Mirdametinib + Palbociclib for Liposarcoma

Recruiting at 6 trial locations

Overseen By William Tap, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: CYP3A inducers, UGT inhibitors

Disqualifiers: Uncontrolled infection, Heart failure, Glaucoma, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

The purpose of this study is to find out whether mirdametinib in combination with palbociclib is an effective and safe treatment for people with metastatic, recurrent, and unresectable liposarcoma. This study will test different doses of mirdametinib in combination with a fixed dose of palbociclib to find the best safe dose for further testing.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take medications that strongly affect certain liver enzymes (CYP3A or UGT). If you're on such medications, you might need to stop or adjust them before joining the trial.

What data supports the effectiveness of the drug combination Mirdametinib and Palbociclib for treating liposarcoma?

Palbociclib has been used in early trials for liposarcoma, showing limited effectiveness with a median progression-free survival of 18 weeks. Additionally, combining CDK4 inhibitors like Palbociclib with other inhibitors has shown potential in treating liposarcoma with specific gene amplifications. ^{1 2 3 4 5}

How is the drug combination of Mirdametinib and Palbociclib unique for treating liposarcoma?

The combination of Mirdametinib and Palbociclib is unique for treating liposarcoma because it targets specific genetic amplifications common in these tumors, such as CDK4, which Palbociclib inhibits, and potentially other pathways that Mirdametinib may affect. This approach is novel as it combines two drugs to address the genetic drivers of liposarcoma, offering a targeted treatment option where few effective therapies exist. ^{1 3 4 5 6}

Research Team

Evan Rosenbaum, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for individuals with liposarcoma, a type of soft tissue tumor that's metastatic, recurrent, or can't be removed by surgery. Participants should not have had prior treatments with similar drugs to those being tested and must be able to take oral medication.

Inclusion Criteria

I can swallow pills.

I have had any number of previous treatments.

My organs and bone marrow are working well.

Exclusion Criteria

Patients receiving any other investigational agents

I've had severe side effects from previous cancer treatments targeting specific proteins.

I have severe heart failure diagnosed within the last 6 months.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Dose escalation phase to determine the maximum tolerated dose of mirdametinib in combination with palbociclib

Up to 1 year

Phase II Treatment

Participants receive the recommended phase 2 dose (RP2D) of mirdametinib plus palbociclib

18 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Mirdametinib (Kinase Inhibitor)
• Palbociclib (CDK4/6 Inhibitor)

Trial Overview The study is testing the effectiveness and safety of combining two drugs: Mirdametinib and Palbociclib. Different doses of Mirdametinib will be used alongside a fixed dose of Palbociclib to determine the best safe dosage for future studies.

Participant Groups

Group I: Phase II Experimental Treatment 2 Interventions

During the phase II portion, 30 patients with advanced DDLPS will be enrolled. All patients in the phase II study will receive the RP2D of mirdametinib plus palbociclib.

Group II: Phase I Experimental Treatment 2 Interventions

Dose escalation phase

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

SpringWorks Therapeutics, Inc.

Industry Sponsor

Trials

14

Recruited

900+

Findings from Research

In a Phase II trial involving 29 patients with advanced well-differentiated/dedifferentiated liposarcoma, sitravatinib achieved a progression-free rate at 12 weeks of 41%, meeting the primary endpoint of the study.

While sitravatinib showed some disease control, it did not result in any confirmed responses, and the most common side effects included diarrhea, hypertension, and hoarseness, indicating a need for careful monitoring of adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Single-Arm Phase II Trial of Sitravatinib in Advanced Well-Differentiated/Dedifferentiated Liposarcoma. Ingham, M., Lee, S., Van Tine, BA., et al.[2023]

In a study of 61 patients with well-differentiated and dedifferentiated liposarcoma treated with palbociclib, the median progression-free survival was only 9.2 months for WDLPS and 2.6 months for DDLPS, indicating limited efficacy of the treatment.

Surgical outcomes showed that while some patients underwent successful resections after palbociclib treatment, there was no overall survival benefit, and the treatment did not significantly prolong tumor control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world use of palbociclib monotherapy in retroperitoneal liposarcomas at a large volume sarcoma center. Nassif, EF., Cope, B., Traweek, R., et al.[2023]

Erdafitinib, a pan-FGFR inhibitor, shows promise in treating dedifferentiated liposarcoma (DDLPS) by reducing cell viability and inducing apoptosis, particularly in tumors with high FGFR1 and/or FGFR4 expression, which correlates with poor prognosis.

Combining erdafitinib with the MDM2 antagonist RG7388 enhances its effectiveness, leading to improved tumor suppression in vitro and in vivo, and has shown disease stabilization in a patient with refractory DDLPS for 12 weeks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Therapeutic Insights in Dedifferentiated Liposarcoma: A Role for FGFR and MDM2 Dual Targeting. Dadone-Montaudié, B., Laroche-Clary, A., Mongis, A., et al.[2020]

References

1. United States pubmed.ncbi.nlm.nih.gov

A Single-Arm Phase II Trial of Sitravatinib in Advanced Well-Differentiated/Dedifferentiated Liposarcoma. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Real-world use of palbociclib monotherapy in retroperitoneal liposarcomas at a large volume sarcoma center. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Frequent amplification of receptor tyrosine kinase genes in welldifferentiated/ dedifferentiated liposarcoma. [2018]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Novel Therapeutic Insights in Dedifferentiated Liposarcoma: A Role for FGFR and MDM2 Dual Targeting. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Progression-Free Survival Among Patients With Well-Differentiated or Dedifferentiated Liposarcoma Treated With CDK4 Inhibitor Palbociclib: A Phase 2 Clinical Trial. [2022]