Grudem, Megan E.

TPS5630 Background: Platinum-resistant ovarian cancer (PROC) portends a poor prognosis and, although treatments are available, response rates are low. Previous studies have demonstrated that DNA topoisomerase I (TOP1) inhibitors exhibit clinical activity in PROC. Irinotecan also has a 15-25% response rate in some studies of platinum-resistant epithelial ovarian cancer but does not have FDA approval for this indication. Additional studies in preclinical models suggest that TOP1 poisons are more active if administered at low doses on prolonged schedules. PLX038 is a long-acting prodrug of the potent TOP1 inhibitor SN-38. In PLX038, SN-38 is covalently conjugated to circulating polyethylene glycol and is slowly released at a constant rate to provide the active agent with a long half-life, a low Cmax and very high exposure – important facets for optimal safety and efficacy of this drug. Further, in preclinical studies the nanoparticle prodrug accumulates and is retained in tumors, where it slowly releases the SN-38. Methods: This single arm, phase 2 clinical trial is open at Mayo Clinic in Rochester, MN. The primary endpoint is overall response rate and secondary endpoints include progression-free survival and assessment of tolerability of PLX038. Correlative goals include i) measurement of TOP1-DNA covalent complexes in tumor biopsies and circulating tumor cells to assess successful target engagement; ii) assessment of homologous recombination status and SLFN11 expression for correlation with tumor response rate; and iii) pharmacokinetics of SN-38 and SN-38G as well as their association with GI toxicity. Assessment of gut microbiota and association with GI toxicity profile are also being investigated. Eligible patients include women with platinum resistant high grade serous ovarian, primary peritoneal, and fallopian tube cancer who have received fewer than two prior chemotherapy regimens in the platinum-resistant setting. All patients must have an ECOG performance status of 0, 1, or 2 and adequate bone marrow, renal, and hepatic function. As of January 31, 2024, 12 of planned 37 patients have enrolled. Clinical trial information: NCT05465941 .

5562 Background: Platinum-resistant or refractory ovarian cancer remains a hard-to-treat disease given the poor prognosis and survival rates. Immune checkpoint inhibitors (ICI; such as pembrolizumab) have not been approved in this indication. Igrelimogene litadenorepvec (Ad5/3-E2F-d24-hTNF-IRES-hIL2; TILT-123), is an oncolytic adenovirus encoding for IL-2 and TNFa, designed to selectively lyse tumor cells while recruiting and activating T-cells, turning immunologically cold tumors hot. The combination of these therapies is appealing as TILT-123 should allow pembrolizumab to be more active, while pembrolizumab should delay emergence of T-cell exhaustion. Methods: PROTA (NCT05271318) is a multicenter open-label phase 1 clinical trial initiated to investigate the safety of TILT-123 in combination with pembrolizumab, in participants bearing ovarian cancer resistant or refractory to platinum-based therapy. In a 3+3 dose-escalation design, TILT-123 was administered intravenously and intratumorally/intraperitoneally to participants with an injectable tumor or carcinomatosis. Pembrolizumab (200mg/Q3wk) was not altered. Eligibility criteria included adequate hepatic and renal functions, and WHO/ECOG performance status of 0-1. Primary endpoint was safety by day 92 evaluated based on adverse events, laboratory values, vital signs, and electrocardiogram. Secondary endpoints included anti-tumor response (RECIST1.1/iRECIST), CA125 levels, pharmacokinetics, transduction of tumors, immune response towards the virus and tumors. Data cutoff was 22Jan2024. Results: 15 patients were enrolled with a median age of 66 (36-78) years, and 14 were evaluable for treatment response with RECIST 1.1/iRECIST. 8 patients were platinum-resistant, and 7 patients were platinum-refractory. Majority of patients had WHO/ECOG performance status 1. Prevalent cancer histology was epithelial ovarian cancer, with some fallopian tube cancer and primary peritoneal cancer. Dose-limiting toxicities were not observed. Frequent grade 1-4 treatment-related AEs (>30% of patients) were anemia, nausea, lymphocyte count decreased, fever and diarrhea. Stable disease (SD) by RECIST1.1 was achieved in 64.3% of evaluable patients and CA125 decreased below baseline in 50% of the patients at least in one timepoint. Median PFS and OS in all patients were 105 and 280 days, respectively. In patients with SD on day 92 by RECIST1.1, median OS was 293 days and median PFS was 174 days. Tumor biopsies indicated the presence of virus and induction of T-cells in injected and non-injected lesions. Conclusions: Combination of TILT-123 and pembrolizumab is safe and appears to induce disease control in a difficult-to-treat patient population. Investigation of TILT-123, pembrolizumab and pegylated liposomal doxorubicin is ongoing in similar patients. Clinical trial information: NCT05271318 .

