, and (11.6%) had either study drug dose reduction or interruption. In the event of infusion-related reactions, systemic corticosteroids may be added to premedication for subsequent E7777 infusions.

Nine patients (13.0%) had an event related to visual impairment; all were AEs of blurred vision, which was Grade 1 in 11.6% and Grade 2 in 1.4%; no Grades 3, 4, or 5. One patient (1.0%) had drug interruption; no events led to study drug dose reduction.

Twenty-five patients (36.2%) had AESI related to hepatoxicity. The TEAEs were Grade 1 in 17.4%, Grade 2 in 7.2%, Grade 3 in 11.6%, and no Grade 4/5. The majority of hepatic adverse events were elevations in transaminases that occurred within the first or second cycle, resolved without medical intervention, and did not require treatment discontinuation.

Conclusion: No new safety signals were observed with E7777 when compared to the safety profile of ONTAK. There is no evidence of cumulative toxicity. Most patients had at least 1 TEAE which were mostly Grade 1/2. Specific AESIs: CLS, infusion reactions, and visual impairment (prior ONTAK Box warnings) were mostly Grade 1/2 and effectively managed. Overall, E7777 was well-tolerated with the use of pre-medications, close patient monitoring, and prompt initiation of supportive measures and drug management.