Cerulean Pharma (United States)

Design Anthropology [DA] has gained significant prominence in recent years, along with increasing adoption of Design Thinking [DT] strategies, new human-centric approaches, and focused attention on the emotional and functional needs of the users. Both DA and DT have emerged during the last few decades as a result of a broader shift away from the profit-centered business models towards the development of value-driven paradigms that are placing the consumers at the center of research and production. This is a meaningful transformation that reflects the recognition of an urgent need for higher global sustainability and a new economy. The process of personalization, which is based on extensive study of consumers’ real needs rather continuous development of products, is the best strategic move to achieve these new global goals and set new social and individual values. Thus, business success in the contemporary world should aspire to merge values of sustainability with a good study of individual needs and lifestyle. DT is not a new way of business thinking and it has existed for decades. Yet, many of its advantages are still unknown, misunderstood, or are being used inefficiently due to lack of knowledge, strategic insights, and proper practices and experience. DT utilizes anthropological methods that provide the best strategies required to unfold hidden needs, heal pain points, and discover core cultural values. Anthropological tools include detailed observations of behavior and various activities, personal interviews, and immersion in the daily lives of individuals and communities studied in order to study their perspective and gain empathy and understanding as an insider. The project presented hereby demonstrates the uses and the professional advantages gained by using DT methods in finding new and creative pathways to complicated solutions in a case study that required the development of a healthcare app for the ASHA workers in India. The ASHA are healthcare activists who became a vital and crucial support system to many families in rural India, especially during the Covid19 pandemic. However, the low social caste to which they belong proved to be as big a challenge to face as the pandemic itself, and DT strategies combined with methodologies of anthropology supported the completion of the project on time with the best outcome possible.

Abstract Cerulean Pharma Inc.'s Dynamic Tumor Targeting™ Platform creates nanoparticle-drug conjugates (NDCs) designed to significantly mitigate a payload's limitations by providing sustained drug delivery to the tumor and superior therapeutic index through controlled release kinetics. By conjugating drug payloads to our novel β-cyclodextrin-PEG copolymer through linker strategies that allow modulation of release and pharmacokinetics (PK), we provide advantages over entrapped nanoparticle strategies, e.g., polymeric nanoparticles and liposomes. Cerulean has two NDCs in the clinic, CRLX101 and CRLX301, evidencing the translatability of our technology. CRLX101 has been dosed in over 350 patients and CRLX301 is in an ongoing Phase 1/2a trial. Our Dynamic Tumor Targeting Platform is applicable to a diverse range of drug payload possibilities, including small molecules with a host of physiochemical properties, i.e., hydrophobic and hydrophilic payloads, and functional groups with chemical handles for conjugation. To illustrate the capabilities of our platform we will present the biological impact of a series of cabazitaxel-containing NDCs with linkers encompassing a diversity of in vitro release rates. In vivo PK studies showed high and sustained levels of released drug in tumor tissues (>168 hrs), and in vivo mouse tumor model studies demonstrated vastly improved efficacy, i.e., tumor regression and significant tumor growth delay, and survival over separately dosed cabazitaxel including efficacy in a taxane-resistant tumor model. Cerulean continues to expand its platform through the development of new and emerging capabilities to treat patients living with cancer. In this regard, we also will address the future evolution of NDCs, including the conjugation of multiple payloads to a single NDC and the development of antibody-conjugated NDCs. This abstract is also being presented as Poster B43. Citation Format: Chester Metcalf, III, Derek van der Poll, Liang Zhao, Tiffany Halo, Doug Lazarus, Adam Stockmann, Christian Peters, Donna Brown, Roy Case, Ellen Rohde, Lata Jayaraman, Hongwei Wang, Tiffany Crowell, Adrian Senderowicz, Scott Eliasof. Significant improvements in therapeutic index for conjugated payloads using a nanoparticle-drug conjugate (NDC) platform to provide sustained drug release and potentially improved anticancer effects. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr PR10.

