Daniel A. Rushing

Results of an International Randomized Phase III Trial of the Mammalian Target of Rapamycin Inhibitor Ridaforolimus Versus Placebo to Control Metastatic Sarcomas in Patients After Benefit From Prior Chemotherapy

PURPOSE Aberrant mammalian target of rapamycin (mTOR) signaling is common in sarcomas and other malignancies. Drug resistance and toxicities often limit benefits of systemic chemotherapy used to treat metastatic sarcomas. This large randomized placebo-controlled phase III trial evaluated the mTOR inhibitor ridaforolimus to assess maintenance of disease control in advanced sarcomas. PATIENTS AND METHODS Patients with metastatic soft tissue or bone sarcomas who achieved objective response or stable disease with prior chemotherapy were randomly assigned to receive ridaforolimus 40 mg or placebo once per day for 5 days every week. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), best target lesion response, safety, and tolerability. RESULTS A total of 711 patients were enrolled, and 702 received blinded study drug. Ridaforolimus treatment led to a modest, although significant, improvement in PFS per independent review compared with placebo (hazard ratio [HR], 0.72; 95% CI, 0.61 to 0.85; P = .001; median PFS, 17.7 v 14.6 weeks). Ridaforolimus induced a mean 1.3% decrease in target lesion size versus a 10.3% increase with placebo (P < .001). Median OS with ridaforolimus was 90.6 weeks versus 85.3 weeks with placebo (HR, 0.93; 95% CI, 0.78 to 1.12; P = .46). Adverse events (AEs) more common with ridaforolimus included stomatitis, infections, fatigue, thrombocytopenia, noninfectious pneumonitis, hyperglycemia, and rash. Grade ≥ 3 AEs were more common with ridaforolimus than placebo (64.1% v 25.6%). CONCLUSION Ridaforolimus delayed tumor progression to a small statistically significant degree in patients with metastatic sarcoma who experienced benefit with prior chemotherapy. Toxicities were observed with ridaforolimus, as expected with mTOR inhibition. These data provide a foundation on which to further improve control of sarcomas.

A Phase I Study of the Safety and Pharmacokinetics of the Hypoxia-Activated Prodrug TH-302 in Combination with Doxorubicin in Patients with Advanced Soft Tissue Sarcoma

Purpose: The purpose of this study was to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety, pharmacokinetics and preliminary activity of TH-302, a hypoxia-activated prodrug, in combination with doxorubicin in patients with advanced soft tissue sarcoma. Patients and Methods: TH-302 was administered intravenously on days 1 and 8 and doxorubicin 75 mg/m2 on day 1 (2 h after TH-302) of every 3-week cycle. TH-302 starting dose was 240 mg/m2 with a classic 3 + 3 dose escalation. Pharmacokinetics were assessed on days 1 and 8 of cycle 1. Tumor assessments were performed after every second cycle. Results: Sixteen patients enrolled. Prophylactic growth factor support was added due to grade 4 neutropenia. The MTD was 300 mg/m2. DLTs at 340 mg/m2 were neutropenia-associated infection and grade 4 thrombocytopenia. Common adverse events included fatigue, nausea and skin rash. There was no evidence of pharmacokinetic interaction between TH-302 and doxorubicin. Five of 15 (33%) evaluable patients had a partial response by RECIST (Response Evaluation Criteria in Solid Tumors) criteria. Conclusions: The hematologic toxicity of doxorubicin is increased when combined with TH-302. This can be mitigated by prophylactic growth factor support. Toxicities were manageable and there was evidence of antitumor activity.

Phase II study of intravenous TZT-1027 in patients with advanced or metastatic soft-tissue sarcomas with prior exposure to anthracycline-based chemotherapy

TZT‐1027, a novel chemotherapeutic agent, is derived from dolastatin 10, and blocks cells during G2/M‐phase by interfering with microtubule assembly and stability. TZT‐1027 has exhibited potential cytotoxic activity in several human cancer cell lines (in vitro) and also demonstrated antitumor activity in human xenografts (in vivo). In addition, Phase I clinical investigations suggested activity in STS (soft‐tissue sarcoma).

SARC009: Phase 2 study of dasatinib in patients with previously treated, high-grade, advanced sarcoma

Dasatinib exhibited activity in preclinical models of sarcoma. The Sarcoma Alliance for Research through Collaboration (SARC) conducted a multicenter, phase 2 trial of dasatinib in patients with advanced sarcoma.

