A phase I dose escalation and dose expansion study of the anti-programmed cell death-1 (PD-1) antibody AK105.
Bibliographic record
Abstract
e14006 Background: AK105 is a humanized IgG1 mAb that blocks PD-1 binding to PD-L1 allowing T-cells to recognize and kill tumor cells. Key attributes of AK105 include antibody engineering to eliminate Fc mediated effector function, and a slower off-rate on antigen binding resulting in improved receptor occupancy (RO). These features offer more robust biological effect and enhance anti-tumor activity of AK105. Methods: A multicenter, Phase I, open-label dose escalation and expansion study in solid tumors (NCT03352531) began in Dec 2017, evaluating the safety and efficacy of AK105 administered IV q2w till confirmed progression (RECIST v1.1). For dose escalation, pts were enrolled at dose cohorts of 1, 3, and 10 mg/kg. Expansion of AK105 at the RP2D of 200 mg q2w is ongoing in pts with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma; esophageal squamous-cell carcinoma; hepatocellular carcinoma (HCC); microsatellite instability-high (MSI-H) colorectal cancer. Results: As of 1 Feb, 2019, 34 pts (median age 66.5 years [30–79], female 44%, ECOG 0/1 ([68%/32%]) in cohorts of 1 mg/kg (n = 3), 3 mg/kg (n = 6), 10 mg/kg (n = 7), and 200 mg q2w (n = 18), received a median of 5 (1–29) doses of AK105. No DLTs were reported. Treatment-related adverse events (TRAEs) occurred in 41% of pts (G3 in 12% [4/34], no G4, treatment interruption in 9% [3/34]). Most frequent TRAEs ( > 5%) were hyperthyroidism (9%), hypothyroidism (6%), fatigue (6%), and rash (6%). PD-1 RO analysis showed that pts maintained full occupancy ( > 80%) for all dose levels. Of 25 evaluable heavily pretreated pts, ORR was 24% (6/25; 29% [4/14] in dose escalation and 18% [2/11] in expansion phase) and disease control rate (DCR) was 56% (14/25). Five responses are confirmed and ongoing (HCC, pancreatic carcinoma, cholangiocarcinoma, GBM, gastric adenocarcinoma), one is pending confirmatory scan (GEJ). Conclusions: The RP2D obtained from the dose escalation phase, reported safety profile and encouraging antitumor activity of AK105 supports continued clinical development, which include: pivotal studies in classic Hodgkin lymphoma and nasopharyngeal carcinoma, phase 2/3 combination studies with chemotherapy in NSCLC and combination study with anlotinib, a multi-targeting tyrosine kinase inhibitor in HCC. PD analysis is ongoing and expansion is ongoing at the RP2D. Clinical trial information: NCT03352531.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.004 |
| Insufficient payload (model declined to judge) | 0.003 | 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".