davamotecan pegadexamer (EP0057) / Lumos Pharma, Ellipses Pharma - LARVOL DELTA

Tumor-targeted top1 inhibitor delivery with optimized parp inhibition in advanced solid tumors: a phase i trial of gapped scheduling. (PubMed, Nat Commun) - P1/2 | "In this trial (NCT02769962), we combined CRLX101, a nanoparticle topoisomerase I inhibitor, with olaparib using a gapped dosing schedule. The combination showed acceptable safety across dose levels. Targeted delivery of a topoisomerase I inhibitor and gapped scheduling allowed higher olaparib dosing, showing promising activity and supporting the strategy's potential to widen the therapeutic window of DNA-damage response inhibitors while reducing toxicity."

Journal • P1 data • Oncology • Solid Tumor • TOP1

Tumor-targeted top1 inhibitor delivery with optimized parp inhibition in advanced solid tumors: a phase i trial of gapped scheduling (Nature) - "The maximum tolerated dose for CRLX101 was 12 mg/m² every two weeks and olaparib 250 mg twice daily on days 3-13 and 17-26. Pharmacokinetics were consistent with monotherapy of each agent, and γH2AX kinetics revealed elevated DNA damage with the combination treatment compared to CRLX101 alone, supporting mechanistic efficacy. Among 19 evaluable patients, 2 patients had partial responses, and 6 had stable disease. Median overall survival was 6.06 months, progression-free survival 2.34 months, and duration of response 7.95 months. The combination showed acceptable safety across dose levels."

P1 data • Cholangiocarcinoma • Colorectal Cancer • Fallopian Tube Cancer • Mesothelioma • Myxofibrosarcoma • Non Small Cell Lung Cancer • Ovarian Cancer • Pancreatic Adenocarcinoma • Thymic Carcinoma

Trial of EP0057, a Nanoparticle Camptothecin With Olaparib in People With Relapsed/Refractory Small Cell Lung Cancer (clinicaltrials.gov) - P1/2 | N=45 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed | Trial completion date: Dec 2027 ➔ Mar 2025

Trial completion • Trial completion date • Bladder Cancer • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Lung Cancer • Oncology • Prostate Cancer • Small Cell Lung Cancer • Solid Tumor • Urothelial Cancer

Camptothecin Triggers Apoptosis in Human and Mouse Drug-resistant Glioblastoma Cells via ROS-mediated Activation of the p53-p21-CD1/CDK2-E2F1-Bcl-xL Signaling Axis. (PubMed, Anticancer Res) - "CPT could effectively induce apoptosis in drug-resistant glioblastoma cells via iROS-mediated activation of the p53-p21-CD1/CDK6-E2F1-Bcl-xL axis."

Journal • Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • BCL2L1 • CASP3 • CCND1 • CDK2 • CDK6 • CDKN1A • E2F1

Improving neoadjuvant chemoradiotherapy for rectal cancer with CRLX101, a nanoparticle-drug conjugate, with a camptothecin payload (ASCO-GI 2015) - Abstract #645; "In the HT29 xenografts model, CRLX101+5FU+XRT delayed tumor growth significantly more than the other treatment regimens evaluated. In the SW480 xenografts model, both CRLX101+5FU+XRT and CRLX101+XRT delayed tumor growth more than other regimens....In the ongoing clinical trial [NCT02010567], none of the first 3 patients enrolled (the first dosing cohort) have experienced dose limiting toxicities and 1 out of 3 patients had a pCR."

P1 data • Preclinical • Colorectal Cancer • Oncology

Multifunctionality of cyclodextrin-based polymeric nanoparticulate delivery systems for chemotherapeutics, combination therapy, and theranostics. (PubMed, Int J Pharm) - "Further, in light of recent studies, the article majorly focuses on conveying how promoting CD to a polymeric and nanoscale elevates the multifunctional advantages against cancer that can be successfully applied in combination therapy and theranostics. Moreover, CD-based delivery systems including CALAA-01, CRLX101, and CRLX301, have demonstrated improved tumor targeting, reduced side effects, and prolonged drug release in preclinical studies and clinical trials."

