CLR 131 Leads a New Generation of Lipid-Based Cancer Drug Delivery Systems

A novel compound that uses abundant lipids in cancer cell membranes to deliver a radioisotope to the tumor environment shows early signs of efficacy in a range of B-cell malignancies, including multiple myeloma.^1,2

CLR 131 is a phospholipid-drug conjugate (PDC) designed to provide a payload of iodine-131 directly to the cytosol and cytoplasm of tumor cells.³ Cellectar Biosciences, a biopharmaceutical company based in Florham Park, New Jersey, is investigating the potential of CLR 131 in hematologic and solid tumors. The company also is exploring its PDC approach as a platform technology for other oncologic conjugates.⁴

Positive clinical trial data have been announced for patients with B-cell malignancies, 2 including multiple myeloma, and CLR 131 has secured fast track designation from the FDA for 3 separate indications.^5-7 If it lives up to its potential, CLR 131 could be the first of many such drugs from Cellectar, with other payloads being explored.¹

Meanwhile, the underlying technology shines a light on the broader use of lipids as vehicles for cancer therapies. With the advent of nanotechnology in medicine, lipid-based carriers have been designed to encapsulate drugs to improve delivery to the tumor site, in the hopes of reducing generalized toxicity and improving therapeutic effect.^8-10

Several FDA-approved liposomal formulations of common chemotherapy drugs are on the market.¹¹ Ongoing clinical efforts aim to improve the efficacy of some of these drugs; notably, daunorubicin plus cytarabine (CPX-351; Vyxeos)¹² and liposomal irinotecan (Onivyde).¹³ CPX-351 was initially approved in 2017 in acute myeloid leukemia settings and Onivyde was cleared in 2015 for progressive metastatic pancreatic adenocarcinoma.

Additionally, newer lipid-based strategies aimed at overcoming the challenges of liposomal formulations are in development. These include SB05-EndoTAG-1 (SynCore Biotechnology), which combines paclitaxel with lipids¹⁴; mRNA-2416 (Moderna), which encodes OX40L in a lipid nanoparticle¹⁵; and Promitil (LipoMedix), a lipid-based form of mitomycin-C.¹⁶

Improving Drug Delivery

Investigators have long sought more specific cancer drugs with reduced off-target toxicity and enhanced therapeutic efficacy. The development of molecularly targeted therapies has been one result, but new drug delivery systems may achieve similar goals. Thanks to the advent of nanotechnology, significant advances in the development of drug carrier technologies for cancer therapy have occurred in the past several decades.^8-10

Broadly speaking, drug carriers are designed to shield drugs from interaction with healthy cells and facilitate accumulation at the tumor site. The latter is believed to occur as a result of the enhanced permeability and retention effect. Nanoparticles are too big to readily pass through the normal vasculature into healthy tissues but not the abnormal, leaky blood vessels characteristic of the tumor microenvironment. The lack of lymphatic drainage from tumor vessels adds to this effect.¹⁷

Nanoparticles prepared from natural polymers, such as lipids, proteins, and peptides, represent the most promising approach. In particular, liposomes are the most extensively studied type of nanoparticle drug carrier and account for first generation of FDA-approved lipidbased drug delivery systems.¹⁸

Liposomes are spherical vesicles composed of 1 or more phospholipid bilayers surrounding an aqueous core. Depending on its properties, a drug can be encapsulated within the core (a hydrophilic drug) or held in the bilayer (a hydrophobic drug) (Figure 1).^8,11

Among their advantages over naked drugs, liposomes and other lipid-based delivery systems can reduce toxicity, prolong half-life in the circulation, and improve pharmacokinetics. Additionally, because of their biocompatibility with cell membranes, they are more readily taken up into cells via endocytosis. Because the drug remains behind a lipid barrier once inside the cell, being released only upon lysosomal degradation, it may avoid eviction from the cell by transporter pumps that play a large role in drug resistance.^9,11,19

