Effect of intratumoral INT230-6 on tumor necrosis and promotion of a systemic immune response: Results from a multicenter phase 1/2 study of solid tumors with and without pembrolizumab (PEM) [Intensity IT-01; Merck KEYNOTE-A10].
Bibliographic record
Abstract
2520 Background: INT230-6 is a new product with a unique dual anti-cancer mechanism. The drug is comprised of cisplatin (CIS) and vinblastine (VIN) co-formulated with an amphiphilic molecule that enables drug dispersion throughout a tumor and passive diffusion into cancer cells following intratumoral (IT) delivery. A neoadjuvant study in breast cancer confirms that a single injection can kill 95% of an injected tumor and recruit TILs. Methods: INT230-6 treatments are Q2W for up to 5 treatments followed by maintenance dosing every 9 weeks. Dose is set by the tumor’s longest diameter or volume. One arm received INT230-6 plus PEM 200mg IV Q3W. Biopsies from injected tumor are taken pretreatment and Day 28 for immunohistochemistry (IHC) analysis. Results: Sixty-two subjects received INT230-6 alone (median age 61, with 4 prior treatments), and 21 INT230-6 + PEM (median age 70, with 3 prior treatments). To these subjects over 575 image guided INT230-6 IT injections were given (320 to visceral tumors such as lung, liver, pancreas). Doses ranged from 0.14 to 175mL (87.5 mg of CIS, 17.5 mg VIN - higher than typical IV doses). Pharmacokinetic data shows > 95% of the INT230-6 active agents remain in the tumor. The most common ( > 25%) adverse events (AEs) related to INT230-6 were localized pain (58%), nausea (40%), and fatigue (29%). The most common AEs attributed to the PEM combination were nausea (62%), localized pain (57%), vomiting (57%), decreased appetite (43%), fatigue (43%) and constipation (29%). The incidence of grade 3 AEs for the INT230-6 arm was 11% and for the PEM combination was 14%. There were no related grade 4 or 5 AEs in the INT230-6 arm; and one grade 4 neutrophil count decrease was seen on the PEM combination. There were no dose limiting adverse events. No patient discontinued therapy due to toxicities related to either drug or injection procedure. The monotherapy arm enrolled patients from 17 tumor types; while the PEM combo recruited primarily pancreatic, CRC, triple negative breast, or bile duct cancer. IHC results confirm a marked reduction in proliferating tumor cells with influx of CD4 and CD8 T-cells. Seven of the INT230-6 monotherapy patients had non injected tumor shrinkage in 9 visceral/deep lesions. Estimated median overall survival (mOS) was over 1 year for both arms. Conclusions: In this clinical trial, deep and superficial tumor injections into patients with widely metastatic disease was feasible and well tolerated. Biopsies confirm the dual anti-cancer mechanism, and study patients live longer than would be expected for these refractory populations. INT230-6’s rapid tumor killing and immune activation properties may offer an alternative to control refractory patients (even those that are chemotherapy refractory) and the product is moving into randomized controlled registration trials. Clinical trial information: NCT03058289.
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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 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".