A Multiple Ascending Dose Study of Milademetan in Subjects With Advanced Solid Tumors or Lymphomas

NCT01877382 | Completed Phase 1 Results

• 1 other identifier: DS3032-A-U101
• Study Type: interventional
• Target: 107
• Locations: 1 country
• Sites: 5

Brief Summary

This will be a Phase 1, open-label study of milademetan to assess its safety and tolerability, identify a maximum tolerated dose (MTD)/tentative recommended phase 2 dose (RP2D), and assess its pharmacokinetic (PK)/ pharmacodynamic (PDy) properties in participants with advanced solid tumors or lymphomas. Approximately 5 US sites are planned for Part 1 (Dose Escalation) and Part 2 (Dose Expansion). The same sites are planned to participate for both parts.

Conditions

Advanced Solid Tumor; Lymphoma

Outcome Measures

Primary Outcomes (3)

• Number of Participants With Treatment-emergent Adverse Events (≥10% Overall) in Participants Receiving Milademetan

  A treatment-emergent adverse event (TEAE) was defined as an adverse event (AE) that emerged during the treatment period (from first dose date until 30 days after the last dosing date), having been absent at pretreatment; or reemerged during treatment, having been present at baseline, but stopped prior to treatment; or worsened in severity after starting treatment relative to the pretreatment state, when the AE was continuous.

  Screening until end of treatment visit, up to approximately 7 years 2 months

• Number of Participants With Dose-Limiting Toxicities In Participants Receiving Milademetan by Preferred Term and Worst Grade by NCI CTCAE

  A dose-limiting toxicity (DLT) was defined as any treatment-emergent AE (TEAE) not attributable to the participant's disease or a disease-related processes that occurred during the observation period (Cycle 1) in each dose-level cohort and was Grade 3 or higher according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0, with a few exceptions.

  Cycle 1, Day 1 to Day 28 (each cycle, 28 days)

• Number of Participants With Melanoma and Diffuse Large B Cell Lymphoma Who Achieved Objective Response

  Tumor response was assessed using RECIST Version 1.1 (in solid tumor participants with measurable disease) or treatment response using the revised International Working Group criteria 7 (in participants with lymphoma). For RECIST, complete response (CR) was defined as a disappearance of all target lesions, partial response (PR) was defined as at least a 30% decrease in the sum of diameters of target lesions, and stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD; at least a 20% increase in the sum of diameters of target lesions. Objective response rate (ORR) was the sum of CR and PR rates.

  Screening up to Cycle 3 and beyond, Day 1 (each cycle, 28 days)

Secondary Outcomes (6)

• Pharmacokinetic Parameter Maximum Plasma Concentration (Cmax) of Milademetan In Participants Receiving Milademetan

  Escalation:Cycle 1,Days 1,2,8,15,18-21 Predose,0.5,1,2,3,6-8 hours(h);Cycle 2,Day 1 Predose,1,3,6-8h,30 days after last dose; Expansion:Cycle 1,Days 1,2,8,15,18-21 Predose,0.5,1,2,3,4,6,8h;Cycle 2,Day 1 Predose,1,2,3,4,6,8h and Day 2 (each cycle, 28 days)

• Pharmacokinetic Parameter Area Under the Curve (AUC) of Milademetan In Participants Receiving Milademetan

  Escalation:Cycle 1,Days 1,2,8,15,18-21 Predose,0.5,1,2,3,6-8 hours(h);Cycle 2,Day 1 Predose,1,3,6-8h,30 days after last dose; Expansion:Cycle 1,Days 1,2,8,15,18-21 Predose,0.5,1,2,3,4,6,8h;Cycle 2,Day 1 Predose,1,2,3,4,6,8h and Day 2 (each cycle, 28 days)

• Pharmacokinetic Parameter Time to Reach Maximum Plasma Concentration (Tmax) of Milademetan In Participants Receiving Milademetan

  Escalation:Cycle 1,Days 1,2,8,15,18-21 Predose,0.5,1,2,3,6-8 hours(h);Cycle 2,Day 1 Predose,1,3,6-8h,30 days after last dose; Expansion:Cycle 1,Days 1,2,8,15,18-21 Predose,0.5,1,2,3,4,6,8h;Cycle 2,Day 1 Predose,1,2,3,4,6,8h and Day 2 (each cycle, 28 days)

• Pharmacokinetic Parameter Apparent Clearance (CL/F) of Milademetan In Participants Receiving Milademetan

  Escalation:Cycle 1,Days 1,2,8,15,18-21 Predose,0.5,1,2,3,6-8 hours(h);Cycle 2,Day 1 Predose,1,3,6-8h,30 days after last dose; Expansion:Cycle 1,Days 1,2,8,15,18-21 Predose,0.5,1,2,3,4,6,8h;Cycle 2,Day 1 Predose,1,2,3,4,6,8h and Day 2 (each cycle, 28 days)

• Pharmacokinetic Parameter Elimination Terminal Half Life Half-Life (T1/2) of Milademetan In Participants Receiving Milademetan

  Escalation:Cycle 1,Days 1,2,8,15,18-21 Predose,0.5,1,2,3,6-8 hours(h);Cycle 2,Day 1 Predose,1,3,6-8h,30 days after last dose; Expansion:Cycle 1,Days 1,2,8,15,18-21 Predose,0.5,1,2,3,4,6,8h;Cycle 2,Day 1 Predose,1,2,3,4,6,8h and Day 2 (each cycle, 28 days)

Study Arms (2)

Part 1, Milademetan Alone

EXPERIMENTAL

Participants receive milademetan alone with different dose schedules.