VEGF pathway-targeting antiangiogenic drugs, such as bevacizumab, when combined with chemotherapy have changed clinical practice for the treatment of a broad spectrum of human cancers. However, adaptive resistance often develops, and one major mechanism is elevated tumor hypoxia and upregulated hypoxia-inducible factor-1α (HIF1α) caused by antiangiogenic treatment. Reduced tumor vessel numbers and function following antiangiogenic therapy may also affect intratumoral delivery of concurrently administered chemotherapy. Nonetheless, combining chemotherapy and bevacizumab can lead to improved response rates, progression-free survival, and sometimes, overall survival, the extent of which can partly depend on the chemotherapy backbone. A rational, complementing chemotherapy partner for combination with bevacizumab would not only reduce HIF1α to overcome hypoxia-induced resistance, but also improve tumor perfusion to maintain intratumoral drug delivery. Here, we evaluated bevacizumab and CRLX101, an investigational nanoparticle-drug conjugate containing camptothecin, in preclinical mouse models of orthotopic primary triple-negative breast tumor xenografts, including a patient-derived xenograft. We also evaluated long-term efficacy of CRLX101 and bevacizumab to treat postsurgical, advanced metastatic breast cancer in mice. CRLX101 alone and combined with bevacizumab was highly efficacious, leading to complete tumor regressions, reduced metastasis, and greatly extended survival of mice with metastatic disease. Moreover, CRLX101 led to improved tumor perfusion and reduced hypoxia, as measured by contrast-enhanced ultrasound and photoacoustic imaging. CRLX101 durably suppressed HIF1α, thus potentially counteracting undesirable effects of elevated tumor hypoxia caused by bevacizumab. Our preclinical results show pairing a potent cytotoxic nanoparticle chemotherapeutic that complements and improves concurrent antiangiogenic therapy may be a promising treatment strategy for metastatic breast cancer. Cancer Res; 76(15); 4493-503. ©2016 AACR.

Abstract Introduction. Nanoparticles (NPs) provide many advantages over small molecule drugs, such as greater solubility, increased duration of exposure, and enhanced tumor delivery, which may lead to improved antitumor activity and reduced toxicity. PK of NPs is complex as the PK is dependent upon the carrier and not the therapeutic entity until the active-drug payload is released. It is important to evaluate the PK of the inactive carrier-associated drug and active released drug. CRLX301 is an investigational NDC containing the payload docetaxel covalently conjugated to a cyclodextrin-polyethylene glycol (CD-PEG) co-polymer that is 10-30 nm in diameter. This study evaluated CRLX301 PK in a phase 1 study in patients with refractory solid tumors. Methods. CRLX301 was administered at 7.5, 15, 30, 60 and 75 mg/m2 IV over 1 h every 21 days. The doses of CRLX301 represent mg of docetaxel. PK studies were performed on days 1-21 of cycles 1, 3 and 6. Plasma samples were processed to measure total (conjugated + released) and released docetaxel. PK parameters area under conc-time curve (AUC0-inf) and volume of distribution (Vd) were estimated. Results were compared to a prior PK study of Taxotere® at 75 mg/m2 IV x 1 every 21 days (Zamboni, et al. CCP 2011). Results. Plasma PK of total and released docetaxel were linear after CRLX301 from 7.5 to 75 mg/m2. CRLX301 plasma PK was similar on cycles 1, 3 and 6 suggesting no accumulation after multiple doses. For CRLX301 at 75 mg/m2 on cycle 1, mean ± SD plasma AUC0-inf of total and released docetaxel were 321,355 ± 9,831 and 3,015 ± 904 ng/mL•h, respectively. Mean ± SD% of docetaxel released from CRLX301 into the plasma was 1.0 ± 0.2%. Exposures of total and released docetaxel in plasma after administration of CRLX301 (7 days) were prolonged compared with Taxotere (24 h). Total docetaxel plasma AUC after CRLX301 at 75 mg/m2 was ∼63-fold greater than for Taxotere. The Vd of CRLX301 total docetaxel and Taxotere were 2.1 ± 0.1 and 74-99 L/m2, respectively. The overall plasma AUC of released docetaxel after CRLX301 (3,015 ± 904 ng/mL•h) was similar to Taxotere (2,000-10,000 ng/mL•h); however, most of the released docetaxel AUC after CRLX301 is associated with exposures at 24-168 h. Early exposures of released docetaxel in plasma after CRLX301 (Cmax = 242 ± 44 ng/mL) were ∼25-fold lower than Taxotere (Cmax = 5,000-8,000 ng/mL). Conclusions. CRLX301 exhibits PK advantages over Taxotere such as higher retention of drug in plasma, slower clearance and controlled slow release of docetaxel from the carrier. CRLX301 exhibits low inter- and intra-patient PK variability. It is anticipated that this unique PK profile of CRLX301 may improve efficacy as well as the tolerability profile when compared to Taxotere. The study continues with dose escalation to further explore the safety, efficacy and PK of CRLX301. Citation Format: William C. Zamboni, Ben Markman, Paul de Souza, E. Claire Dees, Tara Gangadhar, Scott Eliasof, Curran Murphy, Adrian Senderowicz, Hongwei Wang. Pharmacokinetics (PK) of CRLX301, a novel nanoparticle-drug conjugate (NDC) containing the payload docetaxel, in patients with refractory solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2047.

