Taxane-refractory Patients Research Articles

Initial results from a phase 1b study of ORIC-101, a glucocorticoid receptor antagonist, in combination with nab-paclitaxel in patients with advanced solid tumors.

2553 Background: ORIC-101 is a potent and selective, orally bioavailable, small molecule antagonist of the glucocorticoid receptor (GR). Preclinical studies have demonstrated that activation of GR signaling leads to decreased responsiveness to chemotherapeutics (eg, taxanes) and antiandrogens across multiple tumor types. Mechanistically, ORIC-101 inhibits GR transcriptional activity and blocks the prosurvival signals mediated by the activated nuclear hormone receptor. Methods: A 3+3 dose escalation design was used to assess safety, pharmacokinetics (PK), pharmacodynamics (PD), and select the Recommended Phase 2 Dose (RP2D) of ORIC-101 in combination with nab-paclitaxel (nab-pac; NCT03928314). ORIC-101 doses ranging from 80 to 240 mg once daily, given either intermittently or in a continuous dosing regimen, were evaluated in combination with weekly nab-pac at 75 or 100 mg/m2. Plasma PK and PD biomarkers were assessed on day 1 and after repeat dosing. PD modulation in blood-derived peripheral blood mononuclear cells (PBMCs) was assessed by RT-qPCR for GR target genes. Antitumor activity was assessed by RECIST v1.1. Results: 21 patients with 10 different solid tumors, with and without a prior taxane, were treated in 5 cohorts. ORIC-101 exposure increased with dose, with no evidence for drug-drug interaction with nab-pac. In the initial cohort at 240 mg ORIC-101 and 100 mg/m2 nab-pac, 2 patients experienced dose limiting toxicities (DLTs) of Grade 3 fatigue and Grade 4 neutropenia/thrombocytopenia, respectively. No further DLTs were observed in subsequent cohorts and the RP2D was established as 160 mg ORIC-101 dosed once daily continuously for 21 days with nab-pac 75 mg/m2 given on days 1, 8, and 15 of each 28-day cycle, without requirement for prophylactic granulocyte colony-stimulating factor (G-CSF). The most common (> 15%), all grade treatment-related adverse events (AEs) were nausea (38%), diarrhea (33%), fatigue (29%), leukopenia (29%), neutropenia (29%), anemia (24%), and 19% of patients had increased liver function tests and alopecia. Biomarker data demonstrated ORIC-101-induced reduction in GR target gene expression in PBMCs, indicating PD modulation at all dose levels of ORIC-101. Preliminary antitumor activity was observed in 3 taxane-refractory patients with breast, endometrial, and pancreatic cancers. Conclusions: The combination of ORIC-101 and nab-paclitaxel demonstrated an acceptable tolerability profile and does not require prophylactic G-CSF. PK and PD showed no evidence of drug-drug-interaction and demonstrated GR target inhibition. Preliminary antitumor activity was observed in patients with solid tumors that previously progressed on a taxane-containing regimen. Dose expansion is ongoing at the RP2D in dedicated pancreatic, ovarian, triple negative breast cancers, and tissue-agnostic cohorts. Clinical trial information: NCT03928314.

Efficacy and safety of eribulin in taxane-refractory patients in the 'real world'.

Recent clinical, randomized and observational studies showed that eribulin, an analogous of Halichondrin B, was beneficial and well-tolerated in heavily pretreated metastatic breast cancer patients. Here, we aim to evaluate the effectiveness and safety of eribulin in taxane-refractory metastatic breast cancer patients. In this subanalysis of the ESEMPIO study database, we selected 91 subjects with well-defined taxane refractoriness and complete data available. 41 patients (45.2%) showed clinical benefit; one complete response (2.2%) and 16 partial responses (17.6%) were observed. Median progression-free survival and median overall survival were 3.1 and 11.6 months, respectively. The most experienced adverse event was asthenia/fatigue (58%), followed by neutropenia (30%). The treatment-related toxicity led to eribulin-dose reduction in 19 patients and suspension in nine. This study shows that eribulin is effective and well tolerated also in taxane-refractory patients in clinical practice.

