A Phase I Combination Study of Olaparib with Cisplatin and Gemcitabine in Adults with Solid Tumors

Abstract

Purpose: To determine the safety and tolerability of olaparib with cisplatin and gemcitabine, establish the maximum tolerated dose (MTD), and evaluate the pharmacodynamic and pharmacokinetic profile of the combination.Experimental Design: We conducted a phase I study of olaparib with cisplatin and gemcitabine in patients with advanced solid tumors. Treatment at dose level 1 (DL1) consisted of olaparib 100 mg orally every 12 hours on days 1 to 4, gemcitabine 500 mg/m 2 on days 3 and 10, and cisplatin 60 mg/m 2 on day 3. PAR levels were measured in peripheral blood mononuclear cells (PBMC).Results: Dose-limiting toxicities (DLT) in two of three patients at DL1 included thrombocytopenia and febrile neutropenia. The protocol was amended to enroll patients treated with 2 prior severely myelosuppressive chemotherapy regimens and treated with olaparib 100 mg once daily on days 1 to 4 (DLÀ1). No DLTs were seen in six patients at DLÀ1. Because of persistent thrombocytopenia and neutropenia following a return to DL1, patients received 100 mg olaparib every 12 hours on day 1 only. No hematologic DLTs were observed; nonhematologic DLTs included gastrointestinal bleed, syncope, and hypoxia. Of 21 patients evaluable for response, two had partial response. Olaparib inhibited PARP in PBMCs and tumor tissue, although PAR levels were less effectively inhibited when olaparib was used for a short duration.Conclusions: Olaparib in combination with cisplatin and gemcitabine is associated with myelosuppression even at relatively low doses. Modified schedules of olaparib in chemotherapy naive patients will have to be explored with standard doses of chemotherapy.

Synthesis and Evaluation of a Radioiodinated Tracer with Specificity for Poly(ADP-ribose) Polymerase-1 (PARP-1) in Vivo

“…However, a number of early phase clinical trials have reported severe bone marrow toxicity with such therapeutic combinations [5][6][7][8][9][10] which could in part be attributed to suboptimal dosing schedules. 8 Non-invasive in vivo imaging of PARP-1 using a radiolabeled PARPi and techniques such as Positron Emission Tomography (PET) or Single-Photon Emission Tomography (SPECT) could be used to assess the duration of PARP-1 inhibition in different tissues. This could subsequently guide dosing decisions for PARPi when given in combination with chemotherapy such that tumour cytotoxicity is maximized and bone marrow toxicity is minimized.…”

Heat Shock Protein 90 Functions to Stabilize and Activate the Testis-specific Serine/Threonine Kinases, a Family of Kinases Essential for Male Fertility

“…HSP90 possesses an intrinsic ATPase activity that is required for mediating the necessary conformational changes in client proteins for activation (15,17,18) and is also important for stabilization of the HSP90 client proteins (19,20). HSP90 inhibitors 17-allylamino-17-demethoxygeldanamycin (17-AAG) as well as other structurally distinct agents, including SNX-5422 (also known as PF-04929113) and NVP-AUY922, bind to the nucleotide binding pocket of HSP90 and inhibit the progression of the HSP90 complex toward the stabilizing form resulting in the degradation of the client proteins (16,19,(21)(22)(23). It is well established that pharmacological inhibition of HSP90 can lead to degradation of a large variety of client proteins including kinases such as RAF kinase, ERBB2, AKT, v-SRC, and death domain kinase, the transcription factors mutants p53 and HIF-1␣, the mineralocorticoid, glucocorticoid, and mutant androgen receptors, and others such as the cystic fibrosis transmembrane conductance regulator CFTR and huntingtin (19, 21, 24 -32).…”

Molecular Pathways: How Can BRCA-Mutated Tumors Become Resistant to PARP Inhibitors?

“…Ideally, PARP inhibitor resistance is prevented by using drug combinations that completely eradicate tumors (1). To this end, established chemotherapeutic agents may be used, although these may also induce more severe side effects in the presence of PARP inhibitors (62,63). Alternatively, combination with other targeted therapeutics such as inhibitors for PI3 kinase (30,64), cell-cycle checkpoints (65) or other nicotinamide adenine dinucleotide metabolizing enzymes (66) may sensitize tumors to PARP inhibition.…”