Clinical benefit of a precision medicine based approach for guiding treatment of refractory cancers

Patients and Methods Patients with metastatic solid tumors who had progressed on at least one line of standard of care therapy were referred to the Indiana University Health Precision Genomics Program. Tumor samples were submitted for DNA & RNA next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry for actionable targets. A multi-disciplinary tumor board reviewed all results. For each patient, the ratio of progression-free survival (PFS) of the genomically guided line of therapy divided by the PFS of their prior line was calculated. Patients whose PFS ratio was ≥ 1.3 were deemed to have a meaningful improvement in PFS. Results From April 2014–October 2015, 168 patients were evaluated and 101 patients achieved adequate clinical follow-up for analysis. 19 of 44 (43.2%) patients treated with genomically guided therapy attained a PFS ratio ≥ 1.3 vs. 3 of 57 (5.3%) treated with non-genomically guided therapy (p < 0.0001). Similarly, overall PFS ratios (irrespective of cutoff) were higher for patients with genomically guided therapy vs non-genomically guided therapy (p = 0.05). Further, patients treated with genomically guided therapy had a superior median PFS compared to those treated with non-genomically guided therapy (86 days vs. 49 days, p = 0.005, H.R. = 0.55, 95% C.I.:0.37-0.84). Conclusion Patients with refractory metastatic cancer who receive genomically guided therapy have improved PFS ratios and longer median PFS compared to patients who do not receive genomically guided therapy.

Randomized phase II study of trabectedin (ET-743) given by two different dosing schedules in patients (pts) with leiomyosarcomas (LMS) or liposarcomas (LPS) refractory to conventional doxorubicin and ifosfamide chemotherapy

9000 Background: Trabectedin (Yondelis), a marine-derived alkaloid, has shown antitumor activity as therapy for advanced STS in pts refractory to conventional chemotherapy. LMS and LPS pts were selected for further study since these subtypes appeared to have somewhat higher rates of clinical benefit than other STS subtypes. METHODS To evaluate the efficacy and tolerability of ET-743 administered either as a 3-hr IV infusion given weekly for 3 consecutive weeks in a 4 week cycle (Arm A) or as a 24-hr IV infusion q 3 weeks (Arm B) to pts following progression despite prior doxorubicin plus ifosfamide chemotherapy. Pts with PS 0-1, normal bilirubin and alkaline phosphatase (AP) levels, and measurable LMS or LPS were eligible for study. Patients were pretreated with dexamethasone.The ET-743 dose was reduced if any abnormal elevation of bilirubin or AP was noted between cycles, or if any other unacceptable toxicity occurred. Histology will be centrally reviewed and patients whose diagnosis cannot be confirmed will be replaced. RESULTS 60 pts have been accrued so far, at 16 sites, in this multicenter trial. At this time, 29 pts are eligible for evaluation of response. Despite the small number of pts evaluable so far, activity has been noted using both schedules, with 3 pts on the 24 hr infusion schedule exhibiting partial responses. Tolerability overall has been acceptable and consistent with prior experience with this agent. [Figure: see text] Conclusion: ET-743 given by either of these two schedules of administration can induce objective responses in a subset of refractory pts with LMS or LPS. Disease control as demonstrated by stable disease will be an important additional endpoint to evaluate in this population of pts with disease that was objectively progressing at study entry. This trial is ongoing. [Table: see text].

Phase 2 study of dasatinib in patients with alveolar soft part sarcoma, chondrosarcoma, chordoma, epithelioid sarcoma, or solitary fibrous tumor

Alveolar soft part sarcoma (ASPS), chondrosarcoma (CS), chordoma, epithelioid sarcoma, and solitary fibrous tumor (SFT) are malignant tumors that are relatively resistant to chemotherapy and for which more effective drug therapy is needed.

Topiramate in the Treatment of Neuropathic Pain in Patients with Cancer

INTRODUCTION Neuropathic pain has been reported to affect 40%-50% of patients with cancer. PATIENTS AND METHODS Consecutive patients selected from the outpatient/adult patient palliative care clinic of the Roudebush Veterans Affairs Medical Center and the Indiana University Palliative Clinic were reviewed. A verbal pain linear analogue assessment scale was used to assess neuropathic pain. Pain medication history was also reviewed in addition to percent pain relief. The following variables were extracted from the medical record: pain characteristics, location, cause, date of initiation of therapy, maximal tolerated dose, pain scores on the visit of optimal tolerated dose, other concurrent medications, number of months of pain before initiation of topiramate therapy, and total duration of topiramate therapy. Decrease in worst, best, and average pain was recorded, as were the development of any adverse effects. RESULTS Of the 13 patients on second- and third-line therapy, 53.8% had >/= 30% decrease in worst pain; 69.2% had >/= 30% decrease in average pain, and 53.8% had >/= 30% decrease in best pain. Eight of 13 patients (61.5%) experienced adverse effects. Five patients discontinued (38.5%) topiramate because of adverse events. CONCLUSION Because our retrospective study showed topiramate to be a beneficial second- and third-line therapy in patients with cancer who did not experience adequate pain control on previous regimens, further prospective studies are needed to establish this medication in the armamentarium of neuropathic cancer pain management.