P5-19-09: Phase II Trial of Ixabepilone Plus Carboplatin in Patients with Metastatic Breast Cancer: The ECLIPSE Study.

Abstract Introduction: Ixabepilone adds to the antitumor effectiveness of capecitabine in both ER+ and triple negative (TN) breast cancer. Ixabepilone has antitumor activity in taxane-refractory patients, and novel combinations are needed in this poor prognosis population. Carboplatin combined with gemcitabine or paclitaxel has activity in metastatic breast cancer; there is also demonstrated activity of the gemcitabine/carboplatin combination in the ER+ versus TN subsets. A Phase I study of ixabepilone + carboplatin in solid tumor patients demonstrated the safety of this combination.1 We conducted a Phase II trial of ixabepilone + carboplatin at the doses and schedule used in the Phase I trial to determine its effectiveness in hormone receptor positive (HR+) and TN patients. Methods: This was a Phase II, open label, nonrandomized parallel, noncomparative study of 2 groups. Patients could have received up to 2 lines of treatment for metastatic disease. All patients received ixabepilone 20 mg/m2 on Days 1 and 8 and carboplatin AUC=2.5 on Days 1 and 8 of each 21-day cycle. Patients were stratified as either (HR+) (n=50) or (TN) ER-/PR-/HER2− (n=53). Patients received drug until PD or intolerable toxicity. Patients continued treatment for as long as they responded (CR, PR, or SD). The primary objective was to evaluate objective response rate (ORR). Secondary objectives included evaluation of clinical benefit rate (CBR) defined as ORR (CR+PR)+SD≥6 months, progression-free survival (PFS), overall survival (OS), duration of responses, and toxicity. Results: Based on preliminary data, 96 patients (55 [57.3%] HR+ and 40 [41.7%] TN) received study treatment, with 1 patient found ineligible. Median age was 55.2 years; all were females; baseline PS of 0/1/2 was 50/44/2; stage at diagnosis I/II/III/IV/unknown was 12/38/23/21/2, respectively. PR was 26.3% overall. There were no CRs. CBR overall was 41.1% (39), 52.7% (29) for HR+ patients, and 25.6% (10) for TN patients. Median PFS was 7.6 months, and median OS was 12.7 months. The median time to response and duration of response in patients achieving a PR was 1.7 and 6.5 months, respectively. Grade 3/4 hematological toxicities included 49% neutropenia, 10.4% anemia, and 4.2% thrombocytopenia. The most common grade 3/4 non-hematologic toxicities included fatigue (8.3%), nausea (6.3%), neuropathy (6.3%), vomiting (5.2%), and dehydration (5.2%). Of 32 deaths during the study, one was due to neutropenic sepsis, and 25 were due to PD. Conclusion: The combination of ixabepilone plus carboplatin was a tolerable and active regimen for both HR+ and TN breast cancer. In general, it had expected hematologic and manageable non-hematological toxicities. Further follow-up of the remaining 12 patients still on treatment is ongoing. 1. Plummer R, et al. Clin Cancer Res. 2008 Dec 15;14(24):8288–8294. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-19-09.

Phase I pharmacokinetic study of a weekly liposomal paclitaxel formulation (Genexol®-PM) in patients with solid tumors

