Nicole Houston

Combination therapy: intermittent sorafenib with bevacizumab yields activity and decreased toxicity

Background:We previously reported preliminary results of our phase I study of continuous daily sorafenib with bevacizumab every other week for solid tumours. Toxicity was moderate, leading to additional dose levels (DL) testing intermittent sorafenib dosing.Methods:Seventeen patients with advanced solid tumours were treated on three additional DLs testing sorafenib days 1–5 per week. Dose level 4 was sorafenib 200 mg twice daily (b.i.d.) and bevacizumab 5 mg kg−1. DL5 alternated between bevacizumab 10 mg kg−1-sorafenib 200 mg b.i.d. (A) and sorafenib 400 mg b.i.d. with bevacizumab 5 mg kg−1 (B). Outcome and toxicity data from 19 epithelial ovarian cancer (EOC) patients from DL 1–5 were analysed.Results:Fewer patients required sorafenib dose reduction with the intermittent schedule (41 vs 74% daily, P=0.01). Hand–foot skin reaction (HFSR) remained the primary cause of dose reduction (n=5). Partial responses (12%) or disease stabilisation ⩾4 months (53%; median 6 (4–26)) occurred in most patients on the intermittent schedule. Partial response occurred in 47% EOC patients treated in pooled analysis of duration 4–37 months.Conclusion:Intermittent sorafenib dosing with bevacizumab has promising clinical activity and less sorafenib dose reduction and side effects, but does not ameliorate HFSR. We are conducting a phase II clinical trial with intermittent sorafenib and bevacizumab in patients with EOC.

Deleterious BRCA1/2 mutation is an independent risk factor for carboplatin hypersensitivity reactions

Background:We tested the hypothesis that BRCA1/2 mutation carriers with ovarian cancer are at higher risk of carboplatin hypersensitivity reactions (HSRs).Methods:Medical records of women enrolled in two carboplatin+olaparib clinical trials (NCT01237067/NCT01445418) were reviewed. A maximum of eight cycles containing carboplatin were administered.Results:All women (N=87) had good performance status and end-organ function. Incidences of carboplatin HSR before enrolment and on study were 17% and 21%, respectively. Most patients who developed carboplatin HSR had a deleterious BRCA1/2 mutation (93%) vs 50% in patients without HSR (P<0.0001). Multivariable analysis accounting for potential confounding variables including age, history of allergies, and cumulative prior carboplatin cycles confirmed deleterious BRCA1/2 mutation as an independent risk factor for carboplatin HSR (odds ratio 13.1 (95% confidence interval 2.6–65.4), P=0.0017). Mutation carriers had onset of carboplatin HSR at lower cumulative exposure (P=0.003). No significant difference in outcome was observed on our study between patients with and without a history of HSR.Conclusion:Deleterious BRCA1/2 mutation increased susceptibility and shortened time to carboplatin HSR, independently of other reported factors. These data suggest that at-risk women should be counselled regarding likelihood, symptoms, and potential earlier onset of carboplatin HSRs.

Progranulin is a potential prognostic biomarker in advanced epithelial ovarian cancers

OBJECTIVE There are few validated relapse prediction biomarkers for epithelial ovarian cancer (EOC). We have shown progranulin (PGRN) and secretory leukocyte protease inhibitor (SLPI) are up regulated, overexpressed survival factors in EOC. We hypothesized they would predict presence of occult EOC. METHOD PGRN, SLPI, and the known biomarker HE4 were measured in EOC patient plasma samples, prospectively collected every 3 months from initial remission until relapse. Clinical data and CA125 results were incorporated into statistical analyses. Exploratory Kaplan-Meier estimates, dividing markers at median values, evaluated association with progression-free survival (PFS) and overall survival (OS). Area-under-the-curve (AUC) statistics were computed from receiver operating characteristic (ROC) curves to evaluate discrimination ability. A Cox proportional hazards model assessed the association between PFS, OS, and biomarkers, adjusting for clinical prognostic factors. RESULTS Samples from 23 advanced stage EOC patients were evaluated. PGRN at 3 months was the only biomarker independently associated with PFS (P<0.0001) and OS (P<0.003). When used to predict progression by 18 months, sensitivity and specificity were 93% and 100%, respectively, with AUC=0.944. The Cox model hazard ratio for PFS, divided at 59 ng/ml by ROC analysis and adjusted for clinical factors, was 23.5 (95% CI: 2.49-220). Combinations with SLPI, HE4, and/or CA125 did not improve the model. CONCLUSIONS We report pilot data indicating a potential independent association of PGRN on EOC patient PFS and OS. A validation study will be required to confirm this finding and to inform whether PGRN warrants evaluation as a potential screening biomarker.