2526 Background: CRLX301 is an investigational NDC with DOC covalently conjugated to a cyclodextrin-polyethylene glycol co-polymer designed to enhance delivery to tumor tissue. Preclinical studies of CRLX301 showed enhanced drug accumulation in tumor and greater tumor growth suppression in murine models compared to DOC. Methods: Patients (pt) with advanced solid tumors were treated with escalating doses of CRLX301 IV once every 21 days (Q3W). The first two cohorts were single pt cohorts and then adjusted to 3+3 design. Primary objective: MTD and/or RP2D. Secondary objectives: safety, anti-tumor activity and PK. Results: 20 pts were enrolled. All were evaluable for DLT. Prior lines of chemotherapy: median 3 (range 0 to 6); 8 pts had prior taxane therapy. Tumor types: cholangiocarcinoma (5), head and neck (3), lung (2) and others (10). All drug-related AEs were toxicities typically associated with DOC. The most common drug-related AEs (all grades) were fatigue (70%), infusion reaction (40%), nausea (35%), diarrhea (30%), neutropenia (30%), and peripheral neuropathy (20%). Most AEs were ≤ grade 2. Two DLTs, reversible grade 3 transaminases with grade 2 bilirubin ( < 3 d) and grade 4 febrile neutropenia ( < 3 d), were observed at 90 mg/m2. One gr3 and one gr4 infusion reactions were observed at 90 mg/m2; both resolved within 24 hours. Certain common AEs related to DOC, such as fluid retention, were not observed. MTD with Q3W dosing is 75 mg/m2. A pt with B-RAF mutant unknown primary and resistant to a prior B-Raf inhibitor had tumor shrinkage per CT and partial metabolic response per FDG-PET. Stable disease lasting ≥ 3 cycles was observed in 5 pts (max 15 cycles). Plasma PK compared to commercial DOC at equivalent dose of 75 mg/m2: increased Cmax (5 – 8 fold) and increased AUC (60 fold) of total DOC and 25 fold less peak concentrations but more prolonged exposures of released DOC. Conclusions: The data suggest CRLX301 has a predictable and acceptable safety profile with preliminary signs of anti-tumor activity and distinct PK compared to DOC. MTD/RP2D were established as 75 mg/m2 for Q3W dosing. Weekly dosing and expansion cohorts in selected tumor types are planned. Clinical trial information: NCT02380677.

