Dosing Schedule May Be Key to Optimal Administration of Milademetan for Sarcoma Subtype
The switch from a continuous to an intermittent dosing schedule appeared to cut the occurrence of thrombocytopenia in half.
|The following article features coverage from the Connective Tissue Oncology Society (CTOS) 2018 meeting. Click here to read more of Cancer Therapy Advisor's conference coverage.|
Profound thrombocytopenia can restrict the proper dosing of an investigational, orally bioavailable MDM2 inhibitor, milademetan, in a phase 1 trial examining the drug in patients with well-differentiated or dedifferentiated liposarcoma (WD/DD LPS). To combat this thrombocytopenia — which Mrinal Gounder, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, said was a “vexing problem” — researchers switched the dosing schedule of the therapeutic from continuous to intermittent dosing. This change to the dosing schedule allowed researchers to reduce the occurrence of thrombocytopenia seen in participants by half, and also alleviated some of the serious gastrointestinal adverse events that have been linked to the drug when it is given in high doses on a continuous schedule.
Once the optimal dosing schedule was identified, milademetan was found to produce an objective response and durable stable disease in some patients with progressing well-differentiated or dedifferentiated liposarcoma (WD/DD LPS), conferring a median progression-free survival of 7.4 months. The results were presented by Dr Gounder during the Connective Tissue Oncology Society 2018 Annual Meeting in Rome, Italy.1
MDM2 amplification is a hallmark of WD/DD LPS; MDM2 overexpression can inactivate p53, the most commonly mutated protein across cancer types. MDM2 is a negative regulator of p53, promoting degradation of the tumor suppressing protein.
The safety of milademetan was examined across 107 patients with WD/DD LPS, and participants were required to have relapsed or refractory advanced solid tumors or lymphoma with an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1. To be eligible, patients had to have adequate bone marrow, renal, hepatic, and blood-clotting functions.
Although p53 genotyping was not a prerequisite for patients to start treatment when the trial originally began enrollment, consent to undergo sequencing was later an eligibility requirement. Dr Gounder noted that when the trial began, next-generation sequencing was not readily available.
Dr Gounder admitted that the study design was complicated: When the researchers attempted a dose escalation and tried to double the dose of the drug, they observed dose-limiting toxicities. They de-escalated the dose, but patients still experienced significant toxicities, which prompted a second dose change. The dosing in another cohort, schedule B, was also changed to an alternative schedule. Ultimately, when milademetan was administered in an intermittent schedule (260 mg, 3 out of 14 days), the drug was determined to have an acceptable safety profile.
Dr Gounder noted that the identification of biomarkers of clinical benefit is ongoing, but concluded that “Further evaluation of milademetan in WD/DD LPS is warranted.”
Read more of Cancer Therapy Advisor's coverage of the CTOS 2018 meeting by visiting the conference page.
- Gounder M, Bauer TM, Schwartz GK, et al. Milademetan, an oral MDM2 inhibitor, in well-differentiated/de-differentiated liposarcoma: results from a phase 1 study in patients with solid tumors and lymphomas. Presented at: CTOS 2018 Annual Meeting; Rome, Italy: November 14-17. Paper 019.