TRPH-222 Shows Early Antitumor Activity, Tolerability in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma

Francisco Hernandez-Ilizalituri, MD

The antibody-drug conjugate (ADC) TRPH-222 demonstrated early signs of efficacy with favorable tolerability at higher dose levels in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), according to data from a phase 1 trial (NCT03682796) presented during the 2020 ASH Annual Meeting & Exposition.¹

Results showed that TRPH-222 elicited an overall response rate (ORR) of 36.4% in all patients who have received treatment. Notably, activity was reported at all dose levels examined and all histologic subtypes enrolled, including those with indolent and aggressive disease. Six patients achieved a complete remission, and 2 patients experienced a partial response (PR).

The agent was also found to have an acceptable tolerability, although the maximum-tolerated dose (MTD) has not yet been reached.

“TRPH-222 is well tolerated at higher dose levels than typical ADCs with microtubule-inhibiting payloads,” Francisco Hernandez-Ilizalituri, MD, chief of the Lymphoma Section, professor of medicine in the Department of Medicine, head of the Lymphoma Translational Research Lab, and associate professor in the Department of Immunology at Roswell Park Comprehensive Cancer Center, said in a presentation during the meeting. “Early signs of efficacy were demonstrated in patients with indolent and aggressive lymphoma subtypes. Of interest, CRs were maintained in patients off treatment for up to 15 months.”

TRPH-222 is a novel ADC that targets CD22, which is a sialo-glycoprotein that is B-cell restricted and plays an important role in modulating B-cell signaling and survival; it is expressed on almost all B-cell malignancies.² TRPH-222 is comprised of a site-specific modified humanized antibody that is conjugated to a cytotoxic payload that utilizes SMARTag technology and Hydrazino-Pictet-Spengler chemistry, as well as a proprietary 4AP linker.

The novel site-specific linker-conjugation system is predicted to provide a superior Therapeutic Index and a tightly controlled drug–antibody ratio. “This is due to a stable linker that is somehow resistant to Pgp effect and, therefore, has low bystander cytotoxicity,” explained Hernandez-Ilizalituri. The SMARTag technology offers a simple and effective approach for producing optimized site-specific conjugates, he added.

In the multicenter, open-label phase 1 trial, investigators set out to identify the MRD and recommended phase 2 dose of single-agent TRPH-222. Another objective of the research was to examine the safety and tolerability of the agent when used as a monotherapy.

To be eligible for enrollment to stage 1 of the trial, patients had to have histologically confirmed B-cell NHL in the form of diffuse large B-cell lymphoma (DLBCL); follicular lymphoma, including transformed FL; marginal zone lymphoma (MZL); or mantle cell lymphoma (MCL) that was stage 1. Patients had to have relapsed/refractory NHL that required systemic treatment; these patients had to have progressed on, been intolerant to, or are ineligible for potentially curative standard-of-care treatment. Stage 2 of the trial will only enroll patients with DLBCL or follicular lymphoma; however, those with other subtypes may be added per Sponsor discretion.

The stage 1 dose-escalation portion of the trial was comprised of an accelerated phase and a standard 3+3 phase. In the accelerated phase, participants were treated in single-patient cohorts with different doses of the ADC, going from 0.6 mg/kg, to 1.2 mg/kg, to 2.0 mg/kg, to 3.0 mg/kg. In the 3+3 portion, they received the agent at 4.2 mg/kg, to 5.6 mg/kg, to 7.5 mg/kg, up to 10 mg/kg.

The dose was administered intravenously every 3 weeks as scheduled, and there was an 8-day delay in between dosing the first and remaining patients in each cohort. Patients received treatment until first dose-limiting toxicity (DLT), or intermediate toxicity was experienced.

The stage 2 dose-expansion portion of the trial is examining TRPH-222 at a dose of 7.5 mg/kg in patients with DLBCL or follicular lymphoma only.

A total of 22 patients were enrolled to the trial; of these patients, 10 had follicular lymphoma, 10 had DLBCL or transformed follicular lymphoma, 1 had MCL, and 1 had 1 MZL. The median age of all participants was 67.5 years (range, 51-81) and 54% (n = 12) were male. Fifty-five percent (n = 12) of patients had an ECOG performance status of 0, while 55% (n = 12) had a status of 1.

The median line of prior therapies received was 4, with 23% (n = 5) of patients having previously undergone transplant; 18% (n = 4) previously received CAR T-cell therapy, while 41% (n = 9) had prior radiotherapy. Forty-one percent (n = 9) of patients were refractory to the most recent systemic therapy they received and 14% (n = 3) were refractory to the most recent CD20-targeted monoclonal antibody that they were given.