TPS4579 Background: Up to 30% of pts. with RCC present with metastatic disease and 5-year survival among these pts. is less than 10%. VEGF-targeted and mTOR inhibiting drugs constitute SOC in this ...

Patients with advanced solid malignancies were enrolled to an open-label, single-arm, dose-escalation study, in which CRLX101 was administered intravenously over 60 min among two dosing schedules, initially weekly at 6, 12, and 18 mg/m(2) and later bi-weekly at 12, 15, and 18 mg/m(2). The maximum tolerated dose (MTD) was determined at 15 mg/m(2) bi-weekly, and an expansion phase 2a study was completed. Patient samples were obtained for pharmacokinetic (PK) and pharmacodynamic (PD) assessments. Response was evaluated per RECIST criteria v1.0 every 8 weeks. Sixty-two patients (31 male; median age 63 years, range 39-79) received treatment. Bi-weekly dosing was generally well tolerated with myelosuppression being the dose-limiting toxicity. Among all phase 1/2a patients receiving the MTD (n = 44), most common grade 3/4 adverse events were neutropenia and fatigue. Evidence of systemic plasma exposure to both the polymer-conjugated and unconjugated CPT was observed in all treated patients. Mean elimination unconjugated CPT Tmax values ranged from 17.7 to 24.5 h, and maximum plasma concentrations and areas under the curve were generally proportional to dose for both polymer-conjugated and unconjugated CPT. Best overall response was stable disease in 28 patients (64 %) treated at the MTD and 16 (73 %) of a subset of NSCLC patients. Median progression-free survival (PFS) for patients treated at the MTD was 3.7 months and for the subset of NSCLC patients was 4.4 months. These combined phase 1/2a data demonstrate encouraging safety, pharmacokinetic, and efficacy results. Multinational phase 2 clinical development of CRLX101 across multiple tumor types is ongoing.

Abstract Introduction: Topoisomerase-1-inhibiting camptothecin (CPT) and derivatives such as irinotecan (CPT-11) and topotecan demonstrate clinical utility across multiple cancer types. Use of these agents remains limited by insufficient tumor exposure and high systemic toxicity. A novel cyclodextrin-containing polymer conjugate of CPT that self-assembles into nanoparticles, CRLX101 delivers sustained levels of active CPT into cancer cells while substantially reducing systemic exposure. In vitro and in vivo data suggest superior activity of CRLX101 in multiple tumor models. Efforts are made now to demonstrate the safety and efficacy of CRLX101 in human patients with advanced solid tumor malignancies. Experimental Procedures: CRLX101 was administered intravenously over 1 hour every other week (EOW) to patients (pts.) with advanced and multiply pre-treated solid tumor malignancies. In phase 1, 24 pts. received CRLX101 at 5 escalating dose levels. Following identification of a maximum tolerated dose (MTD), a 38 patient phase 2a MTD-expansion cohort was enrolled at 3 clinical sites. Summary of Data: As of a data cut-off of 6/1/11, 62 total pts. (31 F; 31 M) received CRLX101 at doses ranging from 6 mg/m2 to 18 mg/m2 of CPT equivalent per dose. In phase 1, 2 pts. (18 mg/m2) experienced dose limiting toxicity of CTCAE v3.0 grade (G)4 thrombocytopenia with one of these pts. additionally experiencing G4 neutropenia. An MTD/recommended phase 2 dose (RP2D) of CRLX101 was established at 15 mg/m2 EOW. Among 44 phase 1 or 2a pts. receiving the MTD/RP2D, most common grade 3/4 adverse events considered by investigators to be at least possibly related to study drug included neutropenia (9 events observed among 6 pts.) and lymphopenia (3 events observed among 2 pts.). Phase 2a pts. received CRLX101 for periods of time ranging from 1 day to approximately 13 months (mos.) with an average duration of 3.3 mos. Among 36 evaluable phase 2a pts. receiving the MTD, mean plasma Cmax and AUCall were 306 μg./L. and 27.1 mg./L.*hr. (polymer-unconjugated) and 8260 μg./L. and 300 mg./L.*hr. (polymer-conjugated), respectively. Mean urinary clearance of polymer-conjugated and free CPT over the 0–8 hr., 8–24 hr., and 24–48 hr. collection intervals post CRLX101 dosing were 0.0299, 0.0074, and 0.0062 L./hr. (polymer-conjugated) and 0.0888, 0.0898, and 0.1010 L./hr. (free CPT), respectively. Among all phase 2a pts., overall median progression-free survival (mPFS) was 3.7 mos., with mPFS of 4.4 mos. observed among 21 NSCLC pts. (4.8 mos. excluding 6/21 pts. with squamous cell histology). At time of data cut-off, 6 pts. (incl. 3 NSCLC pts.) remain on therapy. Notably, of the 21 NSCLC pts. in phase 2a (with an average of 3 prior regimens of chemotherapy), 66.7% (14/21) achieved stable disease (SD) ≥ 3 mos. and 14.3% (3/21) achieved SD ≥ 6 mos. Conclusions: CRLX101 appears to be extremely well tolerated with an MTD/RP2D of 15 mg/m2 EOW. Pharmacokinetics are linear and suggest prolonged duration of CPT tumor exposure. Similarly, extended periods of stable disease observed across multiple tumor types are encouraging and merit further investigation. Patients are currently being enrolled into a multinational randomized clinical trial in 2nd/3rd line NSCLC and additional studies in renal cell cancer, small-cell lung cancer, ovarian cancer, and gastric cancer are being developed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A97.