Liposomal Carriers

Chemotherapy Delivery

Beginning with the 1995 approval of doxorubicin hydrochloride liposome injection (Doxil) for the treatment of AIDS-related Kaposi sarcoma and, subsequently, multiple myeloma and ovarian cancer, severalliposomal formulations of conventional chemotherapies have become available.^9,11

Despite better developed drug properties, some approved liposomal formulations only moderately improved patient survival compared with conventional chemotherapy.¹¹ Their development revealed a number of inherent challenges. Early on, investigators discovered that liposomes were rapidly recognized and engulfed by macrophages, which led to their destruction by the mononuclear phagocyte system.^10,20

Nevertheless, ongoing clinical development has demonstrated greater efficacy for several of these compounds. CPX-351 continued to show an overall survival (OS) benefit versus conventional 7 + 3 chemotherapy for patients with newly diagnosed high-risk/secondary acute myeloid leukemia in findings from a phase 3 trial (NCT01696084) presented at the 2020 European Hematology Association Virtual Congress.¹²

After a median follow-up of 60.65 months, the median OS was 9.33 months (95% CI, 6.37-11.86) and 5.95 months with CPX-351 and 7 + 3, respectively (HR, 0.70; 95% CI, 0.55-0.91). The estimated 3- and 5-year OS rates were also higher with CPX-351 versus 7 + 3, at 21% versus 9% and 18% versus 8%, respectively.¹²

The combination of Onivyde plus fluorouracil, leucovorin, and oxaliplatin (NALIRIFOX) demonstrated promising outcomes as a frontline treatment for patients with locally advanced or metastatic pancreatic ductal adenocarcinoma. Findings from a phase 1/2 study (NCT02551991) for 32 patients were presented at the European Society of Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer 2020. The NALIRIFOX regimen resulted in a median progression-free survival of 9.2 months (95% CI, 7.69-11.96) and a median OS of 12.6 months (95% CI, 8.74-18.69). The overall response was 34.4% (95% CI, 18.6%-53.2%), consisting of 1 complete response (CR) and 10 partial responses (PRs).13

An international, randomized phase 3 trial (NAPOLI 3; NCT04083235) exploring the use of frontline NALIRIFOX compared with gemcitabine and nab-paclitaxel (Abraxane) in patients with metastatic pancreatic cancer is now under way.

Other Payloads

Besides chemotherapy, other cancer drugs can be contained within liposomes. Nucleic acid–based drugs, which include oligodeoxynucleotides, plasmid DNA, short interfering RNA, and messenger RNA (mRNA), can be used for gene therapy. However, the use of naked genetic material is challenging due to its large size, instability in the circulation, and susceptibility to degradation by nucleases. Lipid-based carriers offer a way to address these issues.^20,21

Bio-Path Holdings is developing prexigebersen (BP1001), BP1002, and BP1003; the latter is still in preclinical testing. All 3 are liposome-encapsulated antisense oligonucleotides that inhibit synthesis of the GRB2, BCL2, and STAT3 proteins, respectively.^22-24 Prexigebersen is most advanced in clinical development; Bio-Path recently announced an updated interim analysis of stage 1 of an ongoing phase 2 study in AML (NCT02781883).

Among 17 evaluable patients treated with a combination of prexigebersen and low-dose cytarabine (LDAC), 11 had a response, including 5 CRs.²⁵ Moving forward, patients in stage 2 of the trial will be treated with a combination of prexigebersen, decitabine, and venetoclax, instead of LDAC, following initial safety testing of this combination in which 3 of 6 patients had a response.²⁶

All the currently approved liposomal formulations rely on passive targeting of the tumor tissue through enhanced permeability and retention.⁹ However, the irregular tumor vasculature thought to be responsible for this effect can also work against effective drug delivery, as can the elevated fluid pressure surrounding the tumor.^10,11

