Sudocetaxel zendusortide (TH1902), a novel sortilin-receptor (SORT1)-targeting peptide-drug-conjugate (PDC) in patients (pts) with advanced solid tumors: Results from part 1 (dose-escalation) of a phase 1, open-label study.
Bibliographic record
Abstract
3089 Background: SORT1 is expressed in a variety of tumors when compared to most healthy tissue. TH1902 is a first-in-class PDC targeting SORT1, that consists of 2 molecules of docetaxel attached to the TH19P01 peptide via a cleavable succinyl linker. Conjugating the short peptide with various anti-cancer agents allows for targeted delivery of payloads to the tumor. Here we report results from Part 1 of a FIH, multicenter, phase 1 study, designed to explore the safety, pharmacokinetics (PK) and efficacy of TH1902 in advanced solid tumors. Methods: Part 1 used a modified rapid intrapatient dose escalation design. A starting dose of 30 mg/m2 Q3W of TH1902 was used for the study based on the available pre-clinical data of TH1902 and the known safety profile of docetaxel. Eligibility criteria included pts with advanced solid tumors (all-comers) that have relapsed or are refractory to standard anticancer treatment. Pts had no limit on previous lines of therapy, and were required to have measurable disease by RECIST, expected survival of ≥3 months, ECOG 0-1, and adequate organ function. Pts were not required to be tested for SORT1 at entry. The primary objective of the study was to characterize the safety and tolerability of TH1902. The primary objective of Part 1 was to identify the maximum tolerated dose and the recommended dose for Part 2 (dose expansion). Additional objectives included the examination of the PK of TH1902 and free docetaxel, and outcomes as related to SORT1 expression. Results: As of April 2022, 18 pts were enrolled in Part 1 and included 6 ovarian, 1 endometrial, 1 cervical, 3 prostate, 3 ER+/Her2+ BC, 3 melanoma and 1 NSCLC. Pts received an average of 8 prior regimens (range: 3-20). All pts received at least 1 dose of study drug and were evaluated after the 1st cycle for a DLT. Dose levels between 30-420 mg/m2 Q3W were studied. Following safety observations among the 6 patients enrolled at the 420 mg/m2 dose level (Gr 3 neuropathy [n=2], Gr 4 neutropenia [n=2], Gr 3 ocular [n=1] and Gr 2 skin toxicities), the dose was reduced to 300 mg/m2. At the at 300 mg/m2 cohort, seven pts received a mean of 2.9 cycles. AEs (regardless of relatedness) occurred in all 7 (100%) pts, mostly Gr 1-2. One pt had Gr 3 worsening anemia (probably related) and Gr 3 abdominal pain/fistula (unrelated). AEs of interest were all Gr 1-2, and included: ocular (keratitis/dryness)=2 pts; GI (nausea/vomiting/diarrhea)=2 pts; neuropathy=2 pts; MSK (arthralgia/myalgia/extremity pain)=2 pts. In 15 evaluable pts in Part 1 clinical benefit was observed in 10 pts: 1 PR (prostate with 53% decrease in target lesion) and 9 SD. PK and SORT1 expression analyses are ongoing. Conclusions: Although biological activity has been observed, the optimal dosing regimen of TH1902 is currently under evaluation. Clinical trial information: NCT04706962 .
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".