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

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

Combining PARP Inhibition with Platinum, Ruthenium or Gold Complexes for Cancer Therapy

“…This found that twenty-four patients (38 %) had stable disease as the best response with nine progression-free (ClinicalTrials.gov identifier: NCT01434316). [147] These findings show the potential of using this combination strategy to re-establish PARPi sensitivity. Bearing in mind many anti-cancer transition metal complexes achieve potent effects on cell-cycle progression without generating cytotoxic or genotoxic DNA damage, this may be a lucrative area for future investigation.…”

“…The combination of veliparib and dinaciclib against patients with advanced solid tumours who are not germline BRCA carriers was evaluated in a phase I study. This found that twenty‐four patients (38 %) had stable disease as the best response with nine progression‐free (ClinicalTrials.gov identifier: NCT01434316) [147] . These findings show the potential of using this combination strategy to re‐establish PARPi sensitivity.…”

Mechanism of Action and Clinical Efficacy of CDK4/6 Inhibitors in BRCA-Mutated, Estrogen Receptor-Positive Breast Cancers: Case Report and Literature Review

“…At present, several ongoing trials are evaluating the combination of CDK inhibitors with PARP inhibitors (46). The combination of dinaciclib (a CDK 1, 2, 5, 9, and 12 inhibitor) with the PARP inhibitor veliparib has shown preliminary clinical benefit in patients with breast cancer, prostate cancer, ovarian cancer, and other gynecologic malignancies (47). By blocking CDK12, CDK1, or CDK2, BRCA wild-type cancer cells turn into HR-deficient cells through inhibition of BRCA1 expression and phosphorylation (48, 49) and, thus, become more susceptible to synthetic lethality induced by PARP inhibitors (46–49).…”

CDK4/6 Inhibition in Cancer: Beyond Cell Cycle Arrest

“…Clinically, there is significant heterogeneity in the response of individual tumors to CDK4/6 inhibitors [48, 49] and it has therefore become imperative that we better understand biomarkers that predict sensitivity to these agents. Equally important is the problem of resistance to CDK4/6 inhibitors – for example, in breast cancer nearly all tumors acquire resistance to these agents after prolonged therapy, and the mechanisms underlying this are also poorly understood [50].…”