The FDA has placed a partial clinical hold on the TELLOMAK trial, which is evaluating the efficacy and safety of lacutamab in patients with advanced T-cell lymphoma.
The FDA has placed a partial clinical hold on the TELLOMAK trial (NCT03902184), which is evaluating the efficacy and safety of lacutamab (IPH4102) in patients with advanced T-cell lymphoma.1 Enrollment of new patients has been suspended in the study, except for in Italy where the trial has been suspended.
Innate Pharma SA, the developer of lacutamab, stated in a press release that it has been in discussions with regulatory authorities regarding Good Manufacturing Practice (GMP) deficiencies at their manufacturing subcontractor site, which manages the fill and finish operations of the drug’s clinical trials. Innate Pharma’s subcontractor, Rentschler Fill Solutions GmbH (RFS), unilaterally withdrew its Certificate of Conformity of batches it produced, including the batch of lacutamab that was currently used in the TELLOMAK study; RFS also filed for bankruptcy.
“The Company’s utmost priority is to ensure patient safety,” Innate Pharma stated in a press release. “An extensive internal and third-party analysis concluded that there was no evidence that the integrity of the product was questioned.”
Patients who are currently enrolled on the trial are permitted to continue treatment, “due to the high degree of unmet medical need, once patients are re-consented,” the company stated in the press release. No new patients are allowed to enroll on the study until there is a new GMP-certified batch. Innate Pharma also stated that it is working to transfer the lacutamab fill and finish manufacturing to another contract manufacturing organization, and that it anticipates a new clinical GMP-certified batch to be available in the second half of 2020.
“The FDA did not cite any safety issues related to the trial medication,” Innate Pharma continued in its statement. “This is consistent with the review conducted by the Independent Data Monitoring Committee (IDMC), which concluded there were no new, unexpected safety issues related to lacutamab, and the product appeared to be well tolerated among current patients enrolled in the trial. In addition, the IDMC determined it would be acceptable to continue recruiting additional patients in the TELLOMAK trial, if agreed by regulatory agencies.”
Lacutamab is a first-in-class anti-KIR3DL2 humanized cytotoxicity-inducing antibody designed as a potential treatment for patients with cutaneous T-cell lymphoma (CTCL). KIR3DL2 is expressed by approximately 65% of patients across all subtypes of CTCL; in certain CTCL subtypes, such as Sézary syndrome, it is expressed in up to 85% of patients, according to Innate Pharma. In January 2019, the FDA granted fast track designation to lacutamab for the treatment of adult patients with relapsed/refractory Sézary syndrome who have received ≥2 prior systemic therapies. It was also granted orphan drug status by the FDA and European Commission.
In the international, open-label, multi-cohort, phase II TELLOMAK trial, investigators are evaluating lacutamab alone and in combination with chemotherapy in patients with advanced T-cell lymphomas.
The expected recruitment is 250 patients; the agent would be given as monotherapy in patients with Sézary syndrome who have received ≥2 prior treatments, including mogamulizumab (n = 60), as monotherapy in patients with mycosis fungoides (MF) who have received ≥2 prior therapies (n = 90), and in combination with standard gemcitabine and oxaliplatin in patients with peripheral T-cell lymphoma (PTCL) who have received ≥1 prior treatment.
There are 2 cohorts in each of the MF and PTCL groups: patients whose tumors express KIR3DL2 and nonexpressers. Both cohorts follow a Simon 2-stage design that will be terminated should lacutamab be considered futile. Additionally, the Sézary syndrome arm of the trial could be a registrational arm, the company stated.
The primary endpoint is objective response rate (ORR); secondary endpoints include treatment-emergent adverse events, quality of life, ORR via central review, ORR lasting ≥4 months, progression-free survival, and overall survival.
The company also added that is awaiting final feedback from the National Agency for the Safety of Medicines and Health Products in France.
“At this point in time, the Company maintains its partial clinical hold guidance globally as it obtains more information from additional regulatory authorities,” Innate Pharma stated in the press release. “The Company will provide a further update in due course.”
Phase I data of lacutamab previously demonstrated encouraging clinical activity in patients with relapsed/refractory CTCL, including those with Sézary syndrome.2 In the international, first-in-human, open-label, phase I trial, investigators explored the agent in dose-escalation and cohort-expansion parts. Patients had an ECOG performance status of 0 to 2, were aged ≥18 years, and had received ≥2 prior systemic therapies.
Using an accelerated 3+3 design, investigators administered lacutamab intravenously to patients at 1 of 10 dose levels ranging from 0.0001 mg/kg to 10 mg/kg. Patients had Sézary syndrome (n = 35), MF (n = 8), and primary CTCL (n = 1).
No dose-limiting toxicities were reported in the dose-escalation phase, and the study’s safety committee recommended a flat dose of 750 mg for the cohort-expansion phase, which corresponded to the maximum-administered dose.
At a median follow-up of 14.1 months, the confirmed global ORR was 36.4% (95% CI, 23.8-51.1); the ORR in patients with Sézary syndrome was 43% (95% CI, 28.0-59.1).
Regarding safety, the most common adverse events (AEs) overall (n = 44) were peripheral edema (27%) and fatigue (20%), all of which were grades 1/2. The most common grade ≥3 AE was lymphopenia (7%). One patient developed fulminant hepatitis 6 weeks after lacutamab discontinuation, which was potentially related to treatment; the patient, who had evidence of human herpes virus-6B infection, subsequently died.