Data from pharmacokinetic studies indicated similar levels of ADC and total antibody in the different patient cohorts who received treatment, said Hernandez-Ilizalituri.

Additionally, when looking more closely at 1 patient who received the lowest dose level of TRPH-222 and 1 patient who received the agent at the highest dose level, no differences in levels of the drug conjugate and total antibody were observed in the blood of these patients during the duration of the first cycle of treatment. “This suggests that there was a very small amount of payload detected in the blood that was unbound,” noted Hernandez-Ilizalituri.Mass spectrometry studies detected a small amount of payload that was free; this was in the range of 50 pg/mL.

With regard to the pharmacodynamics of the agent, CD22 receptor occupancy was 100% at all dose levels within 4 hours of administration of TRPH-222; this was sustained for the duration of the treatment cycle. “Of interest, we saw a partial depletion of B cells at all drug levels,” said Hernandez-Ilizalituri.

When broken down by histologic subgroups, the ORR was 50% (n = %) in 10 patients with follicular lymphoma; 4 patients had a CR, 1 had a 1 PR, 1 achieved stable disease (SD), 3 experienced disease progression, and 1 was not assessed. In the subgroup of 10 patients DLBCL/transformed follicular lymphoma, the ORR was 20% (n = 2), with 1 CR, 1 PR, and 3 SD; 5 patients had progressive disease. The ORR in the MCL subgroup was 100% with the patient achieving a CR. The ORR in the MZL subgroup was 0%, with the patient having stable disease.

To date, 5 patients continue on treatment with the ADC. Additionally, 5 of 6 patients who achieved a CR were permitted to discontinue treatment following cycle 9 and CR confirmation. Notably, all 5 of these patients continue to be off treatment and in CR. A total of 12 patients discontinued treatment with TRPH-222; of these patients, 12 discontinued due to disease progression, 2 due to DLTs, 2 due to toxicities, and 1 per investigator decision.

TRPH-222 was determined to be well tolerated. Although some participants experienced grade 1 or 2 toxicities, the majority of these effects were manageable, according to Hernandez-Ilizalituri, who added that very few grade 3 or 4 adverse effects (AEs) were reported.

Among the most relevant AEs experienced by patients were neutropenia, thrombocytopenia, peripheral neuropathy, and ocular toxicity. Those with neutropenia and thrombocytopenia were asymptomatic and these cases resolved without significant intervention. Peripheral neuropathy was only observed in patients who had a prior history and incidence was relatively infrequent.

“Notably, ocular toxicity was described in several patients receiving TRPH-222. Most of them developed some form of epithelial keratopathy; this has been characterized in other ADCs,” said Hernandez-Ilizalituri. “Patients complain of dry eye, blurry vision, and irritation. However, most of the time, this was grade 1 or 2. Ocular toxicity was easily managed with either dose interruptions or reductions, and over-the-counter use of lubricant eye drops.”

One serious AE (SAE) determined to be associated with the study drug was reported. This patient experienced grade 1 fever at 2 instances in cycles 2 and 3. After a dose reduction, the patient was able to continue on the study and remains enrolled. Four SAEs that were not related to the treatment were also observed; these included grade 3 hypotension, grade 4/5 sepsis, grade 2 worsening facial pain, and grade 4 hypercalcemia. No grade 4 or 5 SAEs related to TRPH-222 were reported.

Three patients discontinued treatment because of toxicities associated with the study drug; 2 of these patients DLTs in the form of elevated liver enzymes, and 1 because of grade 3 ocular effects in the form of dry eye and blurred vision.

“Further assessment of the safety, PK, and efficacy of TRPH-222 is ongoing in an expansion cohort that is enrolling patients with relapsed/refractory DLBCL and follicular lymphoma,” concluded Hernandez-Ilizalituri.

References

1. Hernandez-Ilizaliturri FJ, Flinn IW, Kuruvilla J, et al. A phase I pharmacokinetic (PK) and safety study of Trph-222 in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (R/R NHL): dose-escalation results. Presented at: 2020 ASH Annual Meeting & Exposition; December 5-8, 2020; Virtual. Abstract 701. https://bit.ly/3oy0j4P.
2. TRPH-222. Triphase Accelerator Corporation. Accessed December 8, 2020. https://bit.ly/36Ywe8y.