Pharmacodynamic markers and clinical results from the phase 2 study of the SMAC mimetic birinapant in women with relapsed platinum-resistant or -refractory epithelial ovarian cancer

Inhibitors of apoptosis proteins (IAPs) are key regulators of apoptosis and are frequently dysregulated in ovarian cancer. It was hypothesized that blocking IAPs with birinapant would increase tumor cell death and result in objective responses for women with platinum‐refractory and ‐resistant ovarian cancer.

Feasibility and safety of sequential research-related tumor core biopsies in clinical trials.

There has been increasing interest in serial research biopsies in studies of targeted therapies. Definition of patient characteristics and optimal target tissue for safe research tumor biopsy in the era of antiangiogenic and targeted agents is needed.

Sequence-Specific Pharmacokinetic and Pharmacodynamic Phase I/Ib Study of Olaparib Tablets and Carboplatin in Women's Cancer.

Purpose: Our preclinical studies showed that the PARP inhibitor, olaparib, prior to carboplatin attenuated carboplatin cytotoxicity. We evaluated sequence-specific pharmacokinetic and pharmacodynamic effects, safety, and activity of the combination. Experimental Design: Eligible patients had metastatic or recurrent womens cancer. Olaparib tablets were introduced (100 or 200 mg twice daily, days 1–7) in a 3 + 3 dose escalation with carboplatin AUC4 or 5 every 21 days, up to eight cycles, followed by olaparib 300 mg twice daily maintenance. Patients were randomly assigned to starting schedule: cohort A (olaparib days 1–7, carboplatin on day 8) or B (carboplatin on day 1, olaparib days 2–8) during cycle 1. Patients received the reversed scheme in cycle 2. Blood was collected for olaparib pharmacokinetics, platinum–DNA adducts, comet assay, and PAR concentrations. The primary objectives were to examine schedule-dependent effects on olaparib pharmacokinetics and platinum–DNA adducts. Results: A total of 77 (60 ovarian, 14 breast, and 3 uterine cancer) patients were treated. Dose-limiting toxicity was thrombocytopenia and neutropenia, defining olaparib 200 mg twice daily + carboplatin AUC4 as the MTD. Olaparib clearance was increased approximately 50% when carboplatin was given 24 hours before olaparib. In vitro experiments demonstrated carboplatin preexposure increased olaparib clearance due to intracellular olaparib uptake. Quantities of platinum–DNA adducts were not different as a function of the order of drug administration. Responses included 2 CRs and 31 PRs (46%) with a higher RR in BRCA mutation carriers compared with nonmutation carriers (68% vs. 19%). Conclusions: Tablet olaparib with carboplatin is a safe and active combination. Carboplatin preexposure causes intracellular olaparib accumulation reducing bioavailable olaparib, suggesting carboplatin should be administered prior to olaparib. Clin Cancer Res; 23(6); 1397–406. ©2016 AACR.

CECs and IL-8 have prognostic and predictive utility in patients with recurrent platinum-sensitive ovarian cancer: biomarker correlates from the randomized phase 2 trial of olaparib and cediranib compared with olaparib in recurrent platinum-sensitive ovarian cancer