BackgroundThe aim of this study was to determine the maximum tolerated dose (MTD) and the pharmacokinetic profile of Genexol-PM in Asian cancer patients. Materials and methodsPatients (N=24) refractory to previous chemotherapy received Genexol-PM as an 1-h infusion on a weekly basis for 3 weeks followed by a resting week. The starting dose was 80 mg/m2 and the maximum administered dose was 200 mg/m2. ResultsThe majority of patients had lung, nasopharyngeal and breast cancers and in eleven patients (46%), taxane-based chemotherapy had previously failed. The MTD was defined at 180 mg/m2. The most common grade 3 non-hematologic adverse events in cycle 1 were fatigue (4%) and neuropathy (4%) occurring mainly at 200 mg/m2. Five (21%) patients had partial response, nine (38%) had stable disease and seven (29%) had disease progression. Five of 11 previously taxane-refractory patients showed clinical benefit to Genexol-PM. The pharmacokinetics of Genexol-PM displayed dose-proportionality, with both the maximum concentration (Cmax) and the area under the concentration-time curve from zero to infinity (AUC0–∞) increasing by approximately four- and threefold, respectively, as the dose of Genexol-PM was escalated from 80 to 200 mg/m2. The median total-body clearance of Genexol-PM for all patients was 43.9 l/h. ConclusionThe weekly regimen of Genexol-PM was well tolerated and responses were observed in patients with refractory tumors, including patients who had failed taxane-based chemotherapy previously.

Phase I and Pharmacokinetic Study of XRP6258 (RPR 116258A), a Novel Taxane, Administered as a 1-Hour Infusion Every 3 Weeks in Patients with Advanced Solid Tumors

To assess the feasibility of administering XRP6258, a new taxane with a low affinity for the multidrug resistance 1 protein, as a 1-hour i.v. infusion every 3 weeks. The study also sought to determine the maximum tolerated dose and the recommended dose, to describe the pharmacokinetic (PK) behavior of the compound, and to seek preliminary evidence of anticancer activity. Twenty-five patients with advanced solid malignancies were treated with 102 courses of XRP6258 at four dose levels ranging from 10 to 25 mg/m(2). Dose escalation was based on the occurrence of dose-limiting toxicity (DLT) at each dose level, provided that PK variables were favorable. The maximum tolerated dose was defined as the dose at which at least two patients developed a DLT at the first course. Neutropenia was the principal DLT, with one patient experiencing febrile neutropenia and two others showing prolonged grade 4 neutropenia at the 25 mg/m(2) dose level. Nonhematologic toxicities, including nausea, vomiting, diarrhea, neurotoxicity, and fatigue, were generally mild to moderate in severity. XRP6258 exhibited dose-proportional PK, a triphasic elimination profile, a long terminal half-life (77.3 hours), a high clearance (mean CL, 53.5 L/h), and a large volume of distribution (mean V(ss), 2,034 L/m(2)). Objective antitumor activity included partial responses in two patients with metastatic prostate carcinoma, one unconfirmed partial response, and two minor responses. The recommended phase II dose of XRP6258 on this schedule is 20 mg/m(2). The general tolerability and encouraging antitumor activity in taxane-refractory patients warrant further evaluations of XRP6258.

Farnesyltransferase Inhibitors Reverse Taxane Resistance

The combination of farnesyltransferase inhibitors (FTIs) and taxanes has been shown to result in potent antiproliferative and antimitotic synergy. Recent phase I and II clinical trials have shown that this combination shows clinical activity in taxane-refractory or taxane-resistant cancer patients. To understand the mechanism behind these clinical observations, we used a cancer cell model of paclitaxel resistance and showed that the FTI/taxane combination retains potent antiproliferative, antimitotic, and proapoptotic activity against the paclitaxel-resistant cells, at doses where each drug alone has little or no activity. To probe the mechanistic basis of these observations, paclitaxel activity was monitored in living cells using the fluorescently conjugated paclitaxel, Flutax-2. We observed that all FTIs tested increase the amount of microtubule-bound Flutax-2 and the number of microtubules labeled with Flutax-2 in both paclitaxel-resistant and paclitaxel-sensitive cells. Importantly, we observed a consequential increase in microtubule stability and tubulin acetylation with the combination of the two drugs, even in paclitaxel-resistant cells, confirming that the enhanced taxane binding in the presence of FTI affects microtubule function. Furthermore, this mechanism is dependent on the function of the tubulin deacetylase, HDAC6, because in cells overexpressing a catalytically inactive HDAC6, FTIs are incapable of enhancing Flutax-2-microtubule binding. Similar results were obtained by using an FTI devoid of farnesyltransferase inhibitory activity, indicating that functional inhibition of farnesyltransferase is also required. Overall, these studies provide a new insight into the functional relationship between HDAC6, farnesyltransferase, and microtubules, and support clinical data showing that the FTI/taxane combination is effective in taxane-refractory patients.

