A randomized phase II trial of CRLX101 in combination with bevacizumab versus standard of care in patients with advanced renal cell carcinoma.

BACKGROUND: Nanoparticle-drug conjugates enhance drug delivery to tumors. Gradual payload release inside cancer cells augments antitumor activity while reducing toxicity. CRLX101 is a novel nanoparticle-drug conjugate containing camptothecin, a potent inhibitor of topoisomerase I and the hypoxia-inducible factors 1α and 2α. In a phase Ib/2 trial, CRLX101 + bevacizumab was well tolerated with encouraging activity in metastatic renal cell carcinoma (mRCC). We conducted a randomized phase II trial comparing CRLX101 + bevacizumab versus standard of care (SOC) in refractory mRCC. PATIENTS AND METHODS: Patients with mRCC and 2-3 prior lines of therapy were randomized 1 : 1 to CRLX101 + bevacizumab versus SOC, defined as investigator's choice of any approved regimen not previously received. The primary end point was progression-free survival (PFS) by blinded independent radiological review in patients with clear cell mRCC. Secondary end points included overall survival, objective response rate and safety. RESULTS: In total, 111 patients were randomized and received ≥1 dose of drug (CRLX101 + bevacizumab, 55; SOC, 56). Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). In the clear cell population, the median PFS on the CRLX101 + bevacizumab and SOC arms was 3.7 months (95% confidence interval, 2.0-4.3) and 3.9 months (95% confidence interval 2.2-5.4), respectively (stratified log-rank P = 0.831). The objective response rate by IRR was 5% with CRLX101 + bevacizumab versus 14% with SOC (Mantel-Haenszel test, P = 0.836). Consistent with previous studies, the CRLX101 + bevacizumab combination was generally well tolerated, and no new safety signal was identified. CONCLUSIONS: Despite promising efficacy data on the earlier phase Ib/2 trial of mRCC, this randomized trial did not demonstrate improvement in PFS for the CRLX101 + bevacizumab combination when compared with approved agents in patients with heavily pretreated clear cell mRCC. Further development in this disease is not planned. CLINICAL TRIAL IDENTIFICATION: NCT02187302 (NIH).

Efficacy of the nanoparticle-drug conjugate CRLX101 in combination with bevacizumab in metastatic renal cell carcinoma: results of an investigator-initiated phase I-IIa clinical trial.

BACKGROUND: Anti-angiogenic therapies are effective in metastatic renal cell carcinoma (mRCC), but resistance is inevitable. A dual-inhibition strategy focused on hypoxia-inducible factor (HIF) is hypothesized to be active in this refractory setting. CRLX101 is an investigational camptothecin-containing nanoparticle-drug conjugate (NDC), which durably inhibits HIF1α and HIF2α in preclinical models and in gastric cancer patients. Synergy was observed in the preclinical setting when combining this NDC and anti-angiogenic agents, including bevacizumab. PATIENTS AND METHODS: Patients with refractory mRCC were treated every 2 weeks with bevacizumab (10 mg/kg) and escalating doses of CRLX101 (12, 15 mg/m(2)) in a 3 + 3 phase I design. An expansion cohort of 10 patients was treated at the recommended phase II dose (RP2D). Patients were treated until progressive disease or prohibitive toxicity. Adverse events (AEs) were assessed using CTCAE v4.0 and clinical outcome using RECIST v1.1. RESULTS: Twenty-two patients were response-evaluable in an investigator-initiated trial at two academic medical centers. RCC histologies included clear cell (n = 12), papillary (n = 5), chromophobe (n = 2), and unclassified (n = 3). Patients received a median of two prior therapies, with at least one prior vascular endothelial tyrosine kinase inhibitor therapy (VEGF-TKI). No dose-limiting toxicities were observed. Grade ≥3 AEs related to CRLX101 included non-infectious cystitis (5 events), fatigue (3 events), anemia (2 events), diarrhea (2 events), dizziness (2 events), and 7 other individual events. Five of 22 patients (23%) achieved partial responses, including 3 of 12 patients with clear cell histology and 2 of 10 patients (20%) with non-clear cell histology. Twelve of 22 patients (55%) achieved progression-free survival (PFS) of >4 months. CONCLUSIONS: CRLX101 combined with bevacizumab is safe in mRCC. This combination fulfilled the protocol's predefined threshold for further examination with responses and prolonged PFS in a heavily pretreated population. A randomized phase II clinical trial in mRCC of this combination is ongoing.

Clinical Outcomes and Effectiveness of CRLX101 for Solid Tumors: A Systematic Review and Meta-analysis.