Objective Olaparib (O), a polyADPribose polymerase (PARP) inhibitor, and cediranib (C), a VEGF receptor (VEGFR)1–3 inhibitor together had greater activity than O alone in women with recurrent platinum-sensitive ovarian cancer (OvCa). The objective of this study is to identify potential lead biomarker candidates for response to O + C in the setting of a multi-institutional phase II study of O with and without C in recurrent platinum-sensitive OvCa. Methods A self-selected group of patients participated in a prospectively planned exploratory biomarker substudy of the randomized phase II study of O versus O + C. Whole blood for peripheral blood mononuclear cell (PBMC) and plasma isolation was collected prior to and on day 3 of treatment. Quantitation of circulating endothelial cells (CEC), IL-6, IL-8, VEGF, and soluble VEGFR-2 plasma concentrations, and polyADPribose (PAR) incorporation were performed. Single nucleotide polymorphism analysis of XRCC1 280H, R194W, and Q399R was done. Dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI) was performed at baseline and day 3 of treatment. Parameter changes were compared between the two arms using an exact Wilcoxon rank sum test. Kaplan–Meier and log-rank tests were used to examine survival outcome. Results Thirteen patients elected to participate in the translational substudy, seven patients on O and six patients on O + C. Patients on O + C had a greater decrease in IL-8 concentration and larger CEC fold increase compared with those on O alone (p = 0.026, p = 0.032). The fold increase in CEC on day 3 was associated with duration of progression-free survival (PFS) (R2 = 0.77, 95% CI 0.55–0.97, p < 0.001). IL-8 post-pretreatment changes correlate with PFS (p = 0.028). XRCC1 DNA polymorphisms were not related to PFS. All patients had reduction in PAR incorporation, and all except one had reduction in vascular flow on DCE-MRI. Conclusion Our exploratory correlative studies indicate that CEC and IL-8 changes may be predictive for response to O + C and prognostic in recurrent platinum-sensitive OvCa, requiring prospective validation.

Abstract 1188: BRCA 1/2 mutation status is correlated with increased hypersensitivity reactions to carboplatin.

Background: Carboplatin (Cp) has become the standard first-line chemotherapeutic agent for treatment of ovarian cancer (OvCa), and Cp-related hypersensitivity reaction (HSR) has been observed in 5-20% of patients (pts). The several known potential risk factors for HSR include age, # of prior platinum treatments/cycles, and longer duration of platinum-free interval (PFI). The role of BRCA mutation status has not been studied in the context of Cp HSR, although OvCa pts with BRCAmut+ are treated repeatedly with platinum-based chemotherapies. Methods: The medical records of 74 women who enrolled and initiated at least one cycle of Cp on two phase I clinical trials (NCT01237067 and NCT01445418) with Cp and olaparib (AZD2281) were reviewed. Cp was given with olaparib for a maximum of 8 cycles. Clinical characteristics including BRCA mutation status, history of HSR prior to or on study, and outcomes were analyzed. Results: Primary diagnoses of the 74 pts were ovarian (71), fallopian tube (1), and primary peritoneal (2) carcinomas. Pts had a median age of 56 years (27-80) and ECOG 0-1. 50/74 (68%) pts were BRCA mutation carriers (BRCA 1 [38], BRCA 2 [10], BRCA1/2 [1], BRCApro 68% [1]). All pts had received platinum-based therapy prior to enrollment, and the median # of prior platinum regimens and cycles were 2 (1-6) and 12 (2-42), respectively. The median PFI from the last prior platinum treatment to the first Cp infusion on study was 15.3 months (6-82). 15/74 (20%) pts had a documented history of HSR to Cp prior to enrollment and were pre-medicated with methylprednisolone, H1, and H2 blockers before a slow, incremental Cp infusion. 15/74 (20%) pts developed HSR on study (grade 1 [6], grade 2 [5], and grade 3 [4]), 4 of whom had prior history of Cp HSR. Taken together, the incidence of Cp HSR at any point in the pts’ oncologic history, either prior to or on study, was 35.1% (26/74); prior history of Cp HSR was not predictive of HSR on study. Age, median # of prior platinum cycles, and PFI for the 15 pts with HSR on study vs. those with no HSR history were 52 (27-73) vs. 56 (34-73), 12 (6-20) vs. 10 (2-42), and 21.2 (8-53) vs. 15.3 (6-82), respectively, all of which were not statistically significant. 4/15 (27%) pts with HSR on study (including 2/4 pts with prior history) stopped Cp treatment due to repeated HSR despite pre-medications, while 7/15 (47%) pts stopped therapy for other reasons. The remaining 4/15 (27%) pts successfully completed 8 cycles or are continuing therapy per protocol. BRCA mutation was significantly associated with increased risk of HSR (prior to or on study), 46% (23/50), vs. 11% (2/19) for pts with no BRCA mutation (p = 0.010). Conclusions: Cp re-treatment can be successful for OvCa pts despite prior history of HSR. Prior HSR history did not increase the risk of HSR on study. Being a BRCAmut+ carrier was associated with a statistically significantly greater risk of HSR and may serve as a clinical predictive biomarker of Cp hypersensitivity. Citation Format: Dominic H. Moon, John L. Hays, Christina M. Annunziata, Anne M. Noonan, Lori Minasian, Nicole Houston, Elise C. Kohn, Jung-min Lee. BRCA 1/2 mutation status is correlated with increased hypersensitivity reactions to carboplatin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1188. doi:10.1158/1538-7445.AM2013-1188

