Abstract
In ovarian cancer (OC), IL-17-producing T cells (Th17s) predict improved survival, whereas regulatory T cells predict poorer survival. We previously developed a vaccine whereby ...patient-derived dendritic cells (DCs) are programmed to induce Th17 responses to the OC antigen folate receptor alpha (FRα). Here we report the results of a single-arm open-label phase I clinical trial designed to determine vaccine safety and tolerability (primary outcomes) and recurrence-free survival (secondary outcome). Immunogenicity is also evaluated. Recruitment is complete with a total of 19 Stage IIIC-IV OC patients in first remission after conventional therapy. DCs are generated using our Th17-inducing protocol and are pulsed with HLA class II epitopes from FRα. Mature antigen-loaded DCs are injected intradermally. All patients have completed study-related interventions. No grade 3 or higher adverse events are seen. Vaccination results in the development of Th1, Th17, and antibody responses to FRα in the majority of patients. Th1 and antibody responses are associated with prolonged recurrence-free survival. Antibody-dependent cell-mediated cytotoxic activity against FRα is also associated with prolonged RFS. Of 18 patients evaluable for efficacy, 39% (7/18) remain recurrence-free at the time of data censoring, with a median follow-up of 49.2 months. Thus, vaccination with Th17-inducing FRα-loaded DCs is safe, induces antigen-specific immunity, and is associated with prolonged remission.
AB160 is a 160 nm nano-immunoconjugate consisting of nab-paclitaxel (ABX) nanoparticles non-covalently coated with bevacizumab (BEV) for targeted delivery into tissues expressing high levels of VEGF. ...Preclinical data showed that AB160 resulted in greater tumor targeting and tumor inhibition compared to sequential treatment with ABX then BEV. Given individual drug activity, we investigated the safety and toxicity of AB160 in patients with gynecologic cancers.
A 3+3 phase I trial was conducted with 3 potential dose levels in patients with previously treated endometrial (EC), cervical (CC), and platinum-resistant ovarian cancer (OC) patients to ascertain the recommended Phase II dose (RP2D). AB160 was administered intravenously on Days 1, 8 and 15 of a 28-day cycle (ABX 75-175 mg/m2, BEV 30-70 mg/m2). Pharmacokinetic analyses were performed.
No dose-limiting toxicities (DLTs) were seen among the 3 DLs tested. Grade 3/4 toxicities included neutropenia, thromboembolic events, and leukopenia. DL2 (ABX 150 mg/m2, BEV 60 mg/m2) was chosen as the RP2D. Seven of the 19 patients with measurable disease (36.8%) had confirmed partial responses (95% CI: 16.3%-61.6%). Pharmacokinetic analyses demonstrated that AB160 allowed 50% higher paclitaxel dosing and that paclitaxel clearance mirrored that of therapeutic antibodies.
The safety profile and clinical activity of AB160 supports further clinical testing in patients with gynecologic cancers; the RP2D is DL2 (ABX 150 mg/m2, BEV 60 mg/m2).
Background:
Paclitaxel-treated patients can suffer from years of peripheral neuropathy with pain, numbness, and tingling. Promising preclinical data with poly (ADP-ribose) polymerase (PARP) ...inhibitors led us to explore this class of agents to palliate this neuropathy.
Methods:
We relied on a completed trial that tested the antineoplastic effects of veliparib (NCT01012817). Data from patients who had been enrolled on NCT01012817, who previously received paclitaxel, and who had completed a validated pain assessment instrument were evaluated for improvement in their pain scores.
Results:
All 34 eligible patients were women, and all had a metastatic gynecological malignancy. On a 10-point scale (higher numbers indicative of worse pain), the average baseline score was 3.6 (range: 0-7). Seven patients (21%; 95% confidence interval: 9%-38%) manifested a drop in pain score (1 score lower than baseline followed by at least one consecutive value also below baseline). Of note, no patients initiated other therapy for neuropathy while on NCT01012817.
