A first-in-human phase 1 study of cavrotolimod, a TLR9 agonist spherical nucleic acid, in healthy participants: Evidence of immune activation.

Introduction: Tumor immunotherapy is designed to control malignancies through the host immune response but requires circumventing tumor-dysregulated immunomodulation through immunostimulation, relieving immunorepression, or a combination of both approaches. Here we designed and characterized cavrotolimod (formerly AST-008), an immunostimulatory spherical nucleic acid (SNA) compound targeting Toll-like receptor 9 (TLR9). We assessed the safety and pharmacodynamic (PD) properties of cavrotolimod in healthy participants in a first-in-human Phase 1 study under protocol AST-008-101 (NCT03086278; https://clinicaltrials.gov/ct2/show/NCT03086278). Methods: Healthy participants aged 18 to 40 years were enrolled to evaluate four dose levels of cavrotolimod across four cohorts. Each cohort included four participants, and all received a single subcutaneous dose of cavrotolimod. The dose levels were 5, 10, 12.5 and 18.8 µg/kg. Results and discussion: Cavrotolimod was well tolerated and elicited no serious adverse events or dose limiting toxicities at the doses tested. The results demonstrated that cavrotolimod is a potent innate immune activator, specifically stimulating Th1-type immune responses, and exhibits PD properties that may result in anti-tumor effects in patients with cancer. This study suggests that cavrotolimod is a promising clinical immunotherapy agent.

Onapristone Extended Release: Safety Evaluation from Phase I-II Studies with an Emphasis on Hepatotoxicity.

INTRODUCTION: Antiprogestins have demonstrated promising activity against breast and gynecological cancers, but liver-related safety concerns limited the advancement of this therapeutic class. Onapristone is a full progesterone receptor antagonist originally developed as an oral contraceptive and later evaluated in phase II studies for metastatic breast cancer. Because of liver enzyme elevations identified during clinical studies, further development was halted. Evaluation of antiprogestin pharmacology and pharmacokinetic data suggested that liver enzyme elevations might be related to off-target or metabolic effects associated with clinical drug exposure. OBJECTIVE: We explored whether the use of a pharmaceutic strategy targeting efficacious systemic dose concentrations, but with diminished peak serum concentrations and/or total drug exposure would mitigate hepatotoxicity. Twice-daily dosing of an extended-release formulation of onapristone was developed and clinically evaluated in light of renewed interest in antiprogestin therapy for treating progesterone receptor-positive breast and gynecologic cancers. The hepatotoxic potential of extended-release onapristone was assessed from two phase I-II studies involving patients with breast, ovarian, endometrial, and prostate cancer. RESULTS: Among the 88 patients in two phase I-II studies in progesterone receptor-positive malignancies treated with extended-release onapristone, elevated alanine aminotransferase/aspartate aminotransferase levels were found in 20% of patients with liver metastases compared with 6.3% without metastases. Of five patients with grade 3 or higher alanine aminotransferase elevations with or without bilirubin elevations (four with breast cancer and one with endometrial cancer), four were assessed as unrelated to extended-release onapristone by the safety data review committee. Furthermore, while the fifth patient's liver enzyme elevations were considered possibly drug related by the study investigator, they were adjudicated as unlikely to be related (< 25% likelihood) by a subsequent independent hepatologist. CONCLUSIONS: These results suggest that the extended-release formulation by reducing drug exposure may be associated with a reduced risk of hepatotoxicity, and supports the continued clinical evaluation of extended-release onapristone for treating progesterone receptor-positive cancers.

Oncolytic Measles Virotherapy and Opposition to Measles Vaccination.

Recent measles epidemics in US and European cities where vaccination coverage has declined are providing a harsh reminder for the need to maintain protective levels of immunity across the entire population. Vaccine uptake rates have been declining in large part because of public misinformation regarding a possible association between measles vaccination and autism for which there is no scientific basis. The purpose of this article is to address a new misinformed antivaccination argument-that measles immunity is undesirable because measles virus is protective against cancer. Having worked for many years to develop engineered measles viruses as anticancer therapies, we have concluded (1) that measles is not protective against cancer and (2) that its potential utility as a cancer therapy will be enhanced, not diminished, by prior vaccination.

Phase I study of onapristone, a type I antiprogestin, in female patients with previously treated recurrent or metastatic progesterone receptor-expressing cancers.

INTRODUCTION: Onapristone is a type I progesterone receptor (PR) antagonist, which prevents PR- mediated DNA transcription. Onapristone is active in multiple preclinical models and two prior studies demonstrated promising activity in patients with breast cancer. We conducted a study of extended release (ER) Onapristone to determine a recommended dose and explore the role of transcriptionally-activated PR (APR), detected as an aggregated subnuclear distribution pattern, as a predictive biomarker. METHODS: An open-label, multicenter, randomized, parallel-group, phase 1 study (target n = 60; NCT02052128) included female patients ≥18 years with PRpos tumors. APR analysis was performed on archival tumor tissue. Patients were randomized to five cohorts of extended release (ER) onapristone tablets 10, 20, 30, 40 or 50 mg BID, or immediate release 100 mg QD until progressive disease or intolerability. Primary endpoint was to identify the recommended phase 2 dose. Secondary endpoints included safety, clinical benefit and pharmacokinetics. RESULTS: The phase 1 dose escalation component of the study is complete (n = 52). Tumor diagnosis included: endometrial carcinoma 12; breast cancer 20; ovarian cancer 13; other 7. Median age was 64 (36-84). No dose limiting toxicity was observed with reported liver function test elevation related only to liver metastases. The RP2D was 50 mg ER BID. Median therapy duration was 8 weeks (range 2-44), and 9 patients had clinical benefit ≥24 weeks, including 2 patients with APRpos endometrial carcinoma. CONCLUSION: Clinical benefit with excellent tolerance was seen in heavily pretreated patients with endometrial, ovarian and breast cancer. The data support the development of Onapristone in endometrial endometrioid cancer. Onapristone should also be evaluated in ovarian and breast cancers along with APR immunohistochemistry validation.