Combination therapy • Journal • Review • Oncology

Clinical Outcomes and Effectiveness of CRLX101 for Solid Tumors: A Systematic Review and Meta-analysis. (PubMed, Curr Med Chem) - "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."

Clinical • Clinical data • Retrospective data • Review • Oncology • Solid Tumor

EP0057 in Combination With Olaparib in Advanced Ovarian Cancer (clinicaltrials.gov) - P2 | N=34 | Completed | Sponsor: Ellipses Pharma | Active, not recruiting ➔ Completed | N=60 ➔ 34

Combination therapy • Enrollment change • Metastases • Trial completion • Endometrial Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • BRCA • HRD

A Systematic Review of Clinical Trials on the Efficacy and Safety of CRLX101 Cyclodextrin-Based Nanomedicine for Cancer Treatment. (PubMed, Pharmaceutics) - "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."

Journal • Review • Fatigue • Hematological Disorders • Oncology

EP0057 in Combination With Olaparib in Relapsed Advanced Gastric Cancer and Small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Ellipses Pharma | N=115 ➔ 0 | Not yet recruiting ➔ Withdrawn

Combination therapy • Enrollment change • Metastases • Trial withdrawal • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • ATM • PD-L1

Phase Ib/II study of neoadjuvant chemoradiotherapy with CRLX101 and capecitabine for locally advanced rectal cancer. (ASCO 2017) - P1/2; "...CRLX101 is an investigational nanoparticle-drug conjugate with a camptothecin payload... CRLX101 weekly at 15 mg/m2+ standard capecitabine-based chemoradiotherapy appears to be well tolerated, with promising pCR rates that warrants further evaluation. A larger PhII trial should be considered with this regimen."

Clinical • Biosimilar • Colorectal Cancer

EP0057 in Combination With Olaparib in Advanced Ovarian Cancer (clinicaltrials.gov) - P2 | N=60 | Active, not recruiting | Sponsor: Ellipses Pharma | Recruiting ➔ Active, not recruiting | Trial completion date: Jan 2025 ➔ Mar 2023

Combination therapy • Enrollment closed • Trial completion date • Endometrial Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • BRCA • HRD

EP0057 in Combination With Olaparib in Relapsed Advanced Gastric Cancer and Small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=115 | Not yet recruiting | Sponsor: Ellipses Pharma | Initiation date: Jul 2022 ➔ Apr 2023

Combination therapy • Trial initiation date • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • ATM • PD-L1

Combining CRLX101, a Nanoparticle Camptothecin, With Enzalutamide in People With Progressive Metastatic Castration Resistant Prostate Cancer Following Prior Enzalutamide Treatment (clinicaltrials.gov) - P2 | N=4 | Terminated | Sponsor: National Cancer Institute (NCI) | Completed ➔ Terminated; Study was closed for toxicity.

Trial termination • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

A Single-arm Phase II Study Combining NLG207, a Nanoparticle Camptothecin, with Enzalutamide in Advanced Metastatic Castration-resistant Prostate Cancer Post-Enzalutamide. (PubMed, Oncologist) - P2 | "NLG207 12 mg/m2 in combination with enzalutamide was not well tolerated in patients with mCRPC following several lines of the standard of care therapy."

Journal • P2 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

EP0057 in Combination With Olaparib in Relapsed Advanced Gastric Cancer and Small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=115 | Not yet recruiting | Sponsor: Ellipses Pharma

Combination therapy • New P2 trial • Esophageal Cancer • Gastric Adenocarcinoma • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • ATM • PD-L1

A randomized phase 2 trial of CRLX101 in combination with bevacizumab in patients with metastatic renal cell carcinoma (mRCC) versus standard of care (SOC) (IKCS 2016) - P2; "Within the SOC arm, patients received single-agent bevacizumab (19), axitinib (18), everolimus (7), pazopanib (4), sorafenib (4), sunitinib (2), or temsirolimus (2). CRLX101 is a novel investigational NDC containing the payload camptothecin, a potent inhibitor of topoisomerase I. Additionally, in preclinical models camptothecin has been shown to inhibit hypoxia-inducible factors (HIF) 1a and 2a. Despite a promising signal in the earlier phase 1b/2 trial of mRCC, the current trial did not demonstrate a statistically significant improvement in PFS for the CRLX101 + bevacizumab combination vs SOC in patients with clear cell mRCC. Ongoing and future clinical trials will focus on the treatment of topoisomerase I-sensitive tumor types such as ovarian and gastrointestinal tumors."

