MLN9708, an investigational proteasome inhibitor, in patients (pts) with relapsed/refractory lymphoma: Emerging data from a phase I dose-escalation study.
Bibliographic record
Abstract
8064 Background: MLN9708 is a reversible, orally bioavailable, specific 20S proteasome inhibitor. This study (NCT00893464) studied the safety and determined the MTD of IV MLN9708 in pts with relapsed/refractory lymphoma, and characterized pharmacokinetics (PK) and pharmacodynamics (PD). Methods: Pts aged ≥18 yrs who had failed ≥2 chemotherapeutic regimens received IV MLN9708 on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. One pt was enrolled at the 0.125 mg/m2 starting dose; dose doubling proceeded with 1 pt at each dose up to 1.0 mg/m2. Dose escalation occurred in ≤40% increments using a standard 3+3 scheme based on DLT occurrence in cycle 1. Blood samples were collected at multiple time points after dosing on days 1 and 15 of cycle 1 for PK/PD analyses. Results: At data cut-off (Dec 1 2011), 21 pts had been enrolled and treated: 1 each at 0.125, 0.25, 0.5 and 1 mg/m2, 4 at 1.4 mg/m2, 7 at 1.76 mg/m2, and 6 at 2.34 mg/m2. Median age was 57 yrs (range 23–78); 57% were male. Median number of prior therapies was 5; 29% had prior radiation, 24% prior stem cell transplant. Histologies included T-cell lymphoma (n=5), Hodgkin lymphoma (n=3), follicular lymphoma (n=2), DLBCL (n=1) and other indolent B-cell lymphoma (n=7). Pts had received a median of 2 cycles (range 1–22); 2 DLTs were seen (neutropenia at 1.76 and 2.34 mg/m2). All pts experienced drug-related AEs, including fatigue (48%), nausea (29%), diarrhea (29%), pyrexia, thrombocytopenia, and vomiting (each 24%). 43% had drug-related grade ≥3 AEs, 1 pt discontinued due to drug-related grade 3 neutropenia (2.34 mg/m2). Three pts had drug-related peripheral neuropathy (1 grade 1, 2 grade 2). There were no on-study deaths. Of 18 response-evaluable pts, 3 achieved PR (including 2 who remain in response and on-study for >1 yr) and 4 SD. PK analyses showed linear PK (0.5–2.34 mg/m2) and a terminal half-life of ~6–9 days. There was a dose-dependent increase in maximal whole blood 20S proteasome inhibition. Conclusions: These data suggest IV MLN9708 is generally well tolerated, with infrequent PN, and is clinically active in pretreated lymphoma pts. The trial is ongoing and updated data will be presented.
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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) | 0.000 | 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 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".