Phase 2 results of ABT-751 in subjects with taxane-refractory breast cancer: Interim analysis

724 Background: Therapy is limited for subjects with taxane-refractory metastatic breast cancer. ABT-751, an oral antimitotic agent that binds to the colchicine site of β-tubulin and prevents microtubule polymerization, has shown antitumor activity in breast xenograft models. In addition, ABT-751 is not an MDR substrate, making it an attractive drug candidate for taxane-refractory patients. Methods: This Phase 2, open label, multi-center study evaluated the safety and efficacy of ABT-751 in subjects with advanced breast cancer (N = 18). For each cycle, subjects received 200 mg ABT-751 orally once daily for 21 consecutive days followed by a 7-day break. Safety was evaluated by adverse events (AEs) and laboratory assessments, while tumor response was assessed radiographically every 2 cycles using RECIST. Time to progression (TTP) was analyzed using Kaplan-Meier methodology. Results: The median duration of therapy was 2 cycles (range 1 to 8). AEs were reported for 17/18 subjects, and 9/18 (50%) subjects experienced serious adverse events (SAEs). The most commonly reported AEs, regardless of causality, were constipation (78%), asthenia (56%), nausea (44%), and abdominal pain (33%). The most common Grade 3 or 4 AEs possibly or probably related to study drug were asthenia (11%), constipation (11%), and ileus (11%). The most common SAE was ileus (17%). Three subjects (17%) experienced SAEs considered possibly related to study drug, the most common of which were ileus (11%) and dehydration (6%). The median TTP was 1.8 months (95% CI = 1.4 - 2.3). There were no partial or complete responses, although two subjects exhibited stable disease for 7 to 8 cycles. All 18 subjects have discontinued the study. This study was designed to target a 25% response rate in an advanced taxane-refractory patient population. The target response rate was not met based on the results of this interim analysis. Conclusions: Although the 21-day dosing regimen for ABT-751 was feasible, these data do not suggest a compelling tumor response with single-agent ABT-751 therapy in this highly advanced, taxane-refractory patient population. Future studies may explore potential synergism between ABT-751 and other cytotoxic agents. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories Abbott Laboratories

Phase II Clinical Trial of Ixabepilone (BMS-247550), an Epothilone B Analog, in Metastatic and Locally Advanced Breast Cancer

Ixabepilone (BMS-247550) is an epothilone B analog that stabilizes microtubules and has antitumor activity in taxane-refractory patients in phase I studies. In a phase II trial, we evaluated the efficacy and safety of ixabepilone in women with metastatic and locally advanced breast cancer. Breast cancer patients with measurable disease who had paclitaxel and/or docetaxel as prior neoadjuvant, adjuvant, or metastatic therapy were treated with ixabepilone at 6 mg/m2/d intravenously on days 1 through 5 every 3 weeks. Levels of glutamate (glu) -terminated and acetylated alpha-tubulin, markers of microtubule stabilization, were detected by Western blot and by immunohistochemistry in a subset of matched pre- and post-treatment tumor biopsies. Thirty-seven patients received 153 cycles of ixabepilone. The best responses were a complete response in one patient (3%), partial responses in seven patients (19%), and stable disease in 13 patients (35%). Grade 3 and 4 toxicities included neutropenia (35%), febrile neutropenia (14%), fatigue (14%), diarrhea (11%), nausea/vomiting (5%), myalgia/arthralgia (3%), and sensory neuropathy (3%). Two patients were removed from study because of prolonged grade 2 or 3 neurotoxicity, and three patients were removed from study for other grade 3 and 4 nonhematologic toxicities. Compared with baseline levels, levels of both glu-terminated and acetylated alpha-tubulin were increased in tumor biopsies performed after ixabepilone therapy. An objective response was seen in 22% of the patients in a population who had been previously treated with a taxane. Sensory neuropathy was mild with grade 3 neurotoxicity rarely seen. Microtubule stabilization occurred in tumor biopsies after treatment with ixabepilone.

