ONITT: A phase I study of nanoliposomal irinotecan with talazoparib or temozolomide in children and young adults with recurrent or refractory solid tumors.
Bibliographic record
Abstract
10007 Background: Talazoparib (TAL), a potent PARP inhibitor, demonstrated preclinical activity in Ewing sarcoma when combined with irinotecan (IRN) and temozolomide (TMZ). A phase I study (BMNIRN, NCT02392793) showed clinical benefit of TAL + IRN + TMZ; but dose escalation was limited due to hematologic and gastrointestinal toxicity. We therefore evaluated, for the first time in children, nanoliposomal irinotecan (nal-IRI) in combination with either TAL or TMZ. Methods: Patients (pts) aged 1-30 with recurrent or refractory solid tumors were eligible to receive nal-IRI + TAL (Arm A) or nal-IRI + TMZ (Arm B) using a Bayesian keyboard design. Nal-IRI dosage was escalated with fixed TAL and TMZ doses. Each cycle was 21 days. Maximum tolerated dosage(s) (MTD) and recommended phase 2 dosage(s) (RP2D) were determined. Nal-IRI and TAL plasma pharmacokinetics (PK) were evaluated. Toxicities were assessed using CTCAE v.5 and responses were evaluated by RECIST 1.1. UGT1A1 polymorphisms and serial circulating tumor DNA (ctDNA) samples were evaluated. Results: Forty-six pts enrolled at 5 sites. The first 9 (5 Arm A; 4 Arm B) received nal-IRI days 1, 8. Four pts had dose limiting toxicities (DLTs), so day 8 nal-IRI was removed (Amend 1). After Amend 1, 37 pts (23 male; median age 14 years, range 1-23) enrolled (19 Arm A; 18 Arm B). The most common diagnosis was Ewing sarcoma (n = 16, 35%). Table 1 summarizes DLTs in Cycle 1 and response. The most common serious adverse events included febrile neutropenia (12 Arm A; 2 Arm B), colitis (4 Arm A; 2 Arm B), vomiting (4 Arm A), and diarrhea (3 Arm A). Confirmed responses were seen in five Arm A (1 CR, 4 PR) and five Arm B (1 CR, 4 PR) pts with Ewing sarcoma, CIC-DUX4 sarcoma, synovial sarcoma, and rhabdomyosarcoma. Seven pts (5 Arm A; 2 Arm B) had stable disease. Results of PK, UGT1A1 and ctDNA will be presented. Conclusions: The MTDs were nal-IRI 160mg/m 2 plus TAL (Arm A) and nal-IRI 200mg/m 2 plus TMZ (Arm B). The RP2Ds are pending FDA review. These regimens are feasible with evidence of anti-tumor activity and warrant further investigation. Clinical trial information: NCT04901702 . Dose level Nal-IRImg/m 2 IV Arm ANal-IRI + TAL(po, 600mcg/m 2 /dose)Days (D) # of pts Arm BNal-IRI + TMZ(po, 100mg/m 2 )Days (D) # of pts DLT Cycle 1 (# of pts) Confirmed Response(CR, PR, SD, PD) 1 120 D 1: nal-IRI + TAL divided BIDD 2-6: TAL daily 7 D 1: nal-IRI + TMZD 2-5: TMZ daily 3 Arm A: 1 pt - neutropenia (1) Arm A: CR (1), SD (1), PD (2)Arm B: PR (1), SD (1), PD (1) 2 160 D 1: nal-IRI + TAL divided BIDD 2-6: TAL daily 10 D 1: nal-IRI + TMZD 2-5: TMZ daily 3 Arm A: 3 pts - anemia (1), thrombocytopenia (1), sepsis (1), colitis (1) Arm A: PR (3), SD (4), PD (3)Arm B: PR (1), PD (1) 3 200 D 1: nal-IRI + TAL divided BIDD 2-6: TAL daily 2 D 1: nal-IRI + TMZD 2-5: TMZ daily 12 Arm A: 2 pts – abd pain (1), thrombocytopenia (1), neutropenia (1), diarrhea (1)Arm B: 3 pts – nausea (1), neutropenia (1), sepsis (1), thrombocytopenia (1) Arm A: PR (1)Arm B: CR (1), PR (2), SD (1), PD (6)
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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 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| 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".