Phase 1b trial of STAR-LLD combo for myeloma approved by FDA
Study will test low-dose lenalidomide combo in transplant-ineligible patients
The U.S. Food and Drug Administration (FDA) has cleared the launch of a Phase 1b trial to test STAR-LLD, Starton Therapeutics’ experimental continuous delivery of low-dose lenalidomide into the blood, in people with multiple myeloma.
The U.S.-based study, expected to start in the last months of the year, will evaluate STAR-LLD in combination with Velcade (bortezomib) and dexamethasone as a second line of treatment for patients ineligible for stem cell transplant.
A similar triple combination, using oral lenalidomide (sold as Revlimid, with generics available) instead of STAR-LLD, is approved in Europe for adults newly diagnosed with multiple myeloma and who are not eligible for a transplant.
Revlimid, taken once a day, is a standard myeloma treatment sold by Celgene, a subsidiary of Bristol-Myers Squibb. However, it is associated with fluctuating therapy levels and dose-dependent adverse events.
Starton developed STAR-LLD to provide therapeutic lenalidomide levels for the whole dosing interval, while reducing adverse events.
“Today’s announcement marks a significant development for Starton and patients in need of approved drugs and improved quality of life, and we are excited to begin this critical program in transplant-ineligible patients with multiple myeloma,” Pedro Lichtinger, chairman and CEO at Starton, said in a company press release.
FDA meeting to inform future Phase 2 trials of combo therapy for myeloma
“Treatment of second-line patients at our proposed optimal dose of continuous lenalidomide in combination with the proteasome inhibitor Velcade and dexamethasone allows us to demonstrate activity in an established standard of care regimen by replacing Revlimid with STAR-LLD,” said Jamie Oliver, chief medical officer at Starton.
Lichtinger said that “this study will provide initial evidence of the impact of continuous delivery of lenalidomide both in terms of safety and efficacy, as well as provide clarity for signals of improvement in patients outcomes.”
The FDA agreed to hold a meeting with the company to review the trial’s interim safety and activity data, while patients continue treatment for efficacy measures. The meeting is expected to help inform future Phase 2 trials in myeloma, as well as plans for testing in other types of cancer where lenalidomide has shown activity.
Lenalidomide is an immunomodulatory agent that activates the immune system to kill cancer cells and suppresses the formation of new blood vessels close to the tumor, thereby reducing tumor growth.
Although its oral route is more convenient than into-the-vein administration, patients treated with Revlimid achieve the highest therapy concentration shortly after the pill is taken, with levels dropping continuously until the next dose.
While its highest levels have been associated with adverse events that may result in dose reduction or treatment discontinuation, lower-than-target levels may lead to treatment failure.
Starton is developing new administration systems for lenalidomide that could deliver therapeutic levels at all times. One such system is STAR-LLD’s portable infusion pump, placed under the skin, to continuously deliver the therapy directly into the bloodstream.
According to Starton, a preclinical proof-of-concept study showed that STAR-LLD reduced by 80% myeloma tumors caused by human cells, while lenalidomide abdominal injections were associated with a five-fold tumor increase. If left untreated, tumors grew by 25-fold.
Continuous administration of lenalidomide also led to a 100% overall response rate, corresponding to a reduction in tumor size, while no tumor reductions were observed with once-daily dosing.
STAR-LLD was found well-tolerated by healthy volunteers in earlier study
In addition, a previous Phase 1 trial tested STAR-LLD — given continuously for 24 hours at doses meant to be 48% of the Revlimid dose — against Revlimid in 17 healthy people.
Results showed that the new formulation was well-tolerated, with no dose-related toxicity or adverse events. STAR-LLD showed a maximum concentration 90% lower than Revlimid and a 70% lower total exposure, while having nearly identical bioavailability — how much of the medication was distributed in the body to reach its target areas.
The upcoming Phase 1b trial is expected to recruit up to six patients in three or four U.S. centers to evaluate the tolerability and efficacy of STAR-LLD, at a daily dose of 9.6 mg (400 micrograms per hour), for 10 months.
Researchers will assess the treatment’s impact on immune function biomarkers, including levels of several immune cells — T-cells, NK-cells, and B-cells — and cytokines. Cytokines are small molecules released by cells that are important for modulating the immune function.
Response rates, duration of response, and progression-free survival, or the time during which the disease does not progress, will also be evaluated, as well as minimal residual disease, or the small number of cancer cells that remain in the body after treatment.