A Phase I Pharmacokinetic and Biological Correlative Study of Oblimersen Sodium (Genasense, G3139), an Antisense Oligonucleotide to the Bcl-2 mRNA, and of Docetaxel in Patients with Hormone-Refractory Prostate Cancer

To assess the feasibility of administering oblimersen sodium, a phosphorothioate antisense oligonucleotide directed to the Bcl-2 mRNA, with docetaxel to patients with hormone-refractory prostate cancer; to characterize the pertinent pharmacokinetic parameters, Bcl-2 protein inhibition in peripheral blood mononuclear cell(s) (PBMC) and tumor; and to seek preliminary evidence of antitumor activity. Patients were treated with increasing doses of oblimersen sodium administered by continuous i.v. infusion on days 1 to 6 and docetaxel administered i.v. over 1 h on day 6 every 3 weeks. Plasma was sampled to characterize the pharmacokinetic parameters of both oblimersen and docetaxel, and Bcl-2 protein expression was measured from paired collections of PBMCs pretreatment and post-treatment. Twenty patients received 124 courses of the oblimersen and docetaxel combination at doses ranging from 5 to 7 mg/kg/day oblimersen and 60 to 100 mg/m(2) docetaxel. The rate of severe fatigue accompanied by severe neutropenia was unacceptably high at doses exceeding 7 mg/kg/day oblimersen and 75 mg/m(2) docetaxel. Nausea, vomiting, and fever were common, but rarely severe. Oblimersen mean steady-state concentrations were 3.44 +/- 1.31 and 5.32 +/- 2.34 at the 5- and 7-mg/kg dose levels, respectively. Prostate-specific antigen responses were observed in 7 of 12 taxane-naïve patients, but in taxane-refractory patients no responses were observed. Preliminary evaluation of Bcl-2 expression in diagnostic tumor specimens was not predictive of response to this therapy. The recommended Phase II doses for oblimersen and docetaxel on this schedule are 7 mg/kg/day continuous i.v. infusion days 1 to 6, and 75 mg/m(2) i.v. day 6, respectively, once every 3 weeks. The absence of severe toxicities at this recommended dose, evidence of Bcl-2 protein inhibition in PBMC and tumor tissue, and encouraging antitumor activity in HPRC patients warrant further clinical evaluation of this combination.

In vivo synergism between docetaxel and gemcitabine in patients with metastatic breast cancer: General concepts and future perspectives

The docetaxel and gemcitabine combination is an active regimen as salvage therapy in taxane-resistant or taxane-refractory patients with metastatic breast cancer (MBC). We recently conducted a phase II study administering this combination to patients with MBC after docetaxel failure, with remarkably high response rates that could be attributed to an in vivo synergism between the two drugs. Women with MBC who were refractory or resistant to docetaxel monotherapy as first- or second-line treatment were recruited. Patients with progressive or stable disease after receiving a minimum of four cycles of docetaxel received gemcitabine 900 mg/m 2 on days 1 and 8 plus docetaxel 100 mg/m 2on day 8, every 3 weeks. Forty-six percent of patients responded (three complete responses, 20 partial responses), while 28% had stable disease and 26% had progressive disease. Median duration of response was 6.07 ± 2.43 months. Neutropenia was the only grade 4 toxicity, and reported in seven patients. Other grade 3 toxicities included neutropenia (12 patients), thrombocytopenia (seven patients), and anemia (one patient), while nonhematologic toxicities were easily manageable. These data outline the importance of a rational combination of existing, active chemotherapeutic agents for MBC, and broadens our perspectives for more effective combination regimens in various solid tumors in the future.