Neoplasms

All Conditions

Rare Diseases

Sarcoma

Liposarcoma

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Neoplasms, Adipose Tissue

Soft Tissue Sarcoma

All Drugs and Chemicals

Antineoplastic Agents

Antibodies

Cemiplimab

Immunoglobulins

Immunoglobulin G

Palbociclib

Immunoglobulins, Intravenous

Immunologic Factors

Protein Kinase Inhibitors

Enzyme Inhibitors

Antineoplastic Agents, Immunological

Patients receive palbociclib PO on study. Patients will be allowed to cross over to Arm II following documentation of disease progression. Patients undergo MRI or CT scans throughout the trial. Patients may also undergo blood sample collection on study.

Patients receive palbociclib PO and cemiplimab IV on study. Patients undergo MRI or a CT scan throughout the trial. Patients may also undergo blood sample collection on study.

Magnetic Resonance Imaging

Computed Tomography

Biospecimen collection

Questionnaire Administration

Matthew Ingham, MD

Beth Smith

Site Public Contact

Vanessa Eulo

Shahzad Siddique

Steven I. Robinson

Tatjana Kolevska

Sosipatros A. Boikos

Tanmay Sahai

Bryan A. Faller

Pedro Viveiros

Bruce E. Brockstein

This phase II trial compares the effect of treatment with palbociclib alone to treatment with palbociclib plus cemiplimab for treating patients with dedifferentiated liposarcoma that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Palbociclib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Cemiplimab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. The combination of these two drugs may be more effective in shrinking or stabilizing advanced dedifferentiated liposarcoma compared to palbociclib alone.

PRIMARY OBJECTIVES:

I. To perform a safety lead-in among 6 patients to confirm that the combination of palbociclib and cemiplimab is safe and tolerable.

II. To evaluate whether palbociclib in combination with cemiplimab (Arm 2) demonstrates a superior progression-free survival (PFS) compared to palbociclib monotherapy (Arm 1) for patients with advanced dedifferentiated liposarcoma (DDLPS).

SECONDARY OBJECTIVES:

I. To evaluate the toxicity profile in and across each treatment arm as determined by both Common Terminology Criteria for Adverse Events (CTCAE) and Patient Reported Outcomes (PRO)-CTCAE criteria.

II. To evaluate and compare the objective response rate (ORR) and duration of response (DOR) in and across each treatment arm.

III. To evaluate and compare the overall survival (OS) in and across each treatment arm.

IV. To evaluate and compare progression-free rate at 8 weeks (PFR8) in and across each treatment arm.

EXPLORATORY OBJECTIVES:

I. To collect genomic sequencing data previously collected as standard of care, including data on CDK4 copy number (as determined by fluorescence in situ hybridization \[FISH\] or other molecular testing).

II. To conduct multiplex immunohistochemistry using archival tumor tissue (where available) to define densities of infiltrating immune cell subsets and tumor and immune cell major histocompatibility complex (MHC) and PD-L1 expression.

III. To perform an exploratory analysis to evaluate for any relationship between CDK4 copy number and (a) the tumor immune microenvironment as defined by multiplex immunohistochemistry and (b) clinical outcomes from study treatment.

IV. To explore efficacy and toxicity endpoints, including PFS and ORR, for patients who progress on palbociclib monotherapy and crossover to the palbociclib plus cemiplimab combination.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive palbociclib orally (PO) on study. Patients will be allowed to cross over to Arm II following documentation of disease progression. Patients undergo magnetic resonance imaging (MRI) or computed tomography (CT) scans throughout the trial. Patients may also undergo blood sample collection on study.

ARM II: Patients receive palbociclib PO and cemiplimab intravenously (IV) on study. Patients undergo MRI or CT scans throughout the trial. Patients may also undergo blood sample collection on study.

Testing the Addition of Cemiplimab to Palbociclib for the Treatment of Advanced Dedifferentiated Liposarcoma

Official Title A Randomized Phase 2 Trial With a Safety Lead-In to Evaluate Palbociclib Versus Palbociclib and Cemiplimab for the Treatment of Advanced Dedifferentiated Liposarcoma

Explore data on CDK4 copy number (by fluorescence in situ hybridization \[FISH\] or other molecular testing) through plots and summary statistics.

Conduct multiplex immunohistochemistry using archival tumor tissue (where available) to summarize densities of infiltrating immune cell subsets and tumor and immune cell MHC and PD-L1 expression.

Explore the relationship between CDK4 copy number and (a) the tumor immune microenvironment as defined by multiplex immunohistochemistry and (b) clinical outcomes from study treatment Clinical endpoints include PFS, objective response rate, OS, PFR8, and DoR. Cox regression will be used on time-to-event outcomes and T-test on binary outcomes

Explore the efficacy and toxicity endpoints for patients who progress on palbociclib monotherapy and crossover to the palbociclib plus cemiplimab combination A sensitivity analysis will be conducted to see how crossover effects overall survival. Rate and severity of adverse events will be used to assess differences between crossover and non-crossover patients.

Efficacy analyses will be based on intention to treat principles. PFS will be compared between the two treatment arms using Kaplan-Meier methods. The hazard ratio, median PFS, and estimated PFS rates at 12, 24, 36, and 48 months will be estimated along with corresponding 95% confidence intervals. A log-rank test will be used to compare the PFS distributions between the two treatment arms in this cohort. Cox proportional hazards models will also be used to assess the impact of treatment arm on PFS when stratifying on the stratification factors.