Abstract Results from a 24-patient dose-escalation safety and tolerability Phase 1 study of CRLX101 were presented at the 22nd EORTC-NCI-AACR symposium in November 2010. A Phase 2a expansion study of CRLX101 has been initiated to investigate the biological activity and tolerability in cancer patients with specific tumor types at the maximum-tolerated dose (MTD) of 15 mg/m2. Specifically, a focus of the Phase 2a expansion study is to evaluate CRLX101 biological activity in non-small cell lung carcinoma (NSCLC), amongst other target indications. In this Phase 2a expansion study, thirty-six (36) patients will be enrolled from three (3) clinical sites in the United States. Fifteen (15) patients treated with CRLX101 thus far were patients with advanced NSCLC. Stable disease of greater than 6 months in multiple NSCLC patients treated with CRLX101 has been observed. Dose-limiting bone marrow toxicities of thrombocytopenia and neutropenia were addressed with the longer dosing interval of an every-other-week dosing schedule, which accommodates for the prolonged half-life of CRLX101. Hemorrhagic cystitis, the classic camptothecin toxicity, has not been observed. No other significant adverse events have been observed in the current study. The Phase 2a study will be fully enrolled by the end of 2010 with extensive follow-up on most patients by April of 2011. All of the safety, tolerability, and biological activity data will be presented. At this time, twenty-one (21) of the thirty-six (36) patients have been enrolled. To date, three (3) NSCLC patients have received 4 cycles of therapy and are continuing on study. One (1) NSCLC patients is receiving the seventh cycle of therapy. A controlled, randomized Phase 2 study of CRLX101 in NSCLC is planned and will be initiated in early 2011. CRLX101's favorable tolerability profile may enable combination therapy with other cytotoxic drugs including carboplatin and gemcitabine without added toxicities. Preclinical data on the efficacy and tolerability of such combinations will also be presented. In addition, the dual activity of CRLX101 against both topoisomerase-1 and HIF1α suggest that combination with VEGF antagonists could be synergistic. Similarly, pre-clinical data on the dual mechanism inhibition by CRLX101 based on its pharmacokinetics will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1306. doi:10.1158/1538-7445.AM2011-1306