Clinical trial NCT05012397: Milademetan in Advanced/Metastatic Solid Tumors
Official title: A Phase 2 Basket Study of Milademetan in Advanced/Metastatic Solid Tumors (MANTRA-2)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Solid Tumors
Head and Neck Carcinoma
Cholangiocarcinoma
Sarcoma
Lung Adenocarcinoma
Bladder Urothelial Carcinoma
Stomach Adenocarcinoma
Breast Cancer Invasive
Ovarian Carcinoma
Cervical Cancer
Non Small Cell Lung Cancer
Gastric Cancer
Biliary Tract Cancer
Melanoma
Pancreas Cancer
MDM2 Gene Amplification
Testicular Germ Cell Tumor
Adrenocortical Carcinoma
Keywords: MDM2
Milademetan
Basket Study
Lead sponsor: Rain Oncology Inc
Sponsor class: INDUSTRY
First posted: 2021-08-19
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Phase 2, multicenter, single-arm, open-label basket study designed to evaluate the safety and efficacy of milademetan in patients with advanced or metastatic solid tumors refractory or intolerant to standard-of-care therapy that exhibit wild-type (WT) TP53 and MDM2 copy number (CN) ≥ 8 using prespecified biomarker criteria.

Detailed description: Approximately 65 patients will be enrolled to receive milademetan.

Patients will receive the study drug until reaching unequivocal disease progression (per Response Evaluation Criteria in Solid Tumors \[RECIST\] version \[v\]1.1), as determined by the Investigator; experiencing unmanageable toxicity; or until other treatment discontinuation criteria are met. Patients may be treated beyond tumor progression if they are experiencing clinical benefit based on the assessment of the Investigator in discussion with the Medical Monitor.

All patients will be followed for documentation of disease progression and survival information (i.e., date and cause of death). Long-term follow-up will continue every 12 weeks (± 7 days) until the endpoint of death, the patient is lost to follow-up, or for 24 months following the final dose of the study drug, whichever comes first.

Eligibility criteria: Inclusion Criteria:

* Histologically and/or cytologically confirmed diagnosis of a cancer that is a locally advanced or metastatic solid tumor
* Measurable tumor lesion(s) in accordance with RECIST v1.1
* Received all standard therapy appropriate for their tumor type and stage of disease or, in the opinion of the Investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard-of-care therapy
* Resolution of any clinically relevant toxic effects of prior chemotherapy, surgery, radiotherapy, or hormonal therapy
* Presence of WT TP53 and MDM2 gene amplification by tumor tissue/blood testing, defined as ≥ 8 copies in tumor tissue by central laboratory or ≥ 8 copies or 4-fold increase in tumor tissue or blood by local testing
* Prescreening for TP53 and MDM2 at a Central Laboratory:

  * MDM2 amplification: CN unknown and where CN cannot be derived for documentation by interpretation of reported results
  * MDM2 amplification: CN 6 to 7.9
  * MDM2 amplification: 3-3.9-fold increase
  * MDM2 amplification with CN ≥ 8 and with equivocal TP53 mutation upon discussion with Sponsor's Medical Monitor
* ECOG performance status of 0 or 1
* Adequate bone marrow function:

  * Platelet count ≥ 100 × 10\^9/L
  * Hemoglobin ≥ 9.0 g/dL
  * Absolute neutrophil count ≥ 1.5 × 10\^9/L
* Adequate renal function

  * Creatinine clearance ≥ 30mL/min, as calculated using the modified Cockcroft-Gault equation
* Adequate hepatic function

  * Alanine aminotransferase and aspartate aminotransferase ≤ 3 × upper limit of normal (ULN) if no liver metastases are present; ≤ 5 × ULN if liver metastases are present
  * Total bilirubin ≤ 1.5 × ULN, or ≤ 3 x ULN in the presence of liver metastases

Exclusion Criteria:

* Prior treatment with a murine double minute 2 (MDM2) inhibitor
* Well-differentiated/dedifferentiated liposarcoma or intimal sarcoma/cardiac sarcoma
* Primary malignancies that required systemic antineoplastic treatment within the previous 2 years, except for localized cancers that have apparently been cured
* Has a primary malignant brain tumor of any grade or histology
* Untreated brain metastases
* Gastrointestinal conditions that could affect the absorption of milademetan, in the opinion of the Investigator
* Known HIV infection or active hepatitis B or C infection
* Major surgery ≤ 3 weeks of the first dose of milademetan
* Curative-intent radiation therapy ≤ 4 weeks or palliative radiation therapy
* Uncontrolled or significant cardiovascular disease

  1. QTcF at rest, where the mean QTcF interval is \> 480 milliseconds
  2. Myocardial infarction within 6 months
  3. Uncontrolled angina pectoris within 6 months
  4. New York Heart Association Class 3 or 4 congestive heart failure
  5. Uncontrolled hypertension

Primary outcomes:
measure: To Determine the ORR of Treatment With Milademetan in Patients With Advanced/Metastatic Solid Tumors With MDM2 Gene Amplification.
timeFrame: From first dose date to first confirmed complete or partial response or study completion date; up to 23.5 months.
Secondary outcomes:
measure: Duration of Response (DOR)
timeFrame: From start date of response to first PD or study completion date; up to 23.5 months
measure: Progression-free Survival (PFS)
timeFrame: From the first dose date to the earliest date of recurrence, progression, death, or study completion; up to 23.5 months
measure: Growth Modulation Index (GMI)
timeFrame: From the start date of the most recent prior line of therapy to the PD date on the study; up to 23.5 months
measure: Disease Control Rate (DCR)
timeFrame: From first dose date to first CR, PR, or stable disease (SD) >= 16 weeks, or study completion date; up to 23.5 months
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford University Medical Center
state: California
city: Fort Myers
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Saint Petersburg
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Syracuse
country: United States
facility: Hematology Oncology Associates of Central NY
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Sioux Falls
country: United States
facility: Sanford Health
state: South Dakota
city: Nashville
country: United States
facility: Tennessee Oncology, PLLC
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Tacoma
country: United States
facility: Northwest Medical Specialities
state: Washington
Study officials:
References:
citation: Gounder MM, Bauer TM, Schwartz GK, Weise AM, LoRusso P, Kumar P, Tao B, Hong Y, Patel P, Lu Y, Lesegretain A, Tirunagaru VG, Xu F, Doebele RC, Hong DS. A First-in-Human Phase I Study of Milademetan, an MDM2 Inhibitor, in Patients With Advanced Liposarcoma, Solid Tumors, or Lymphomas. J Clin Oncol. 2023 Mar 20;41(9):1714-1724. doi: 10.1200/JCO.22.01285. Epub 2023 Jan 20.