Conclusion:
The PARP inhibitors merit further study for chemotherapy-induced peripheral neuropathy. For patients suffering from peripheral neuropathy, these putative palliative effects might prompt earlier consideration of a PARP inhibitor as part of cancer treatment.
Purpose
Paclitaxel causes the paclitaxel-induced acute pain (PIAP) syndrome. Based on preclinical data, we hypothesized that the protein kinase C (PKC) iota inhibitor, auranofin (a gold salt used for ...other pain conditions), palliates this pain.
Methods
In a randomized, double-blinded manner, patients who had suffered this syndrome were assigned a one-time dose of auranofin 6 mg orally on day #2 of the chemotherapy cycle (post-paclitaxel) versus placebo. Patients completed the Brief Pain Inventory and a pain diary on days 2 through 8 and at the end of the cycle. The primary endpoint was pain scores, as calculated by area under the curve, in response to “Please rate your pain by circling the one number that best describes your pain at its worse in the last 24 hours.”
Results
Thirty patients were enrolled. For the primary endpoint, mean area under the curve of 55 units (standard deviation 19) and 61 units (standard deviation 22) were observed in auranofin-treated and placebo-exposed patients, respectively (
p
= 0.44). On day 8 and at the end of the cycle, pain scores in auranofin-treated patients were more favorable, although differences were not statistically significant.
Conclusions
In the dose schedule studied, auranofin did not palliate the PIAP syndrome, but delayed beneficial trends suggest further study for this indication.
Objective:
A growing number of cancer antineoplastic agents can cause life-threatening acute infusion reactions. Because previous studies have not studied these reactions from the perspective of ...patients, this study was undertaken with that objective in mind.
Methods:
Patients who had an acute infusion reaction were interviewed based on the Leventhal model. Once saturation of content was achieved, interviews were transcribed and analyzed with qualitative methodology.
Results:
Twenty-one patients were enrolled. Most were women (n = 15); the median age was 58 years, and paclitaxel was the most common inciting agent. Three themes emerged. First, these reactions are frightening; patients made remarks such as “I was just thinking oh my God, I am dying.” Second, prior education about these reactions seemed to mitigate this fear, “Basically everything the nurses told me potentially could happen, like happened. So, I was prepared.” Third, when health-care providers were prompt and attentive during the reaction, patients described less fear with future chemotherapy, “So no, I’m really not fearful about going in tomorrow because I know they’ll be there and they’ll be watching me.”
Conclusion:
These reactions evoke fear which can be mitigated with education prior to and with prompt responsiveness during the acute infusion reaction.
This trial was undertaken (1) to determine the feasibility of enrolling asymptomatic ovarian cancer patients with CA-125 elevation in a trial with the protein kinase C iota (PKCι) inhibitor auranofin ...and (2) to understand patients' perceptions of CA-125 monitoring.
Asymptomatic ovarian cancer patients with CA-125 elevation received 3 mg auranofin orally twice per day and were evaluated. The patients participated in interviews about CA-125 monitoring.
Ten patients were enrolled in slightly over 6 months, exceeding our anticipated accrual rate. Four manifested stable CA-125 levels for 1 month or longer. The median progression-free survival was 2.8 months (95% CI: 1.3-3.8); auranofin was well tolerated. One patient had baseline and monthly CA-125 levels of 5,570, 6,085, 3,511, and 2,230 U/ml, respectively, stopped auranofin because of radiographic progression at 3 months, and manifested an increase in CA-125 to 7,168 U/ml approximately 3 months later. Patient interviews revealed (1) the important role of CA-125 in cancer monitoring, (2) ardent advocacy of CA-125 testing, and (3) an evolution toward CA-125 assuming a life of its own.
This study showed the feasibility of enrolling asymptomatic ovarian cancer patients with CA-125 elevation in a trial with auranofin. One patient had a decline in CA-125, suggesting that PKCι inhibition merits further study in ovarian cancer.
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