Continuous Low-Dose Lenalidomide Safe in Healthy People in Trial

STAR-LLD therapy being developed for multiple myeloma patients

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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STAR-LLD, an investigational continuous delivery of low doses of lenalidomide into the blood — being developed as a new treatment option for multiple myeloma — was well-tolerated in healthy volunteers in a Phase 1 clinical trial, with no dose-related toxicity or adverse events, data show.

Moreover, the treatment candidate maintained therapeutic levels across all doses tested.

An oral formulation of lenalidomide, sold as Revlimid, is a standard anti-cancer treatment for people with multiple myeloma, but it’s associated with fluctuating levels and adverse events.

Notably, trial data also showed that STAR-LLD was associated with a 70% lower total body exposure than that achieved with once-daily Revlimid, while having a nearly identical bioavailability — how much of the medication was distributed in the body to reach its target areas.

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According to Starton Therapeutics (formerly ChemioCare), the developer of STAR-LLD, the trial reached all of its primary and secondary goals.

STAR-LLD in trial

“Lenalidomide has been an effective immunomodulatory drug in [blood] malignancies for years, however adverse events … have limited its use in certain patient settings,” Jamie Oliver, Starton’s chief medical officer, said in a company press release.

“We believe STAR-LLD may be able to expand the use of lenalidomide where the oral form is not used today,” Oliver added.

The trial’s results will aid in the selection of a dose for an upcoming Phase 1b/2 trial in multiple myeloma patients. The company remains on track to begin enrollment by year’s end, and three clinical sites in Europe are already confirmed.

Starton is planning to seek approval to conduct clinical studies in other countries, including the U.S.

“We are thrilled to have successfully completed our first clinical study for STAR-LLD,” said Pedro Lichtinger, Starton’s chairman and CEO. “The delivery system and program have proven viability and we believe we are well situated to advance to Phase 1b/2 in multiple myeloma patients.”

Lenalidomide is an immunomodulatory agent that activates the immune system to fight cancer. It also suppresses the formation of new blood vessels in the tumor’s vicinity, preventing its growth through these two mechanisms.

While its oral route is more convenient for patients than into-the-vein (intravenous) infusions, Revlimid has been associated with significant dose-dependent adverse events (side effects), including a reduction in the numbers of neutrophils, a type of white blood cell.

This condition, called neutropenia, limits the therapy’s tolerance, with patients having to undergo dose reductions or treatment discontinuation.

Also, data show that patients on Revlimid — sold by Celgene, a subsidiary of Bristol-Myers Squibb — have had problems with fluctuating levels of the medication. The highest concentration is reached shortly after the pill is taken, but levels then drop continuously until the next dose.

This means that at its peak concentration, the therapy may cause toxicity, while lower-than-target levels may lead to treatment failure.

Starton’s goal was to create new systems that keep lenalidomide at its optimal levels at all times.

The company is developing three delivery systems for STAR-LLD. One, the portable infusion pump, placed under the skin, was tested in the Phase 1 trial. The others are a skin patch and a patch/pump on-body injector.

The trial, conducted in Groningen, Netherlands, enrolled 17 healthy people. It assessed the safety and pharmacokinetics — a medication’s movement into, through, and out of the body — of a continuous infusion of lenalidomide for 24 hours versus Revlimid.

Participants received one of three escalating infusion rates: 2.4 milligrams per day (mg/day), 4.8 mg/day, and 9.6 mg/day. Each was projected to be 48% of the oral Revlimid dose, which ranged from 5 to 20 mg/day.

Results showed that continuous under-the-skin infusion of STAR-LLD was well tolerated, with no dose-related toxicity or adverse events. Its relative bioavailability was 90% of the comparative Revlimid dose and was consistent at each dose level.

In addition, compared with Revlimid, STAR-LLD showed a 90% lower maximum concentration and 70% lower total exposure. Sustained minimum concentrations were at targeted dose levels.

“The Phase 1 study results successfully established STAR-LLD bioavailability, safety, and pharmacokinetics,” and “established the compatibility and utility of the continuous ambulatory infusion device with our proprietary subcutaneous [under-the-skin] formulation,” Oliver said.

In a multiple myeloma animal model, continuous under-the-skin infusions were previously shown to result in a 71% reduction in lenalidomide maximum effective dose compared with once-daily dosing.

According to Starton, a previous preclinical proof-of-concept study showed human multiple myeloma tumors shrank by 80% over a 29-day period with STAR-LLD, compared with a five-fold increase when treated with pulsatile intraperitoneal (into the abdomen) injections of lenalidomide.

A pulsatile delivery means that a portion of the total payload is released in a burst, followed by periods of little or no medication in a defined period of time.

The study also showed that continuous dosing of 144 micrograms of lenalidomide resulted in a 100% overall response rate, which refers to a reduction in tumor size, and a 20% rate of tumor elimination. Conversely, no tumor size reductions were seen with the daily pulsatile once daily dosing.