Drug: Milademetan

Part 2, Milademetan Alone

EXPERIMENTAL

Participants with advanced melanoma and diffuse large B cell lymphoma (DLBCL) receive milademetan alone with different dose schedules.

Drug: Milademetan

Interventions

Milademetan DRUG

DS-3032b will be administered as an oral capsule. It will be supplied in 5, 20, 80, and/or 200 mg capsules individually packaged in desiccant-embedded aluminum blisters.

Part 1, Milademetan Alone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Dose Escalation Cohorts (Part 1)
• Has a histologically or cytologically documented advanced solid tumor or lymphoma that has relapsed from or is refractory to standard treatment, or for which no standard treatment is available.
• Participants with melanoma who are ineligible to receive or have declined ipilimumab treatment or who are refractory or intolerant to ipilimumab may enroll.
• Participants with certain tumor types such as those with high prevalence of MDM2 amplification or overexpression (eg, well-differentiated \[WD\]/dedifferentiated \[DD\] liposarcoma) may be preferentially enrolled in Part 1.
• Dose Expansion Cohort (Part 2)
• Has a histologically or cytologically documented advanced melanoma or diffuse large B cell lymphoma (DLBCL), with measurable disease that is refractory to standard treatment or for which no standard treatment is available.
• Participants with melanoma who are ineligible to receive or have declined ipilimumab treatment or who are refractory or intolerant to ipilimumab may enroll.
• Participants with DLBCL who have failed, been deemed ineligible for, or refused autologous stem cell transplantation may enroll.
• Man or woman ≥ 18 years old.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Has adequate bone marrow function, defined as:
• Platelet count ≥ 100 x 10\^9/L
• Hemoglobin ≥ 9.0 g/dL
• Absolute neutrophil count ≥ 1.5 x 10\^9/L.
• Has adequate renal function, defined as creatinine clearance ≥ 60 mL/min, as calculated using the modified Cockcroft Gault equation, (\[{140 - age in years} × {actual weight in kg}\] divided by \[{72 × serum creatinine in mg/dL} multiply by 0.85 if female\]), OR creatinine ≤ 1.5 x ULN.

You may not qualify if:

• Has a tumor that contains an inactivating mutation, insertion, or deletion in the TP53 gene determined previously or at screening.
• Has a history of primary central nervous system malignancy.
• Has gastrointestinal conditions that could affect the absorption of milademetan in the opinion of the Investigator.
• Has an uncontrolled infection requiring intravenous antibiotics, antivirals, or antifungals, known human immunodeficiency virus infection, or active hepatitis B or C infection.
• Has received an allogeneic bone marrow or allogeneic stem cell transplant.
• Has a concomitant medical condition that would increase the risk of toxicity, in the opinion of the Investigator or Sponsor.
• Has clinically active brain metastases, defined as untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. Participants with treated brain metastases that are no longer symptomatic and who require no treatment with steroids may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 4 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment (2 weeks for stereotactic radiotherapy).
• Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI-CTCAE v4, grade ≤ 1 or baseline. Participants with chronic grade 2 toxicities may be eligible per the discretion of the Investigator and Sponsor (eg, grade 2 chemotherapy-induced neuropathy).
• Had an autologous transplant within 3 months of starting study drug treatment.
• Is receiving concomitant treatment with a strong inducer of CYP3A.
• Had systemic treatment with anticancer therapy, antibody-based therapy, retinoid therapy, or hormonal therapy within 3 weeks before study drug treatment; or treatment with nitrosoureas or mitomycin C within 6 weeks before study drug treatment; or treatment with small-molecule targeted agents within 2 weeks before study drug treatment. Previous and concurrent use of hormone replacement therapy, the use of gonadotropin releasing hormone modulators for prostate cancer, and the use of somatostatin analogs for neuroendocrine tumors are permitted if such therapy has not been changed within 8 weeks before study drug treatment.
• Had therapeutic radiation therapy or major surgery within 4 weeks before study drug treatment or palliative radiation therapy within 2 weeks before study drug treatment.
• Participated in a therapeutic clinical study within 3 weeks before study drug treatment, or current participation in other therapeutic investigational procedures.
• Prolongation of corrected QT interval by Fridericia's method (QTcF) at rest, where the mean QTcF interval is \> 450 milliseconds (ms) for males and \> 470 ms for females based on triplicate ECG.
• Pregnant or breastfeeding.

Sponsors & Collaborators

• Daiichi Sankyo: lead

Study Sites (5)

Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Columbia University College of Physicians and Surgeons

New York, New York, 10032, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Tennessee Oncology

Nashville, Tennessee, 37203, United States

Location

UT MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• 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.

  PMID: 36669146 RESULT

Related Links

• Related Info

MeSH Terms

Conditions

Lymphoma

Interventions

milademetan

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Results Point of Contact

• Title: Clinical Director
• Organization: Daiichi Sankyo, Inc.

CTRinfo@dsi.com

908-992-6400

Study Officials

• Global Clinical Leader

  Daiichi Sankyo

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 11, 2013
• First Posted: June 13, 2013
• Study Start: July 11, 2013
• Primary Completion: October 8, 2020
• Study Completion: December 3, 2020
• Last Updated: March 27, 2025
• Results First Posted: July 18, 2024

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Completed studies that has reached a global end or completion with all data set collected and analyzed, and for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents on completed clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.

Locations

US (5)