Antitumor Activity Observed at Interim Analysis of Phase 2 MANTRA-2 Basket Trial of Milademetan in Advanced Solid Tumors

Patients with advanced solid tumors treated with milademetan experienced promising anti-tumor activity at the interim analysis for the phase 2 MANTRA-2 basket trial.

Updated results from the phase 2 MANTRA-2 basket trial (NCT05012397) identified promising preliminary antitumor activity for patients with MDM2-amplified advanced tumors who received milademetan, according to a press release Rain Therapeutics.

At the data cutoff of October 26, 2022, 17 patients were enrolled. Two unconfirmed partial responses were observed in patients with pancreatic and lung cancer with a tumor regression of 34% and 30% with lung cancer, respectively. Additionally, there was promising tumor regression of 29% in a patient with biliary tract cancer and 27% in a patient with breast cancer; both are receiving continued investigational therapy.

Milademetan is an oral inhibitor of the MDM2-p53 complex that helps to reactivate p53. The agent has previous shown antitumor activity within a subgroup of patients with MDM2-amplified liposarcoma and other solid tumors, according to phase 1 research.

“We are encouraged by the preliminary observations from the MANTRA-2 trial,” Avanish Vellanki, co-founder and chief executive officer of Rain, said in the press release. “Treatment with milademetan led to tumor regression in patients previously treated with a multitude of therapies across a range of cancers. We look forward to expanding this dataset as the trial continues to enroll.”

Of the patients enrolled on the trial, 15 have been treated with milademetan. Overall, 10 patients were evaluable for efficacy with a copy number of 8 or more by central testing. All patients had diverse tumor histologies, with most tumors having co-alterations in oncogenes or tumor suppressors in KRAS, EGFR, and PIK3CA. Patients were treated with milademetan at an oral dose of 260 mg once daily on days 1 to 3 and 15 to 17 of each 28-day cycle.

The primary end point of the trial was overall response rate, with secondary end points including duration of response, progression-free survival, growth modulation index, disease control rate, and overall survival.

Anti-tumor activity was observed on patients who were heavily pretreated or refractory with a median of 4 prior therapies. The safety profile remained consistent with previously reported phase 1 findings.

To be eligible for treatment, patients were required to have histologically or cytologically confirmed disease, measurable lesions, and have received standard therapy appropriate for tumor type and stage. There also needed to be a resolution to any clinically relevant toxic effects, a presence of wild-type TP53 and MDM2 gene amplification by tumor testing. Additionally, patients needed an ECOG performance status of 0 or 1, and adequate bone marrow, renal, and hepatic function.

Exclusion criteria included having prior treatment with an MDM2 inhibitor, having well-differentiated or dedifferentiated liposarcoma or intimal sarcoma, or primary malignancies that need antineoplastic treatment within the 2 previous years. If patients had a primary brain tumor, untreated brain metastases, or gastrointestinal conditions they were also excluded. Major surgery within 3 weeks of study treatment, receiving curative-intent radiation therapy within 4 weeks of treatment, or having uncontrolled or significant cardiovascular disease they were excluded from the trial.

“In the first 10 evaluable patients, we have observed activity with 2 unconfirmed partial responses at their first scan and promising tumor regression activity in 2 patients following milademetan monotherapy. In addition, anti-tumor activity was observed in patients with genetic co-alterations, and in tumors with MDM2 copy number above 8. Hence, we plan to revise the protocol to include patients tested locally for MDM2 copy number of 8 and greater. We are encouraged by these preliminary data and we look forward to continuing the trial and evaluating additional data as they become available in the coming months,” Richard Bryce, MBChB, chief medical officer at Rain, concluded.


Rain Therapeutics provides interim pnalysis of Phase 2 basket trial of milademetan for MDM2-amplified advanced solid tumors (MANTRA-2). News release. Rain Therapeutics, November 4, 2022. Accessed November 7, 2022.