Abstract CT047: Phase 1 dose-escalation study of the CDK inhibitor dinaciclib in combination with the PARP inhibitor veliparib in patients with advanced solid tumors
Bibliographic record
Abstract
Abstract Background: Although PARP inhibition is effective against HR repair-deficient cancers, efficacy is limited by HR proficiency, whether present de novo or as a result of acquired resistance, prompting HR disrupting strategies to sensitize tumor cells. Inhibition of CDK1 and CDK12 compromise HR by blocking BRCA1 phosphorylation, affecting recruitment to sites of DNA damage, and by reducing HR gene expression, respectively. Dinaciclib is a pan-CDK inhibitor that inhibits both CDK1 and CDK12 at nanomolar potency. We conducted a Phase 1 study combining dinaciclib and veliparib in patients with advanced solid tumors who are not germline BRCA carriers. Methods: A 3+3 design was utilized. Veliparib was administered twice daily continuously in 28-day cycles. Dinaciclib was administered intravenously on days 8 and 22. In part 1A, escalation followed a two-dimensional schema, utilizing doses of dinaciclib between 10 - 45 mg/m2 and veliparib between 20 - 120 mg. In part 1B, veliparib was escalated between 200 mg - 400 mg with dinaciclib maintained at 30 mg/m2. PK and PD assessments were performed at baseline, after veliparib, and after the combination. Preliminary Results: Sixty-three heavily pretreated patients were enrolled in part 1A (n = 39) and 1B (n = 24). Thirty-four patients had breast or gynecologic malignancies. The MTD was 400 mg twice-daily veliparib with dinaciclib at 30 mg/m2. DLTs included G4 neutropenia > 7 days (n =1), febrile neutropenia (n = 1), mucositis (n = 1) and fatigue (n = 1). Common drug-related toxicities were neutropenia (78%), nausea (75%), fatigue (67%), electrolyte abnormalities (59%), elevated liver function tests (57%), diarrhea (52%), lymphopenia (52%), anemia (43%), dehydration (37%), anorexia (30%), vomiting (29%), hypoalbuminemia (29%), dizziness (29%), headache (22%), mucositis (18%), elevated creatinine (16%), alopecia (16%), thrombocytopenia (14%), abdominal pain (13%), insomnia (13%), and dysgeusia (11%). The median number of cycles completed was 2 (r: 1 - 10). One patient with TNBC achieved complete resolution of axillary adenopathy lasting > 8 months. Twenty-four patients (38%) had stable disease as the best response, with 9 progression-free > 4 months (TNBC, gynecologic and thymic ca). Paired tumor biopsies from one patient demonstrated reduced Ki-67 and increased gamma-H2AX staining after combination treatment compared to after veliparib alone. Conclusions: Dinaciclib administered at doses known to produce PD effects is tolerable with full dose veliparib. Anti-tumor activity is limited in non-BRCA carriers, possibly related to intermittent administration of a CDK inhibitor with known short half-life. Additional patients are being enrolled utilizing dinaciclib in more dose-intense schedules. Citation Format: Geoffrey I. Shapiro, Khanh T. Do, Sara M. Tolaney, John F. Hilton, James M. Cleary, Andrew Wolanski, Brian Beardslee, Faith Hassinger, Ketki Bhushan, Dongpo Cai, Elizabeth Downey, Solida Pruitt-Thompson, Suzanne M. Barry, Bose Kochupurakkal, Joseph Geradts, Christine Unitt, Alan D. D'Andrea, Alona Muzikansky, Richard Piekarz, L. Austin Doyle, Jeffrey Supko. Phase 1 dose-escalation study of the CDK inhibitor dinaciclib in combination with the PARP inhibitor veliparib in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT047. doi:10.1158/1538-7445.AM2017-CT047
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| 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".