A Phase 1 trial of autologous monocytes stimulated ex vivo with Sylatron ® (Peginterferon alfa-2b) and Actimmune ® (Interferon gamma-1b) for intra-peritoneal administration in recurrent ovarian cancer

BackgroundOvarian cancer has no definitive second line therapeutic options, and largely recurs in the peritoneal cavity. Locoregional immune therapy using both interferons and monocytes can be used as a novel approach. Interferons have both cytostatic and cytotoxic properties, while monocytes stimulated with interferons have potent cytotoxic properties. Due to the highly immune suppressive properties of ovarian cancer, ex vivo stimulation of autologous patient monocytes with interferons and infusion of all three agents intraperitoneally (IP) can provide a strong pro-inflammatory environment at the site of disease to kill malignant cells.MethodsPatient monocytes are isolated through counterflow elutriation and stimulated ex vivo with interferons and infused IP through a semi-permanent catheter. We have designed a standard 3 + 3 dose escalation study to explore the highest tolerated dose of interferons and monocytes infused IP in patients with chemotherapy resistant ovarian cancer. Secondary outcome measurements of changes in the peripheral blood immune compartment and plasma cytokines will be studied for correlations of response.DiscussionWe have developed a novel immunotherapy focused on the innate immune system for the treatment of ovarian cancer. We have combined the use of autologous monocytes and interferons alpha and gamma for local–regional administration directly into the peritoneal cavity. This therapy is highly unique in that it is the first study of its type using only components of the innate immune system for the locoregional delivery consisting of autologous monocytes and dual interferons alpha and gamma.Trial Registration ClinicalTrials.gov Identifier: NCT02948426, registered on October 28, 2016. https://clinicaltrials.gov/ct2/show/NCT02948426

Abstract 2043: Effects of 24-h carboplatin pretreatment on olaparib clearance in women's cancers using noncompartmental and population pharmacokinetic analyses

Background: Olaparib (OLA) is a PARP inhibitor approved for use in deleterious germline BRCA mutated recurrent or refractory ovarian cancer. Combining OLA with carboplatin (CARBO) could have additive effects based on platinum-DNA adducts requiring PARP for DNA repair. Preclinical data suggest greater cytotoxicity when CARBO is given prior to OLA. However, the optimal treatment sequence of these agents has not been studied previously in patients. We therefore investigated: 1) the effects of CARBO treatment on the pharmacokinetics (PK) and pharmacodynamics (PD) of OLA; 2) in vitro mechanisms of the interaction between CARBO and OLA. Methods: Clinical PK and PD data of OLA were obtained from 58 patients with confirmed recurrent or refractory women9s cancers participating in a two arm, parallel design, phase 1 trial (NCT01237067). In cycle 1 OLA tablets (200 mg BID) were given for 7 days either followed by CARBO (AUC 4) on day 8 (arm A) or after CARBO on day 1 (Arm B). In cycle 2 the arms received the reversed scheme. PK of OLA were assessed in both cycles by noncompartmental (NCA) and population pharmacokinetic (PPK) analyses. For PK/PD analyses, PAR levels were measured at baseline and 24 h after the first OLA dose. In vitro mechanistic studies were carried out by incubating whole human blood and avian DT40 PARP-1 KO cells with 10 μM CARBO for 24 h, followed by 1h-treatment of isolated PBMCs and PARP-1 KO cells with 10 μM OLA. Intracellular OLA concentrations were determined using UPLC-MS/MS. Results: Both NCA and PPK analyses showed a ∼50% increase in OLA clearance when CARBO was administered 24-h prior (P Conclusion: This is the first known PK analysis showing a significant increase in OLA clearance after pretreatment with CARBO, possibly leading to subtherapeutic plasma concentrations of OLA. Preclinical experiments are ongoing to reveal the exact pharmacological mechanisms of this interaction. Citation Format: Andrew K.L. Goey, Cody J. Peer, Tristan M. Sissung, Jeffrey Roth, Shandiz Shahbazi, Jeffers Nguyen, Christina M. Annunziata, Nicole Houston, Elise C. Kohn, Jung-Min Lee, William D. Figg. Effects of 24-h carboplatin pretreatment on olaparib clearance in women9s cancers using noncompartmental and population pharmacokinetic analyses. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2043.