FDA Lifts Partial Clinical Hold on TELLOMAK Trial With Lacutamab in Advanced T-Cell Lymphomas

The FDA has lifted a partial clinical hold that had been placed on the phase 2 TELLOMAK trial (NCT03902184), which is examining the safety and efficacy of lacutamab (IPH4102) in patients with advanced T-cell lymphoma, according to an announcement from the drug’s developer, Innate Pharma SA.¹

The decision is based on a quality assessment of a new Good Manufacturing Practice (GMP)–certified batch that has been successfully manufactured for the clinical development program for the agent, which includes TELLOMAK.

In light of this feedback, the commercial stage oncology-focused biotech company can now recommence the recruitment of patients in the United States with relapsed/refractory Sézary syndrome and mycosis fungoides (MF) who have previously received at least 2 systemic therapies.

Operational measures are being made to reactivate the clinical trial sites in the United States. Authorities in Spain, Italy, and Germany are being consulted to resume the trial in those countries, as well, in light of this decision.

“We are pleased that the FDA has approved the new clinical batch for the TELLOMAK trial, and we can resume enrollment of patients with Sézary syndrome and MF given the importance of novel and effective treatment options needed for these patient populations,” Pierre Dodion, MD, executive vice president and chief medical officer of Innate Pharma, said in a press release issued by the company. “We’re confident in our ability to supply lacutamab in this important trial moving forward and look forward to reactivating the trial globally as quickly as possible.”

In January 2020, the FDA made the decision to place a partial clinical hold on TELLOMAK, and as such, enrollment of new patients onto the study had been suspended.² In Europe, the national regulatory authorities in Spain, Italy, and Germany temporarily suspended the trial. French and UK regulatory authorities agreed to resume recruitment for the trial for earlier this year.

Innate Pharma SA issued a statement saying that it had been in discussion with regulatory authorities regarding GMP deficiencies at their manufacturing subcontractor site, which runs the fill and finish operations of the lacutamab clinical vials for the trial. The subcontractor, Rentschler Fill Solutions GmbH (RFS), withdrew its Certificate of Conformity of batches it produced, including the batch of lacutamab that had been used in the study. At that time, RFS also filed for bankruptcy.

Lacutamab, a first-in-class anti-KIR3DL2 humanized cytotoxicity-inducing antibody, was developed to serve as a potential therapeutic option for patients with cutaneous T-cell lymphoma (CTCL). Notably, more than half of patients across all subtypes of CTCL express KIR3DL2; in fact, in certain disease subtypes such as Sézary syndrome, KIR3DL2 is expressed in 85% of patients, according to Innate Pharma.

The agent was granted a fast track designation for use in adult patients with relapsed/refractory Sézary syndrome who had previously received at least 2 systemic therapies. Lacutamab also received orphan drug status from both the FDA and the European Commission.

In the open-label, multicohort TELLOMAK trial, investigators are assessing the use of lacutamab both alone and in combination with chemotherapy in patients with T-cell lymphomas. Investigators expect to enroll a total of 250 participants.

The agent will be administered as a monotherapy in patients with Sézary syndrome who had previously received at least 2 systemic therapies, including mogamulizumab (n = 60); as a single agent in patients with MF who had been given at least 2 prior therapies (n = 90); and in combination with a standard chemotherapy regimen comprised of gemcitabine and oxaliplatin in patients with peripheral T-cell lymphoma (PTCL) who had received at least 1 prior treatment.

The MF and PTCL arms are comprised of 2 cohorts each: those with KIR3DL2-expressing tumors and those without. Both of these cohorts are designed such that they will be terminated if the drug is determined to be futile. Additionally, the Sézary syndrome arm of TELLOMAK could be a registrational arm, according to Innate Pharma.

The primary end point of the trial is objective response rate (ORR), with secondary end points comprised of treatment-emergent adverse events, quality of life, ORR per central review, ORR lasting 4 months or longer, progression-free survival, and overall survival.

Early data with the agent in patients with relapsed/refractory CTCL were reported from a first-in-human, open-label phase 1 trial.³ In the trial, the agent was examined in 2 parts: dose-escalation and cohort-expansion. To be eligible for participation, patients had to have an ECOG performance score ranging from 0 to 2, had to have been at least 18 years old, and had received 2 or more prior systemic therapies.

In a 3+3 design, lacutamab was delivered intravenously at 1 to 10 dose levels that ranged from 0.0001 mg/kg to 10 mg/kg. A total of 35 patients had Sézary syndrome, 8 patients had MF, and 1 patient had primary CTCL. In the dose-escalation phase of the trial, no dose-limiting toxicities were observed and the trial’s safety committee recommended a flat dose of 750 mg to be examined in the cohort-expansion phase; this corresponded with the maximum-administered dose.

Results showed a confirmed global ORR of 36.4% (95% CI, 23.8-51.1) at a median follow-up of 14.1 months; in patients with Sézary syndrome, the ORR was 43% (95% CI, 28.0-59.1).

With regard to safety, the most common toxicities reported with the agent were peripheral edema (27%) and fatigue (20%), which were grade 1 or 2 in severity. The most common grade ≥3 or higher adverse event was lymphopenia (7%). Six weeks following lacutamab discontinuation, 1 patient developed hepatitis, a toxicity that was determined to potentially be associated with the treatment; this patient subsequently died.

References

1. US Food and Drug Administration lifts partial clinical hold on lacutamab TELLOMAK trial in advanced T-cell lymphomas. News release. Innate Pharma, SA. June 24, 2020. Accessed June 24, 2020. bit.ly/37XlLcp.
2. Innate Pharma provides update from regulatory agencies on lacutamab TELLOMAK trial. News release. Innate Pharma, January 9, 2020. Accessed June 24, 2020. bit.ly/36Fhjh0.
3. Bagot M, Porcu P, Marie-Cardine A, et al. IPH4102, a first-in-class anti-KIR3DL2 monoclonal antibody, in patients with relapsed or refractory cutaneous T-cell lymphoma: an international, first-in-human, open-label, phase 1 trial. Lancet Oncol. 2019;20(8):1160-1170. doi: 10.1016/S1470-2045(19)30320-1