Phase I study to evaluate the safety and efficacy of MEDI4736 in combination with tremelimumab in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN).
Bibliographic record
Abstract
TPS3090 Background: Despite advances in the treatment of SCCHN, the outlook for patients (pts) with R/M disease remains poor. Development of immunotherapies to treat this disease may hold promise. High mutational burden due to tobacco and expression of human papilloma virus (HPV)-associated viral antigens is linked to immunogenicity in SCCHN tumors. Despite this immunogenicity, tumors can evade immune detection by exploiting inhibitory checkpoints. PD-L1 is up-regulated on SCCHN tumors and is associated with antitumor T-cell response inhibition. MEDI4736 (M), a human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80 with high affinity and selectivity, has shown a manageable safety profile and promising antitumor activity in R/M SCCHN (ORR 24% in PD-L1+ pts, phase I)(Fury M, et al. Poster presented at ESMO 2014, 988PD). Tremelimumab (T), a selective human IgG2 mAb inhibitor of CTLA-4, has also shown antitumor activity in several tumor types (Tarhini AA. Immunotherapy 2013;5:215–29). Preclinical data suggest that combining anti-PD-L1 and anti-CTLA-4 provides non-redundant immune checkpoint blockade and synergistic antitumor activity. Preliminary data for M + T in NSCLC show encouraging clinical activity in both PD-L1-positive and PD-L1-negative pts (Antonia S, et al. Poster presented at ESMO 2014, 1327P). Here we describe a study assessing the safety, efficacy, and potential biomarkers of response to M + T, in pts with R/M SCCHN. Methods: This is a phase I, multicenter, open-label study (NCT02262741) in pts (N~164) with R/M SCCHN deemed incurable by local therapy. The dose exploration phase will evaluate the combination of M + T, followed by dose expansion in treatment-naive or pretreated R/M pts. Pts will have PD-L1 status determined prior to dosing with M IV + T IV or T IV alone. The primary objective is to assess safety/tolerability of M + T and T alone. Secondary objectives are to assess antitumor activity via RECIST (including ORR, DCR, DoR, PFS, and OS), PK/PD, immunogenicity, and if clinical activity correlates with potential biomarkers, including PD-L1 expression, HPV status, and tobacco use. Recruitment is ongoing. Clinical trial information: NCT02262741.
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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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
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".