Abstract Purpose: AB160 is a 160-nm nano-immunoconjugate consisting of nab-paclitaxel (ABX) nanoparticles noncovalently 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 with sequential treatment with ABX then BEV. Given individual drug activity, we investigated the safety and toxicity of AB160 in patients with gynecologic cancers. Patients and Methods: A 3+3 phase I trial was conducted with three potential dose levels in patients with previously treated endometrial, cervical, and platinum-resistant ovarian cancer 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. Results: No dose-limiting toxicities (DLT) were seen among the three dose levels 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% confidence interval, 16.3%–61.6%). Pharmacokinetic analyses demonstrated that AB160 allowed 50% higher paclitaxel dosing and that paclitaxel clearance mirrored that of therapeutic antibodies. Conclusions: 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).

e18097 Background: AB160 is a 160 nm nano-immunoconjugate consisting of nab-paclitaxel (NP) nanoparticles non-covalently coated with bevacizumab (BEV) for targeted delivery into tissues expressing high levels of vascular-endothelial growth factor (VEGF). Both taxanes (GOG-0129C, GOG-0126R, GOG-0127V) and BEV (GOG-0229E, AURELIA, GOG-0227C) have demonstrated clinical activity in previously treated metastatic endometrial cancer (EC), ovarian cancer (OC), and cervical cancer (CC), respectively. Methods: A 3+3 phase I trial was conducted in patients with EC, platinum-resistant OC and CC who had prior systemic treatment for metastatic disease to determine the maximum tolerated dose of AB160 administered intravenously on days 1, 8 and 15 of a 28-day cycle. The starting dose level (DL1) was NP at 125 mg/m2 with BEV at 50 mg/m2. There were 2 higher dose levels: DL2 (NP at 150 mg/m2 with BEV at 60 mg/m2) and DL3 (NP at 175 mg/m2 with BEV at 70 mg/m2). Dose limiting toxicities (DLT) included grade (G) 4 neutropenia or anemia, PLT < 25,000, serum creatinine ≥2 times baseline, G2-4 neurologic toxicity or G3-4 non-hematologic toxicities. Disease evaluations were conducted after every 2 treatment cycles using RECIST criteria. Patients were treated until disease progression or intolerability. Samples were collected for pharmacokinetic (PK) studies. Results: Nine women 41 – 74 years of age (median 57) have enrolled (5 with EC and 4 with OC); data are available for the first 8. No DLTs have been observed among the 3 women enrolled on DL1, 3 women on DL2, and 2 women on DL3. All 3 patients on DL3 continue on treatment. The other 6 patients have discontinued due to adverse reactions (3), progression (2), and patient choice (1). The median number of cycles administered is 6 (4-14). The most common severe (G3/4) toxicities include neutropenia (37.5%) and leukopenia (25%). There have been 5 partial responses (62.5%): 1 on DL1 and 2 each on DL2 and DL3. PK evaluation is pending. Conclusions: AB160 therapy is safe and demonstrates promising clinical activity in patients with previously treated metastatic gynecologic malignancies. Further clinical testing is being pursued in this patient population. Clinical trial information: NCT02020707.

Background: Seventy percentage of patients who receive paclitaxel have diffuse, refractory myalgias, and arthralgias. Based on anecdotal reports, this study explored whether loratadine, an antihistamine, palliates these symptoms. Methods: The medical records of postoperative ovarian and patients with endometrial cancer were studied, as these patients are routinely prescribed paclitaxel. Records were screened for patients who received paclitaxel and loratadine concurrently. Results: Forty patients are the focus of this report. Eight had paclitaxel-induced myalgias and arthralgias and then took loratadine; of these, 6 (75%; 95% confidence interval: 35%, 97%) manifested evidence of symptom improvement: “She did experience some migrating generalized body aches and pains…but this has resolved.” Of those already receiving loratadine but with no myalgias and arthralgias, only 11 of 32, or 34% (95% confidence interval: 19%, 53%), developed myalgias and arthralgias (in contrast to the previously reported symptom rate of 70%). No adverse events were clearly attributed to loratadine. Conclusion: These preliminary data support further study of loratadine for paclitaxel-induced myalgias and arthralgias.

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.

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.