Efficacy and safety of trabectedin or dacarbazine in patients with advanced uterine leiomyosarcoma after failure of anthracycline-based chemotherapy: Subgroup analysis of a phase 3, randomized clinical trial

OBJECTIVE Trabectedin demonstrated significantly improved disease control in leiomyosarcoma and liposarcoma patients in a global phase 3 trial (NCT01343277). A post hoc analysis was conducted to assess the efficacy and safety of trabectedin or dacarbazine in women with uterine leiomyosarcoma (uLMS), the largest subgroup of enrolled patients (40%). METHODS Of 577 patients randomized 2:1 to receive trabectedin 1.5mg/m2 by 24-hour IV infusion or dacarbazine 1g/m2 by 20-120-minute IV infusion once every three weeks, 232 had uLMS (trabectedin: 144; dacarbazine: 88). The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), objective response rate (ORR), clinical benefit rate (CBR: complete responses+partial responses+stable disease [SD] for at least 18weeks), duration of response (DOR), and safety. RESULTS PFS for trabectedin was 4.0months compared with 1.5months for dacarbazine (hazard ratio [HR]=0.57; 95% CI 0.41-0.81; P=0.0012). OS was similar (trabectedin 13.4months vs. dacarbazine 12.9months, HR=0.89; 95% CI 0.65-1.24; P=0.51) between groups. ORR was 11% with trabectedin vs. 9% with dacarbazine (P=0.82). CBR for trabectedin was 31% vs. 18% with dacarbazine (P=0.05); median DOR was 6.5months for trabectedin vs. 4.1months for dacarbazine (P=0.32). Grade 3/4 treatment-emergent adverse events observed in ≥10% of patients in the trabectedin group included transient aminotransferase (aspartate/alanine) elevations, anemia, leukopenia, and thrombocytopenia. CONCLUSIONS In this post hoc subset analysis of patients with uLMS who had received prior anthracycline therapy, trabectedin treatment resulted in significantly longer PFS versus dacarbazine, with an acceptable safety profile. There was no difference in OS.

Abstract CT145: A phase I open-label study to evaluate the effect of olaratumab on the pharmacokinetics (PK) of doxorubicin (Dox) in patients with advanced soft tissue sarcoma (STS)

Olaratumab (Olara), a fully human monoclonal antibody that selectively binds human platelet-derived growth factor receptor alpha and blocks ligand binding, shows encouraging efficacy in combination with Dox in STS. Patients with metastatic or locally advanced STS not amenable to treatment with surgery or curative radiotherapy, aged ?18 years with an ECOG PS of 0-2 and documented LVE fraction ?50% were included. The primary objective was to assess the effect of Olara on the PK of Dox. Secondary objectives were to further characterize the PK and safety profiles of Olara alone and in combination with Dox. Drug-drug interaction (DDI) was assessed in 21-day cycles, where patients received each drug alone (Cycle 1) then in combination (Cycle 2). In Cycles 3-8, patients with clinical benefit could continue treatment with Olara+Dox. 15-mg/kg Olara was given IV over ∼60 min; 75-mg/m2 Dox was given IV over ∼15 min. Overall, 25 patients (10 male and 15 female, aged 27-83 years) received at least one dose of study drug; as planned, 15 patients were evaluable for PK and DDI assessment. The AUC and Cmax for Dox were similar with or without Olara; the 90% CIs for the ratios of geometric LS means for AUC were within the standard no-effect boundary (0.8, 1.25); the 90% CI for Cmax was only slightly out of the boundary but with a Cmax ratio close to unity (0.984). After the first infusion of Olara alone (Cycle 1, Day 10), a mean Olara Cmax of 293μg/mL was achieved at ∼2h post start of infusion, with a mean t1/2 of ∼157h. The mean Olara CL was 0.0259L/h. After the second infusion (Cycle 2, Day 1, Olara+Dox), Olara serum concentration had a median tmax of ∼2.8h post start of infusion, and the mean Cmax was higher (393μg/mL), due to the residual Olara serum concentrations from cycle 1. The mean t1/2 (∼131h) and CL (0.0218L/h) were, however, similar to those obtained after the first infusion. These Olara PK results are consistent with those previously reported. No deaths occurred. The most common treatment-emergent AE reported during the study were nausea (48%) and fatigue (44%). One Grade 4 IRR was observed; there was no evidence of QT prolongation. IV infusion of Olara did not have a clinically relevant effect on systemic exposure to Dox when both agents were given in combination. The PK of Olara alone and with Dox was consistent with previously reported data. Olara+Dox had an acceptable safety profile Citation Format: Victor Villalobos, Mark Agulnik, Seth M. Pollack, Daniel A. Rushing, Arun Singh, Brian A. Van Tine, Chukwuemeka Okereke, Wee Teck Ng, Damien M. Cronier. A phase I open-label study to evaluate the effect of olaratumab on the pharmacokinetics (PK) of doxorubicin (Dox) in patients with advanced soft tissue sarcoma (STS). [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 CT145.