BACKGROUND: While it has been demonstrated that delivery of cytotoxic chemotherapy using nanoparticles greatly improves patient drug tolerance and reduces toxicity when compared to the standard formulation, the crucial question of whether they also increase anticancer efficacy remains. The CRLX101 is a nanoparticle composed of cyclodextrin and 20(S)-camptothecin cytotoxic chemotherapy. OBJECTIVE: In order to compare the efficacy of the CRLX101 to its corresponding traditional formulation, we carried out this systematic literature search for randomized clinical and non-randomized trials. METHODS: Multiple electronic databases, including PubMed, Scopus, Embase, Web of Science, the Cochrane Library, and clinicaltrials.gov, were used to conduct a thorough literature search. By employing a technique akin to a random-effects model, the median of the study-specific was taken into account as the pooled median estimate with a 95% confidence interval. RESULTS: Finally, nine clinical studies were chosen for the meta-analysis. The treatment and control groups' overall survival were examined in five and three trials, respectively. Additionally, six out of nine trials and two out of nine trials, respectively, examined the treatment and control groups for progression-free survival (PFS). Meta-analysis revealed that the treatment group had a lower median overall survival (OS) but a greater median progression-free survival than the control group. CONCLUSION: Our meta-analysis shows that CRLX101 outperforms camptothecin in PFS despite its inferior OS. Unresolved pharmacology limits carrier-mediated drug therapeutic application. Carrier-mediated dosages may differ from normal formulations because they are rarely studied.

A Systematic Review of Clinical Trials on the Efficacy and Safety of CRLX101 Cyclodextrin-Based Nanomedicine for Cancer Treatment.

CRLX101 is a cyclodextrin-based nanopharmaceutical designed to improve the delivery and efficacy of the anti-cancer drug camptothecin. Cyclodextrins have unique properties that can enhance drug solubility, stability, and bioavailability, making them an attractive option for drug delivery. The use of cyclodextrin-based nanoparticles can potentially reduce toxicity and increase the therapeutic index compared to conventional chemotherapy. CRLX101 has shown promise in preclinical studies, demonstrating enhanced tumor targeting and prolonged drug release. This systematic review followed PRISMA guidelines, assessing the efficacy and toxicity of CRLX101 in cancer treatment using clinical trials. Studies from January 2010 to April 2023 were searched in PubMed, Scopus, Web of Science, and Cochrane Database of Systematic Reviews, using specific search terms. The risk of bias was assessed using ROBINS-I and Cochrane risk-of-bias tools. After screening 6018 articles, 9 were included in the final review. These studies, conducted between 2013 and 2022, focused on patients with advanced or metastatic cancer resistant to standard therapies. CRLX101 was often combined with other therapeutic agents, resulting in improvements such as increased progression-free survival and clinical benefit rates. Toxicity was generally manageable, with common adverse events including fatigue, nausea, and anemia.

Pilot trial of CRLX101 in patients with advanced, chemotherapy-refractory gastroesophageal cancer.

BACKGROUND: CRLX101 is an investigational nanoparticle-drug conjugate with a camptothecin payload. Preclinical evidence indicated preferential uptake in tumors, and tumor xenograft models demonstrate superiority of CRLX101 over irinotecan. A pilot trial was conducted at recommended phase 2 dosing (RP2D) using the bimonthly schedule to assess preferential uptake of CRLX101 in tumor vs. adjacent normal tissue in endoscopically accessible tumors in chemotherapy-refractory gastroesophageal cancer. Results from the biopsies were previously reported and herein we present the clinical outcomes. METHODS: Patients initiated CRLX101 dosed at RP2D (15 mg/m2) on days 1 and 15 of a 28-day cycle. Detection of preferential CRLX101 tumor uptake was the primary endpoint and objective response rate (ORR) was a secondary endpoint. With a sample size of ten patients, the study had 90% power to detect ≥1 responder if the true response rate is ≥21%. RESULTS: Between Dec. 2012 and Dec. 2014, ten patients with chemotherapy-refractory (median 2 prior lines of therapy, range 1-4) gastric adenocarcinoma were enrolled. The median time-to-progression was 1.7 months. Best response was seen in one patient with stable disease (SD) for 8 cycles. Only ≥ grade 3 drug-related toxicity occurred in one patient with grade 3 cardiac chest pain who was able to resume therapy after CRLX101 was reduced to 12 mg/m2. CONCLUSIONS: Bimonthly CRLX101 demonstrated minimal activity with SD as best response in this heavily pretreated population. Future efforts with CRLX101 in gastric cancer should focus on combination and more dose-intensive strategies given its favorable toxicity profile and evidence of preferential tumor uptake.