A phase I and pharmacological study of MK-1775, a Wee1 tyrosine kinase inhibitor, in both monotherapy and in combination with gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors
Bibliographic record
Abstract
3510 Background: MK-1775 is an inhibitor of Wee1, a kinase that phosphorylates CDC2 to inactivate the CDC2/cyclin B complex (regulating the G2 checkpoint). Since most human cancers harbor p53-dependent G1 checkpoint abnormalities, they are dependent on the G2 checkpoint. G2 checkpoint abrogation may therefore sensitize p53 deficient tumor cells to anti-cancer agents. Methods: This study is evaluating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of MK-1775 administered as both monotherapy (MT) and combination therapy (CT) with gemcitabine (G), cisplatin (P), or carboplatin (C). PART 1 consists of a single dose of MK-1775 followed by 14 days observation. If well tolerated, the same pt continues on to one of three treatment arms in PART 2: a single lower dose of MK-1775 in combination with: 1) 1000 mg/m2 G, 2) 75 mg/m2 P or 3) C AUC 5. Maximum Tolerated Doses (MTDs) will be established for MK-1775 as both monotherapy and in combination. PD biomarkers include IHC analysis for pCDC2/CDC2 in plucked hair and skin biopsies, peripheral blood, and tumor biopsies. Wee1 gene expression signature is measured in plucked hair and tumor biopsies by qPCR. Results: To date, 37 pts (median age 61; up to 4 prior therapies) have been treated with MK-1775. 4 pts experienced DLT. One pt on G + 200mg MK-1775 had gr3 leucopenia and neutropenia; one pt on P + 200mg MK-1775 had gr3, fatigue, diarrhea and hypokalemia and another pt gr2 nausea/vomiting > 48hrs requiring hospitalization. One pt on C + 325mg MK-1775 was hospitalized for gr3 bilirubin. Linear PK was demonstrated at 100, 200, 325, 650 and 1300 mg MK-1775. Terminal T½ of MK-1775 was 7.6–12.2 hrs and Tmax was 1.0–6.0 hrs. Preliminary MTDs of MK-1775 in combination with G, C and P were 200, 325 and 200mg, respectively. Significant changes in Wee1 signature gene expression were observed in plucked hair. Of 28 evaluable pts, >50% regression of axillary lymphadenopathy was seen in 1 pt with melanoma on the P arm, and stable disease in 14 other pts (median duration). Conclusions: MK-1775 is a first in class Wee1 inhibitor that is well tolerated and shows promising anti-tumor activity in previously treated pts. [Table: see text]
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".