Palbociclib + INCMGA00012 for Liposarcoma

Recruiting at 6 trial locations

Overseen By William Tap, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: CDK4 inhibitors, Anti-PD-1/PD-L1

Disqualifiers: Uncontrolled illness, Autoimmune disease, 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: Unknown

Duration: 48 weeks

42 Participants Needed

Trial Summary

What is the purpose of this trial?

The researchers are doing this study to find out whether combining the study drugs palbociclib and INCMGA00012 is an effective and safe treatment for advanced liposarcoma. "Funding Source - FDA OOPD"

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 CYP3A enzymes. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Palbociclib and INCMGA00012 for treating liposarcoma?

Research suggests that combining CDK4 inhibitors like Palbociclib with other targeted therapies may be effective for liposarcoma, especially in cases with specific gene amplifications. This is based on findings that simultaneous inhibition of CDK4 and other pathways can suppress tumor growth in liposarcoma cell lines. ^{1 2 3 4 5}

What safety data exists for Palbociclib and INCMGA00012 (Retifanlimab) in humans?

Palbociclib has been used in early trials for liposarcoma, with some patients experiencing progression of their disease, but specific safety concerns were not highlighted. There is no safety data available for INCMGA00012 (Retifanlimab) in the provided research articles. ^{1 6 7 8 9}

What makes the drug combination of Palbociclib and INCMGA00012 unique for treating liposarcoma?

The combination of Palbociclib and INCMGA00012 is unique because it targets specific genetic amplifications common in liposarcoma, such as CDK4, which Palbociclib inhibits. This approach is novel as it combines a CDK4 inhibitor with another agent, potentially offering a new treatment option for a condition with limited effective therapies. ^{2 3 4 8 10}

Research Team

Sandra D'Angelo, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for adults with advanced liposarcoma that can't be removed by surgery or needs systemic therapy before an operation. Participants must have measurable disease, agree to use contraception, and have stable brain metastasis if present. They should not have had prior CDK4 inhibitor or anti-PD-1/PD-L1 treatment, uncontrolled illnesses, symptomatic heart failure, severe autoimmune disease in the past 2 years, certain infections like HIV or hepatitis B/C unless controlled.

Inclusion Criteria

I can swallow pills.

AST (SGOT) /ALT (SGPT) ≤ 3 x institutional ULN

Creatinine Clearance > 50 mL/min (calculated by Cockcroft-Gault method)

Exclusion Criteria

I am on replacement therapy for a condition like hypothyroidism, diabetes, or adrenal insufficiency.

I have not had severe heart failure in the last 6 months.

You are currently taking any other experimental drugs or treatments.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive palbociclib and INCMGA00012 in 28-day cycles. Palbociclib is taken daily for 21 days followed by 7 days off, and INCMGA00012 is administered every 28 days.

48 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Long-term Safety Follow-up

Safety will be assessed using CTCAE v 5.0 to define the adverse event profile of the treatment combination.

2 years

Treatment Details

Interventions

• INCMGA00012
• Palbociclib

Trial Overview The study is testing the combination of palbociclib and INCMGA00012 as a treatment for advanced liposarcoma. It aims to determine whether this drug duo is effective and safe for patients who meet specific health criteria.

Participant Groups

Group I: Palbociclib and INCMGA00012 Experimental Treatment 2 Interventions

Initial design (safety lead-in and expansion): One treatment cycle will consist of 28 days. Patients in both study phases will start palbociclib on Day 1 and INCMGA00012 on day 15 (+/- 7 days) of each cycle at the following dose schedule: INCMGA00012: 500 mg IV (flat dose) q28 days Palbociclib: 125 mg PO daily for 21 days, followed by 7 days off, q28 days Palbociclib will be taken on Day 1 of each cycle for 21 consecutive days followed by 7 days off (days 22-28 of each Cycle). INCMGA00012 will be administered on Day 15 of (+/- 7 days) each cycle and repeat every 28 days.(No longer using this) Amended design (Expansion only): One treatment cycle will consist of 28 days. Patients in both study phases will start palbociclib and INCMGA00012 on day 1 of each cycle: 500 mg IV (flat dose) of INCMGA00012 will be administered q28 days concurrently with palbociclib 125 mg PO daily for 21 days, followed by 7 days off, q28 days.

INCMGA00012 is already approved in United States, European Union for the following indications:

Approved in United States as Zynyz for:

• Metastatic or recurrent locally advanced Merkel cell carcinoma

Approved in European Union as Zynyz for:

• Metastatic or recurrent locally advanced Merkel cell carcinoma

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Findings from Research

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]

The study of RG7112, an MDM2 antagonist, in 20 patients with MDM2-amplified liposarcoma showed significant activation of the P53 pathway, with P53 and P21 levels increasing by 4.86 and 3.48 times, respectively, after 8 days of treatment.

While RG7112 demonstrated the ability to inhibit tumor cell proliferation, resulting in one partial response and 14 cases of stable disease, it also caused adverse effects in all patients, with common issues including nausea and thrombocytopenia.

NCBI (Pubmed)

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. Ray-Coquard, I., Blay, JY., Italiano, A., et al.[2022]

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]

References

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

FDA Approval Summary: Eribulin for Patients with Unresectable or Metastatic Liposarcoma Who Have Received a Prior Anthracycline-Containing Regimen. [2023]

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

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

3. 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]

4. 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]

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

Discovery of novel candidates for anti-liposarcoma therapies by medium-scale high-throughput drug screening. [2022]

6. China pubmed.ncbi.nlm.nih.gov

Recent translational research into targeted therapy for liposarcoma. [2020]

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

A Single-Arm Phase Ib/II Study of Lenvatinib plus Eribulin in Advanced Liposarcoma and Leiomyosarcoma. [2023]

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

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

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

Activity of Eribulin in Patients With Advanced Liposarcoma Demonstrated in a Subgroup Analysis From a Randomized Phase III Study of Eribulin Versus Dacarbazine. [2017]

10. England pubmed.ncbi.nlm.nih.gov

Overview of systemic therapy options in liposarcoma, with a focus on the activity of selinexor, a selective inhibitor of nuclear export in dedifferentiated liposarcoma. [2022]