A randomized, double-blind, placebo-controlled, phase 3 study of rituximab with or without ibrutinib for Waldenstrom’s macroglobulinemia (PCYC-1127-CA).
Bibliographic record
Abstract
TPS8599 Background: Current treatments for Waldenstrom’s macroglobulinemia (WM) are not curative, and a standard of care does not exist. A highly recurrent somatic mutation in WM, MYD88 L265P, signals through interleukin-1 receptor-associated kinase 1 and Bruton’s tyrosine kinase (BTK) to mediate the constitutive activation of the NF-κB pathway (Yang, 2013). Ibrutinib (ibr), an oral inhibitor of BTK, impairs crosstalk between MYD88 and BTK, and blocks BTK dependent downstream signaling within the B-cell receptor pathway inducing apoptosis of WM cells (Treon, 2012).Thus, ibr offers a novel therapeutic approach for pts with WM. Pts with previously treated WM receiving different ibr doses achieved durable responses in a phase (Ph) 1 study (Advani, 2013). This was confirmed in a Ph 2 trial of ibr 420 mg daily (overall response rate [ORR] of 87%; Treon, 2014) leading to the first FDA approval in WM. Ibr + rituximab (rtx) showed activity and tolerability in high-risk CLL and MCL. This Ph 3 study evaluates the safety and efficacy of ibr + rtx vs. placebo + rtx in pts with WM. Methods: Approximately 150 pts will be randomized in a 1:1 ratio to receive rtx 375 mg/m2 IV weekly for 4 weeks, followed by a second 4-weekly rtx course 3-months later, and either ibr 420 mg daily or matching placebo until progressive disease (PD) or unacceptable toxicity. Key inclusion criteria include WM with documented PD or no response (stable disease) to last treatment if previously treated; symptomatic disease requiring treatment per the 2nd International Workshop on WM; and adequate hematologic, hepatic, and renal function. Exclusion criteria include CNS involvement and clinically significant cardiovascular disease. Pts refractory to the last rtx-containing therapy excluded from the randomized study are eligible for the open-label single-agent ibr substudy (n = 30). The primary endpoint is progression-free survival assessed by an independent review committee. Secondary endpoints are ORR, overall survival, hematologic improvement, time to next treatment, and safety. Pts in the control arm may receive single-agent ibr after confirmation of PD. Enrollment began in July 2014 (NCT02165397). Clinical trial information: NCT02165397.
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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 | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.003 | 0.001 |
| Meta-epidemiology (broad) | 0.004 | 0.002 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.001 | 0.002 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.003 | 0.005 |
| Insufficient payload (model declined to judge) | 0.015 | 0.003 |
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".