Ribociclib + Everolimus for Dedifferentiated Liposarcoma and Leiomyosarcoma

Not currently recruiting at 1 trial location

Overseen By Margaret von mehren, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Fox Chase Cancer Center

Must be taking: Statins

Must not be taking: CYP3A4/5 inhibitors, Corticosteroids

Disqualifiers: Concurrent malignancy, CNS involvement, others

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine how effectively a combination of Ribociclib and Everolimus can combat certain advanced cancers: dedifferentiated liposarcoma and leiomyosarcoma. Participants will be divided into two groups based on their specific cancer type to assess the treatment's effectiveness for each. The trial targets individuals who have these cancers and have previously tried at least one other systemic treatment but continue to experience disease progression. Those with advanced liposarcoma or leiomyosarcoma whose cancer has grown after treatment might find this trial suitable. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group, providing an opportunity to explore new treatment options.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using ribociclib and everolimus together may help treat certain cancers. In some studies, this combination prevented cancer from worsening for at least 16 weeks in some patients, indicating that the treatment might be effective.

However, like many treatments, side effects can occur. Some patients in these studies experienced changes in their health, though the specifics of these changes aren't always clear. These treatments have undergone prior testing, and their inclusion in this trial indicates they are considered safe enough for further evaluation.

For those who have undergone other treatments and are considering this one, discussing it with a doctor is crucial. A doctor can help explain the potential benefits and risks. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using ribociclib and everolimus for treating dedifferentiated liposarcoma and leiomyosarcoma because of their unique mechanisms of action. Unlike traditional chemotherapy, which targets rapidly dividing cells non-selectively, ribociclib is a CDK4/6 inhibitor that specifically interferes with cancer cell division. Everolimus, on the other hand, is an mTOR inhibitor that disrupts cancer cell growth and proliferation pathways. This combo targets the cancer cells more precisely than standard treatments, potentially leading to better outcomes with fewer side effects.

What evidence suggests that this trial's treatments could be effective for dedifferentiated liposarcoma and leiomyosarcoma?

This trial will evaluate the combination of ribociclib and everolimus for treating dedifferentiated liposarcoma (DDL) and leiomyosarcoma (LMS). Research has shown that using ribociclib and everolimus together may help treat DDL, with studies indicating that patients maintained stable disease for 16 weeks or more, a key goal of the research. For LMS, early results suggest this combination might also be beneficial. This treatment targets the growth of cancer cells, potentially slowing or stopping the disease. This combination therapy could offer new hope for patients with these conditions. ^{1 3 4 6 7}

Who Is on the Research Team?

Margaret von Mehren, MD

Principal Investigator

Fox Chase Cancer Center

Are You a Good Fit for This Trial?

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.

Measurable disease per RECIST 1.1

Exclusion Criteria

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

Treatment with an investigational agent within specified timeframes

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

Timeline for a Trial Participant

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.

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.11515

Outcomes in the dedifferentiated liposarcoma cohort of ... The combination of ribociclib and everolimus demonstrates activity in DDL with prolonged stable disease (>16 weeks) meeting the primary protocol endpoint.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37967116/

SAR-096: Phase II Clinical Trial of Ribociclib in Combination ... The combination of ribociclib and everolimus demonstrates activity in DDL with prolonged stable disease (≥16 weeks) meeting the primary endpoint.

3. aacrjournals.org aacrjournals.org/clincancerres/article/30/2/315/733184/SAR-096-Phase-II-Clinical-Trial-of-Ribociclib-in

SAR-096: Phase II Clinical Trial of Ribociclib in Combination ... This was a multicenter study that tested the combination of ribociclib and everolimus in patients with dedifferentiated liposarcoma (DDL) and leiomyosarcoma ( ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03114527?term=AREA%5BConditionSearch%5D(%22Dedifferentiated%20Liposarcoma%22)%20AND%20AREA%5BInterventionSearch%5D(%22mtor%20inhibitors%22)&rank=1

Study Details | Phase II Trial of Ribociclib and Everolimus in ... An unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain amount of ...

5. onclive.com onclive.com/view/ribociclib-everolimus-elicits-responses-in-dedifferentiated-liposarcoma

Ribociclib/Everolimus Elicits Responses in Dedifferentiated ... The combination of ribociclib (Kisqali) and everolimus (Afinitor) elicits responses in patients with advanced dedifferentiated liposarcoma (DDLPS) and offers a ...

6. aacrjournals.org aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-23-2469/730127/am/SAR-096-Phase-II-clinical-trial-of-ribociclib-in

SAR-096: Phase II clinical trial of ribociclib in combination with ... The primary endpoint was progression free rate (PFR) at 16 weeks. Secondary endpoints included progression free (PFS) and overall survival, safety and biomarker ...

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.11544

SAR-096: A phase II trial of ribociclib in combination with ... Outcomes in the dedifferentiated liposarcoma cohort of SAR-096, a phase II trial of ribociclib in combination with everolimus in advanced ...