To further enhance active tumor-targeted drug delivery, development of functionalized liposomes has also been explored, in which properties of the liposome are engineered for improvements. This includes altering the type of lipid to affect the size or charge of the liposome or conjugating other drugs to the liposome surface. Immunoliposomes, for example, are generated by chemically coupling liposomes with antibodies or antibody fragments against cancer cell–specific antigens, such as EGFR.^9,11,18,19

SB05-EndoTAG-1 encapsulates paclitaxel in positively charged liposomes. These are designed to interact with the negatively charged endothelial cells of newly formed blood vessels, releasing paclitaxel into these cells, killing them, and cutting off the tumor’s blood supply.¹⁴ Phase 3 trials are ongoing in locally advanced/metastatic pancreatic cancer (NCT03126435) and triple-negative breast cancer (NCT03002103).

Lipid-Drug Conjugates

Other types of lipid-based drug deliverysystems, beyond lyposomes, come with advantages and disadvantages. There are several major types of lipid nanoparticles; the lipid core may be solid, liquid, or both, and the core may contain single or multiple compartments of drug, among other distinctive features.^8,19

Moderna Therapeutics is developing 2 lipid nanoparticle-based encapsulation systems that contain synthetic mRNAs encoding immunostimulatory proteins.²⁷ Results from an ongoing study of mRNA-2416 (NCT03323398), in which the encapsulated mRNA encodes OX40L, were presented at the 2020 American Association for Cancer Research Virtual Meeting I. Despite being well tolerated, mRNA-2416 had modest antitumor activity, but it is hoped that this may be enhanced by combining it with durvalumab (Imfinzi), a PD-L1 inhibitor. This combination is being evaluated in part B of the study.¹⁵

Lipid-drug conjugates (LDCs), in which cancer drugs are linked with lipid molecules, are among the most promising types of lipid nanoparticle. LDCs also can facilitate the loading of hydrophobic drugs into other lipid-based carrier systems.^8,28

Promitil is an LDC involving mitomycin-C that is further encapsulated in a pegylated liposomal carrier.¹⁶ In a phase 1a doseescalation study, toxicity was lower and dose tolerability higher than historical data for “naked” mitomycin-C. In the phase 1b portion of the trial in patients with advanced, chemorefractory colorectal cancer, Promitil was evaluated alone or combined with either capecitabine or capecitabine and bevacizumab (NCT01705002).

Among 36 response-evaluable patients, stable disease was observed in 42% at week 12. Median survival was 8.7 months, and adding capecitabine and bevacizumab to Promitil had no further effect. AEs were mostly mild to moderately severe.²⁹

Targeting Lipid Rafts

Cellectar Biosciences is developing a different kind of LDC. CLR 131 is a PDC, a proprietary mix of phospholipid ethers (PLEs) covalently linked to a cytotoxic radioactive isotope of iodine-131.³

PDCs offer a lipid-based carrier system with a unique feature: They exploit the altered lipid composition of cancer cell membranes to more actively target tumors. PLEs are naturally occurring lipids that are taken up into cells via lipid rafts, cholesterol-rich regions of the plasma membrane that play a key role in cell signaling. PLEs accumulate in cancer cells, in part because their cell membranes contain an enhanced number of lipid rafts.^1,30-32

Thus, the lipid rafts on the surface of cancer cells are bound by multiple PDCs via their PLE moiety. When the lipid rafts eventually undergo transmembrane flipping, they deliver the PLEs and their radioactive payload into the cancer cell. Proposed advantages of this system include the PDCs’ ability to gain entry into a wide variety of cancer types and indiscriminately target all cells within a tumor without relying on expression of a specific antigen.¹

Furthermore, the technology could offer considerable flexibility in the types of payloads that can be used and could be further refined via linker design (Figure 2).¹ Cellectar has several other PDCs in preclinical development, including agents designed to produce cell cycle arrest, inhibit protein translation, and disrupt the cytoskeleton.³³