P2 data • Biosimilar • Oncology • Renal Cell Carcinoma

Combining CRLX101, a Nanoparticle Camptothecin, With Enzalutamide in People With Progressive Metastatic Castration Resistant Prostate Cancer Following Prior Enzalutamide Treatment (clinicaltrials.gov) - P2 | N=3 | Completed | Sponsor: National Cancer Institute (NCI) | Trial completion date: Feb 2022 ➔ Jun 2021 | Trial primary completion date: Feb 2022 ➔ May 2021

Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Combining CRLX101, a Nanoparticle Camptothecin, With Enzalutamide in People With Progressive Metastatic Castration Resistant Prostate Cancer Following Prior Enzalutamide Treatment (clinicaltrials.gov) - P2 | N=3 | Completed | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Completed | Trial completion date: Jun 2023 ➔ Feb 2022 | Trial primary completion date: Dec 2022 ➔ Feb 2022

Trial completion • Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

A Phase II study of NLG207 (formerly CRLX101) in combination with weekly paclitaxel in patients with recurrent or persistent epithelial ovarian, fallopian tube or primary peritoneal cancer (AACR 2019) - "Background: NLG207 (formerly CRLX101) is an investigational nanoparticle-drug conjugate (NDC) composed of a cyclodextrin-based polymer backbone linked to camptothecin, a topoisomerase-1 inhibitor. NLG207 is a potentially best-in-class topoisomerase 1 inhibitor with demonstrated antitumor activity in recurrent ovarian cancer including those who have become resistant to platinum therapy. AE profile of this combination is consistent with that seen for paclitaxel as a single agent except for cystitis, hematuria and UTI. It was well-tolerated in combination with weekly paclitaxel in heavily pre-treated patients."

Clinical • Combination therapy • P2 data • Oncology • Ovarian Cancer • Solid Tumor

CRLX101 plus olaparib in patients with metastatic castration-resistant prostate cancer. (ASCO 2018) - P1/2; "In the past several years, despite multiple new therapeutics (docetaxel, abiraterone and enzalutamide) have been approved by FDA, the majority patients will become resistant to treatments in 2-3 years. Synergistic activity between camptothecin and olaparib has been shown in preclinical data. The primary endpoint of this study is overall response rate (ORR), the secondary endpoints include safety and progression-free survival (PFS), duration of response and PSA responses."

Clinical • Prostate Cancer

Sequential Phase II clinical trials evaluating CRLX101 as monotherapy and in combination with bevacizumab in recurrent ovarian cancer. (PubMed, Gynecol Oncol) - "CRLX101 meets the clinical need for an effective and tolerable topoisomerase I inhibitor and can be safely combined with bevacizumab."

Clinical • Combination therapy • Journal • Monotherapy • P2 data • Fatigue • Hematological Disorders • Hypertension • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor

Combining CRLX101, a Nanoparticle Camptothecin, With Enzalutamide in People With Progressive Metastatic Castration Resistant Prostate Cancer Following Prior Enzalutamide Treatment (clinicaltrials.gov) - P2; N=3; Active, not recruiting; Sponsor: National Cancer Institute (NCI); Recruiting ➔ Active, not recruiting; N=30 ➔ 3

Clinical • Enrollment change • Enrollment closed • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

EP0057 in Combination With Olaparib in Advanced Ovarian Cancer (clinicaltrials.gov) - P2; N=60; Recruiting; Sponsor: Ellipses Pharma; Trial primary completion date: Jul 2022 ➔ Nov 2022

Clinical • Combination therapy • Trial primary completion date • Endometrial Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • BRCA • HRD

Combining CRLX101, a Nanoparticle Camptothecin, With Enzalutamide in People With Progressive Metastatic Castration Resistant Prostate Cancer Following Prior Enzalutamide Treatment (clinicaltrials.gov) - P2; N=30; Recruiting; Sponsor: National Cancer Institute (NCI); Trial completion date: Dec 2021 ➔ Jun 2023; Trial primary completion date: Jun 2021 ➔ Dec 2022

Clinical • Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor