Pulsatile, convection-enhanced delivery of topotecan using a novel subcutaneous catheter-pump system implanted into the brain showed promising efficacy signals in patients with glioblastoma, according to findings from a phase 1b clinical trial.
Chronic, pulsatile convection-enhanced delivery (CED) of the chemotherapy topotecan (Hycamtin) using a subcutaneously catheter-pump system implanted into the brain may be a safe and effective therapy for recurrent glioblastoma, according to data from a first-in-patient phase 1b clinical trial (NCT03154996).
Investigators successfully completed chronic CED of topotecan to 5 patients from January 26, 2018, to July 8, 2019, using this system. At a median follow-up of 12 months, the median survival duration was 12 months (interquartile range [IQR], 10-17) and the median overall survival (OS) from initial diagnosis was 23 months (IQR, 21-28).
The only notable grade 3 adverse event (AE) was intraoperative supplemental motor area syndrome, which affected 1 patient. There were no grade 4 AEs. Additionally, tissue analysis following treatment yielded significantly reduced counts of proliferating tumor cells in all 5 patients.
“We used this system to significantly reduce proliferating tumor cells in patients with refractory glioblastoma, delivering multiple cycles of topotecan at high concentrations, directly into the tumor and surrounding brain over 4 weeks, without serious neurological or neurobehavioral events, thereby circumventing the limitations associated with traditional systemic delivery and with stable quality of life,” the investigators wrote. “Using MRI to non-invasively monitor the distribution of co-infused gadolinium as a surrogate for topotecan distribution, we found large and stable volumes of drug distribution effectively targeting peritumoral brain tissue where unresectable invasive tumor cells reside.”
The single-center, open-label, single-arm, phase 1b clinical trial was conducted at the Columbia University Irving Medical Center in New York and enrolled a total of 6 patients, 1 of whom was later excluded for lacking recurrent tumor according to histopathological analysis of their pre-treatment biopsy. All 5 patients who underwent treatment had IDH1 wild-type glioblastoma with tumor volumes ranging from 1.9 to 18.0 mL. All patients were White, 3 were male, and 2 were female. The median age was 56 years (IQR, 48-57).
Catheters were stereotactically implanted into the glioma-infiltrated peritumoral brain and connected to subcutaneously implanted pumps. Patients received a total of 4 infusions through this delivery system, each comprising 146 µM of topotecan at 200 µL per hour for 48 hours. A washout period of 5 to 7 days followed each infusion, and after the fourth, the tumor was radically resected. Removal of the pump-catheter occurred 4 weeks later. Investigators optimized selections of localized tumor biopsies and catheter trajectories using preoperative MRIs.
All 5 patients eventually died from tumor progression, but none of the deaths were found to be related to the treatment. Chronic CED of topotecan was generally well tolerated, with infrequent and transient complications. The most common treatment complaints included pain at the incision site (n = 5, 100%), fatigue (n = 3, 60%), and headache (n = 2, 40%), all grade 1/2 effects. Worsening of a baseline supplementary motor area syndrome and other complications affected 1 patient, but they were managed with dose reductions and other strategies, and the patient still completed treatment. The remaining 4 patients completed the protocol as intended.
Pre- and post-treatment tissue analyses revealed significant reductions in both the SOX2 labelling index (18.5% vs 25.8%; P = .031) and the Ki67 labelling index (1.4% vs 3.9%; P = .0090) among the 5 patients after treatment. CED of topotecan also resulted in reductions in glucose uptake of 17.2%, 12.7%, and 6.2% in patients 3, 4, and 5, respectively.
“The pump-tubing-catheter construct that we used was improvised from various commercial sources and was designed to be used with a skill set common to neurosurgeons,” the investigators concluded. “… Because the blood-brain barrier is bypassed by our system, new classes of drugs and targeted compounds could potentially be used, including high-molecular-weight compounds, proteins, viruses, liposomes, nanoparticles, and other biologicals that would not be feasible with systemic delivery because of toxic effects or metabolic breakdown.”
Spinazzi EF, Argenziano MG, Upadhyayula PS, et al. Chronic convection-enhanced delivery of topotecan for patients with recurrent glioblastoma: a first-in-patient, single-centre, single-arm, phase 1b trial. Lancet Oncol. 2022;23(11):1409-1418. doi:10.1016/S1470-2045(22)00599-X