A single-dose PK study of onapristone including the effect of food on absorption.

PURPOSE: Onapristone is an antiprogestin with activity in breast cancer and is under investigation for use in endometrial, ovarian and prostate cancers. Megestrol acetate and abiraterone generally show variability in absorption and, depending on the formulation, food effect. This study was conducted to determine the effect of food on 10 mg oral immediate-release (IR) onapristone and to help identify a formulation to minimize variability. METHODS: This is an open-label, randomized, crossover study to determine the pharmacokinetic profile of onapristone and its main metabolite, N-mono-desmethyl onapristone. Twelve healthy female subjects received 10 mg of oral IR onapristone after an overnight fast, or within 30 min of a high-fat, high-calorie meal with a 2-week washout between dosing periods. RESULTS: Onapristone plasma t1/2 (mean ± SD) was 4.36 ± 0.81 h for the fasted state and 3.76 ± 0.36 h for the fed state. Following food, onapristone tmax was delayed from 1 to 4 h. Food intake was also associated with a small increase in AUC0-∞ of approximately 13 % and a statistically significant decrease in Cmax of approximately 18 %. One subject experienced a 23-day delay in menses after one 10 mg onapristone dose, while another subject experienced transient grade 2 NCI-CTCAE liver enzyme elevation 3 weeks post dose. CONCLUSION: The results are consistent with previous observations, indicating that there is a small increase in onapristone exposure and a significant decrease in Cmax when taken with food. These changes are within acceptable limits set out by the FDA. Thus, our findings indicate that onapristone could be administered without regard to food.

Antitumor activity and safety of combination therapy with the Toll-like receptor 9 agonist IMO-2055, erlotinib, and bevacizumab in advanced or metastatic non-small cell lung cancer patients who have progressed following chemotherapy.

BACKGROUND: IMO-2055 is a Toll-like receptor 9 (TLR9) agonist that potentially enhances the efficacy of antitumor agents through immune stimulation. The objective of this phase Ib dose-escalation trial (3 + 3 design) was to determine the recommended phase II dose (RP2D) of IMO-2055 when combined with erlotinib and bevacizumab in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Patients with stage 3/4 NSCLC and progressive disease (PD) following chemotherapy received IMO-2055 0.08, 0.16, 0.32, or 0.48 mg/kg once weekly plus erlotinib 150 mg daily and bevacizumab 15 mg/kg every 3 weeks. Patients could receive treatment until PD or unacceptable toxicity. RESULTS: Thirty-six patients were enrolled; 35 received at least one treatment dose. Two dose-limiting toxicities were observed across the dose range (Grade 3 dehydration and fatigue) with neither suggestive of a consistent toxicity pattern. IMO-2055 0.32 mg/kg was adopted as RP2D based on clinical and pharmacodynamic data. The most common treatment-emergent adverse events (TEAEs) were diarrhea (74 %), nausea (51 %), fatigue (51 %), rash (51 %), and injection-site reactions (49 %). Four patients experienced serious TEAEs considered to be study drug related. Five patients died, all due to PD. High-grade neutropenia and electrolyte disturbances previously reported with TLR9 agonists combined with platinum-based therapy were not observed in this study. Five of 33 patients evaluable for response (15 %) achieved partial response; another 20 (61 %) had stable disease, including 13 with stable disease ≥4 months. CONCLUSIONS: IMO-2055 demonstrated good tolerability and possible antitumor activity in combination with erlotinib and bevacizumab in heavily pretreated patients with advanced NSCLC.

Capecitabine plus 3-weekly irinotecan (XELIRI regimen) as first-line chemotherapy for metastatic colorectal cancer: phase II trial results.

BACKGROUND: Capecitabine results in superior response rate, improved safety, and improved convenience compared with 5-fluorouracil (FU)/leucovorin (LV) in metastatic colorectal cancer (MCRC). Irinotecan in combination with 5-FU/LV has been shown to improve efficacy compared with 5-FU/LV alone in MCRC. Therefore, we evaluated the efficacy and safety of capecitabine plus irinotecan every 3 weeks (XELIRI regimen) as first-line treatment. METHODS: Patients with MCRC who were <65 years of age received irinotecan 250 mg/m i.v. on day 1 + capecitabine 1000 mg/m orally twice daily on days 1 to 14, every 3 weeks. Patients >or=65 years of age and those with impaired renal function or with a history of prior radiotherapy received lower doses of both agents (200 mg/m and 750 mg/m twice daily, respectively). RESULTS: A total of 52 patients (29 men, 23 women) were enrolled between October 2001 and August 2003. Median age was 57.5 years (range, 30-79 years); median Karnofsky performance status was 90 (range, 70-100). Treatment led to a response rate of 50% (ITT population) and a disease control rate of 71%. With a median cohort follow-up of 30.5 months, median time to progression and overall survival are 7.8 months (95% confidence interval, 5.6-10.0) and 16.8 months (95% confidence, 11.9 to not reached), respectively. Most common treatment-related grade 3/4 adverse events were neutropenia (25%), diarrhea (20%), vomiting (16%), dehydration (10%), nausea (6%), abdominal pain (6%), and hand-foot syndrome (6%). CONCLUSION: XELIRI is an active first-line treatment of MCRC. Implementation of upfront dose reductions for both agents in patients with risk factors for toxicity appears to have produced a safer regimen compared with previous studies of XELIRI without such dose reductions.