Ribociclib + Everolimus for Dedifferentiated Liposarcoma and Leiomyosarcoma

Recruiting at 1 trial location

Overseen By Margaret von mehren, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Fox Chase Cancer Center

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: Until disease progression, unacceptable toxicity, or withdrawal of consent

48 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a combination of two drugs, Ribociclib and Everolimus, in patients with advanced DDL and LMS who have not responded to previous treatments. Ribociclib blocks proteins that help cancer grow, while Everolimus stops cancer cells from multiplying. Everolimus is an oral mTOR inhibitor that is approved for various cancers, including renal cell carcinoma and breast cancer.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as strong inducers or inhibitors of CYP3A4/5, at least 7 days before starting the study drug. If you are on these medications, you will need to discuss with your doctor about stopping them before joining the trial.

What data supports the effectiveness of the drugs Ribociclib and Everolimus for treating dedifferentiated liposarcoma and leiomyosarcoma?

While there is no direct data on the combination of Ribociclib and Everolimus for these specific cancers, similar drugs like the CDK4 inhibitor abemaciclib have shown potential benefits in treating dedifferentiated liposarcoma by targeting specific tumor characteristics. This suggests that Ribociclib, which is also a CDK4 inhibitor, might offer some benefit in this context. ^{1 2 3 4 5}

What safety data exists for the use of Everolimus in humans?

Everolimus, used for various cancers, is generally well tolerated but can cause side effects like mouth sores, rash, infections, lung inflammation, and high blood sugar. In some cases, these side effects can be severe, leading to treatment discontinuation. ^{6 7 8 9 10}

How is the drug combination of Ribociclib and Everolimus unique for treating dedifferentiated liposarcoma and leiomyosarcoma?

The combination of Ribociclib and Everolimus is unique because it targets specific pathways involved in tumor growth, such as the CDK4 and mTOR pathways, which are often amplified in these sarcomas. This approach is different from traditional chemotherapy, which is less targeted and often has more side effects. ^{2 3 4 11 12}

Research Team

Margaret von Mehren, MD

Principal Investigator

Fox Chase Cancer Center

Eligibility Criteria

Adults with advanced dedifferentiated liposarcoma (DDL) or leiomyosarcoma (LMS) who've had at least one prior systemic therapy can join this trial. They should be in good physical condition, able to take oral medication, and have measurable disease progression after their last treatment. Women must not be pregnant or nursing, and all participants must agree to use effective contraception.

Inclusion Criteria

My cancer is a type of sarcoma that has spread or is not responding to treatment.

My blood tests show my organs and bone marrow are working well.

I am 18 years old or older.

Exclusion Criteria

I have a stomach or intestine problem that affects how I absorb medicine.

Patient has any other concurrent severe and/or uncontrolled medical condition

I do not have uncontrolled heart disease or abnormal heart rhythms.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Ribociclib orally at 300 mg/day for 21 days of each 28-day cycle and Everolimus 2.5 mg orally on a continuous 28-day cycle. Clinical and laboratory assessments are made on day 1, day 15 of cycle 1 and 2, and day 1 of each subsequent cycle.

Until disease progression, unacceptable toxicity, or withdrawal of consent

Day 1 and day 15 of cycle 1 and 2, and day 1 of each subsequent cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment. Tumor response is assessed by RECIST 1.1 at week 8, 16, 24, and every 12 weeks thereafter.

Through study completion

Long-term follow-up

Participants are followed until death or are lost to follow-up for analysis of secondary endpoints.

Treatment Details

Interventions

• Everolimus
• Ribociclib

Trial Overview The study is testing a combination of two drugs: Ribociclib taken orally for three weeks with a one-week break, and Everolimus taken continuously every day. The goal is to see how well these drugs work together against DDL and LMS by monitoring tumor response using scans at specific intervals.

Participant Groups

Group I: Leiomyosarcoma Arm Experimental Treatment 2 Interventions

Patients receive ribociclib orally at 300mg/day for 21 days of each 28 day cycle and everolimus 2.5mg orally on a continuous 28 day cycle.