CLR 131 has been granted orphan drug status in multiple myeloma, Ewing sarcoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, and lymphoplasmacytic lymphoma (LPL).³⁴ CLR 131 also has fast track designation for multiple myeloma, diffuse large B-cell lymphoma (DLBCL), and LPL/Waldenstr.m macroglobulinemia (WM).^5-7

The most recent fast track designation, for LPL/WM, follows positive results from the ongoing phase 2 CLOVER-1 trial (NCT02952508); Cellectar announced that all 4 treated participants with LPL/WM so far achieved an objective response, with 1 achieving CR.^2,7,34

In this trial, patients with relapsed/refractory (R/R) B-cell lymphomas, multiple myeloma, and non-Hodgkin lymphoma (NHL) were treated with 3 doses of CLR 131: less than 50 mCi total body dose (TBD; an intentionally subtherapeutic dose), 50 mCi TBD, and 75 mCi TBD. Patients in both the multiple myeloma and NHL cohorts had a median age of 70 years and were heavily pretreated.³⁴

The overall response rate (ORR) for patients with multiple myeloma (n = 33) was 34.5% across all doses (42.8% at the 75 mCi dose; 26.3%, 50 mCi). In patients with NHL, the ORR among 19 patients was 42% (43%, 75 mCi; 42%, 50 mCi). Subtype assessments demonstrated ORRs of 30% (with 1 CR) in patients with DLBCL and 33% for patients with chronic lymphocytic leukemia, small lymphocytic leukemia, and marginal zone lymphoma. CLR 131 was well tolerated across all dose groups.³⁴

Cellectar simultaneously announced the completion of a phase 1 dose-escalation study of CLR 131 in patients with R/R multiple myeloma (NCT02278315). In this trial, 4 single-dose cohorts were examined (25, 37.5, 50, and 62.5 mCi TBD). The study was modified in 2018 to test fractionated doses (2 doses of 31, 37.5, or 40 mCi TBD, given 1 week apart). For both the single- and fractionated-dose cohorts, CLR 131 was administered as 30-minute intravenous infusions in combination with 40-mg weekly low-dose dexamethasone.34

All patients (n = 17) enrolled in the single-dose cohorts experienced clinical benefit, with 16 participants achieving stable disease. Pooled median OS from the 4 cohorts was 22 months.

Compared with patients administered the highest single dose of CLR 131, the cohort that received the lowest fractionated dose showed better tolerability and safety; despite receiving an 18% higher dose overall, these patients required less supportive care (such as blood transfusions) and had a 50% greater reduction in M protein levels, a surrogate marker of efficacy.³⁴

The next fractionated-dose cohort, which received a total 75 mCi TBD (2 Å~ 37.5 mCi TBD; n = 4), had a 50% PR rate, defined as at least a 50% decrease in M protein from baseline. The remaining 2 patients experienced a minimal response, defined as an M protein decrease between 25% and 49.9%.

The authors concluded that CLR 131 showed a clear dose response, with higher doses producing greater efficacy without unacceptable toxicity.³⁵

References:

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6. Cellectar receives FDA fast track designation for CLR 131 in diffuse large B-cell lymphoma. News release. Cellectar Biosciences. July 9, 2020. Accessed May 25, 2020. https://www.cellectar.com/news-media/press-releases/detail/211/cellectar-receives-fda-fast-track-designation-for-clr-131

7. Cellectar receives FDA fast track designation for CLR 131 in lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia. News release. Cellectar Biosciences. May 26, 2020. Accessed June 1, 2020. https://www.cellectar.com/news-media/press-releases/detail/238/cellectar-receives-fda-fast-track-designation-forclr-131

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35. Longcor J, Ailawadhi S, Oliver K, Callander N, Stiff P. CLR 131 demonstrates high rate of activity in a phase 1, dose escalation study in patients with relapsed or refractory multiple myeloma (RRMM). Clin Lymphoma Myeloma Leuk. 2019;19(suppl 10):E356-E357. doi:10.1016/j.clml.2019.09.589