PRECISION 1 Trial to End After Nab-Sirolimus is Projected to Miss Efficacy Threshold in TSC1/2+ Solid Tumors

The phase 2 PRECISION 1 trial (NCT05103358) evaluating nab-sirolimus (Fyarro) in patients with solid tumors harboring TSC1 or TSC2 inactivating alterations will be stopped after an analysis by an independent data monitoring committee showed that the study was unlikely to meet an efficacy threshold to support accelerated approval, according to an announcement from Aadi Bioscience^.1

Approximately 25 patients being treated on the study who are experiencing a benefit with nab-sirolimus will be permitted to transition to an expanded access protocol. Full data from the study will be presented at a later date.

“We are humbled by the effort of the investigators, support staff, and most importantly, the patients and their families who took part in PRECISION 1. While nab-sirolimus showed monotherapy activity in the study population, the trial fell short of delivering what we believe would be required to support an accelerated approval in the broad TSC1/TSC2inactivating mutations indication,” David Lennon, president and chief executive officer of Aadi Bioscience, stated in a news release. “I want to thank the dedicated Aadi employees who worked tirelessly on this trial and are negatively impacted by this outcome. Given the change in the development pipeline, we have taken the necessary steps to immediately preserve cash runway and have hired an advisory firm to explore all options to maximize value for shareholders.”

Furthermore, enrollment will be paused for two ongoing phase 2 trials evaluating nab-sirolimus in patients with advanced or recurrent endometrioid-type endometrial cancer (NCT05997017) and those with neuroendocrine tumors (NETs; NCT05997056); however, dosing will continue as planned in both trials. The endometrial cancer study (n = 20) and the NETS study (n = 10) have reached sufficient enrollment to evaluate efficacy signals for the agent in these populations, and data are expected later in 2024.

In November 2021, the FDA approved nab-sirolimus for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor (PEComa).²

PRECISION 1 was an open-label basket trial enrolling patients at least 12 years of age with malignant solid tumors harboring pathogenic inactivating TSC1 or TSC2 alterations, which needed to be centrally confirmed and were allowed to be identified via next-generation sequencing with a tumor tissue or liquid biopsy.3 Patients needed to have metastatic or locally advanced solid tumors where surgical resection was not an option or likely to result in severe morbidity, and prior treatment with all standard therapies was required. Alternatively, patients were allowed to enroll if the investigator deemed that they were unlikely to tolerate or derive benefit from standard therapies, or if they had no alternative treatment options.

Other key inclusion criteria consisted of at least 1 measurable target lesion per RECIST 1.1 criteria; an ECOG performance status of 0 or 1, a Karnofsky performance status of at least 80, or a Lansky performance status of at least 80 for pediatric patients; and adequate liver, renal, and hematologic function.

Prior treatment with an mTOR inhibitor, including nab-sirolimus, was not permitted, and those with primary brain tumors or PEComa were excluded. Those with severe grade 3 or higher ongoing infections requiring parenteral or oral anti-infective treatment within 7 days of enrollment were also excluded.

The study included an arm for patients with TSC1 alterations and another arm for those with TSC2 alterations. All patients received nab-sirolimus.

Overall response rate as assessed by independent radiology review per RECIST 1.1 criteria was the trial’s primary end point. Secondary end points included duration of response, disease control rate, time to response, progression-free survival, overall survival, patient-reported outcomes, and safety.

References

1. Aadi Bioscience provides PRECISION1 trial and corporate updates. News release. Aadi Bioscience. August 20, 2024. Accessed August 21, 2024. https://ir.aadibio.com/news-releases/news-release-details/aadi-bioscience-provides-precision1-trial-and-corporate-updates
2. FDA approves sirolimus protein-bound particles for malignant perivascular epithelioid cell tumor. FDA. November 22, 2021. Accessed August 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sirolimus-protein-bound-particles-malignant-perivascular-epithelioid-cell-tumor
3. Phase 2 basket trial of nab-sirolimus in patients with malignant solid tumors with pathogenic alterations in TSC1/​TSC2 genes (PRECISION 1). ClinicalTrials.gov. Updated June 3, 2024. Accessed August 21, 2024. https://www.clinicaltrials.gov/study/NCT05103358