Group II: Dedifferentiated Liposarcoma Arm Experimental Treatment 2 Interventions

Patients receive ribociclib orally at 300mg/day for 21 days of each 28 day cycle and everolimus 2.5mg orally on a continuous 28 day cycle.

Everolimus is already approved in United States, European Union for the following indications:

Approved in United States as Afinitor for:

• Advanced renal cell carcinoma
• Subependymal giant cell astrocytoma
• Progressive neuroendocrine tumors of pancreatic origin
• Advanced hormone receptor-positive, HER2-negative breast cancer
• Tuberous sclerosis complex-associated partial-onset seizures

Approved in European Union as Votubia for:

• Subependymal giant cell astrocytoma
• Renal angiomyolipoma
• Tuberous sclerosis complex-associated partial-onset seizures

Approved in United States as Zortress for:

• Prevention of organ rejection in kidney transplant patients

Who Is Running the Clinical Trial?

Fox Chase Cancer Center

Lead Sponsor

Trials

236

Recruited

39,300+

Findings from Research

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]

In a phase II trial involving 10 patients with advanced solid tumors and specific genetic alterations, everolimus did not show significant anti-tumor activity, as no complete or partial responses were observed, and the study did not progress to the second stage.

Despite the lack of efficacy, everolimus was well-tolerated, with no severe toxicities reported, indicating a safety profile that warrants further exploration with different treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prospective phase II trial of everolimus in PIK3CA amplification/mutation and/or PTEN loss patients with advanced solid tumors refractory to standard therapy. Kim, ST., Lee, J., Park, SH., et al.[2022]

Everolimus, an oral mTOR inhibitor, significantly improves progression-free survival in patients with clear cell renal cancer, increasing it from a median of 1.9 months to 4.9 months in a phase III trial with a hazard ratio of 0.33 (P < 0.001).

The treatment is generally well-tolerated, with mild to moderate side effects that can be managed, and it has been approved as a validated option for patients who have progressed on VEGFR inhibitors, with ongoing trials exploring its use in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Everolimus: the first approved product for patients with advanced renal cell cancer after sunitinib and/or sorafenib. Coppin, C.[2021]

A genomic analysis of 56 liposarcoma samples revealed that while there were few gene mutations, over half of the samples exhibited gene amplifications, particularly of MDM2, CDK4, and receptor tyrosine kinases (RTKs).

In laboratory tests, combining CDK4 and IGF1R inhibitors effectively suppressed the growth of a well-differentiated liposarcoma cell line with IGF1R amplification, suggesting that this combination therapy could be a promising treatment for patients with these tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Frequent amplification of receptor tyrosine kinase genes in welldifferentiated/ dedifferentiated liposarcoma. Asano, N., Yoshida, A., Mitani, S., et al.[2018]

References

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

A Single-Arm Phase Ib/II Study of Lenvatinib plus Eribulin in Advanced Liposarcoma and Leiomyosarcoma. [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

Dedifferentiated Liposarcoma: Systemic Therapy Options. [2021]

4. England pubmed.ncbi.nlm.nih.gov

A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of Regorafenib Versus Placebo in Advanced/Metastatic, Treatment-Refractory Liposarcoma: Results from the SARC024 Study. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Anti-Tumor Effect of Apatinib and Relevant Mechanisms in Liposarcoma. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Prospective phase II trial of everolimus in PIK3CA amplification/mutation and/or PTEN loss patients with advanced solid tumors refractory to standard therapy. [2022]

7. Germany pubmed.ncbi.nlm.nih.gov

Management of adverse events in patients with hormone receptor-positive breast cancer treated with everolimus: observations from a phase III clinical trial. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Management of adverse events associated with the use of everolimus in patients with advanced renal cell carcinoma. [2022]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Everolimus: the first approved product for patients with advanced renal cell cancer after sunitinib and/or sorafenib. [2021]

10. Uganda pubmed.ncbi.nlm.nih.gov

[Tolerablity of everolimus in clinical practice: a retrospective study]. [2020]

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

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

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

Myxoid liposarcoma and the mammalian target of rapamycin pathway. [2021]