Patients will be evaluated for adverse events using the National Cancer Institute Common Toxicity Criteria for Adverse Events version 5.0. Summary statistics (e.g., mean, median, standard deviation) and frequency tables will be used to describe the distributions of adverse events. Rates of adverse events occurring in the treatment arm will be compared to the control arm with chi-squared tests (or suitable alternative) used for comparisons where applicable. Tolerability will also be evaluated, summarizing rates of dose delays or modifications, reasons patients end treatment, and time to end of active treatment.

Defined for all evaluable patients who have achieved an objective response as the date at which the patient's earliest best objective status is first noted to be either a complete response or partial response to the earliest date progression is documented, or death if no prior evidence of disease progression. The distribution of DoR will be estimated using the method of Kaplan-Meier.

Defined as the time from randomization to death due to any cause. Patients who are alive will be censored at last follow-up for OS. The distribution of survival time will be estimated using the method of Kaplan-Meier. OS will be compared between treatment arms using the log-rank test. OS medians, survival rates and hazard ratio will be estimated along with 95% confidence intervals.

Defined as the proportion of evaluable patients who are alive and without evidence of disease progression 8 weeks after initiation of study therapy. The final PFR8 point estimate and corresponding 95% confidence interval calculated using Clopper-Pearson method.

National Cancer Institute (NCI)

Alliance for Clinical Trials in Oncology

Digestive System Diseases

Skin and Connective Tissue Diseases

Osteosarcoma

Gastrointestinal Stromal Tumors

Histiocytoma, Malignant Fibrous

Histiocytoma

Neoplasms, Connective Tissue

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Neoplasms, Bone Tissue

Neoplasms, Fibrous Tissue

Undifferentiated Pleomorphic Sarcoma

Nivolumab

Antibodies, Monoclonal

Ipilimumab

Immune Checkpoint Inhibitors

Patients receive nivolumab IV over 30 minutes once every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress after 10 weeks on single agent nivolumab may elect to cross over to Arm II.

Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 90 minutes once every 3 weeks for 12 weeks. Patients then receive nivolumab IV over 30 minutes every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress by imaging during the first 12 weeks of therapy may continue treatment, at the discretion of the patient and treating investigator.

Laboratory Biomarker Analysis

Quality-of-Life Assessment

Sandra P D'Angelo

This randomized phase II trial studies how well nivolumab with or without ipilimumab works in treating patients with sarcoma that has spread from the primary site to other parts of the body (metastatic) or cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether nivolumab works better with or without ipilimumab in treating patients with metastatic or unresectable sarcoma.

PRIMARY OBJECTIVE:

I. To evaluate the confirmed response rate of single agent nivolumab and dual agent nivolumab plus ipilimumab in patients with locally advanced/unresectable or metastatic soft tissue sarcoma.

SECONDARY OBJECTIVES:

I. To evaluate adverse event rates (National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version \[v\]4.0) within each treatment arm.

II. To evaluate duration of response, clinical benefit rate, time to progression, progression-free survival, and overall survival within each treatment arm.

CORRELATIVE SCIENCE OBJECTIVES:

I. To potentially detect an early signal of confirmed response rate within a histologically defined patient cohort.

II. To assess the potential association between programmed cell death 1 ligand 1 (PD-L1) expression (by immunohistochemistry \[IHC\]) and clinical outcome, within each treatment.

III. To evaluate associations between selected biomarker measured in serial peripheral blood and with clinical efficacy, within each treatment.

IV. To evaluate the association between selected biomarker measured in tumor tissue with clinical efficacy, within each treatment.

V. To evaluate the association between baseline tumor mutational burden and neoantigen production with clinical efficacy within each treatment.

EXPLORATORY PHASE II OBJECTIVES (CROSSOVER TREATMENT):

I. To evaluate secondary endpoints within patients crossing over to dual agent nivolumab plus ipilimumab after experiencing progressive disease while receiving single agent nivolumab.

II. To evaluate correlative science objectives endpoints within patients crossing over to dual agent nivolumab plus ipilimumab after experiencing progressive disease while receiving single agent nivolumab.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive nivolumab intravenously (IV) over 30 minutes once every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress after 10 weeks on single agent nivolumab may elect to cross over to Arm II.

ARM II: Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 90 minutes once every 3 weeks for 12 weeks. Patients then receive nivolumab IV over 30 minutes every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress by imaging during the first 12 weeks of therapy may continue treatment, at the discretion of the patient and treating investigator.

After completion of study treatment, patients are followed up at 4 weeks and then every 6 months 3 years.

Nivolumab With or Without Ipilimumab in Treating Patients With Metastatic Sarcoma That Cannot Be Removed by Surgery

Randomized Phase II Study of Nivolumab With or Without Ipilimumab in Patients With Metastatic or Unresectable Sarcoma

Categorical data analysis and logistic regression will be used to evaluate the associations between PD-L1 expression (by IHC) and clinical outcome (e.g., response, clinical benefit, progression-free survival, and survival). Kaplan-Meier methodology and Cox proportional hazards models will be used to evaluate time to event endpoints.

Summary statistics will be used to for describing changes across time. The time course of biomarker outcomes will be investigated graphically, by summary plots or individual patient plots. If there is suggestion of meaningful trend, methods such as linear mixed models may be used to characterize the pattern of change over time. Kaplan-Meier methodology and Cox proportional hazards models will be used to evaluate time to event endpoints.

Categorical data analysis and logistic regression will be used to correlated biomarkers with and clinical outcome (e.g., response, clinical benefit, time to progression, progression free survival, and survival) within each study component. Kaplan-Meier methodology and Cox proportional hazards models will be used to evaluate time to event endpoints.

Confirmed response will be evaluated in patients who crossover from single agent nivolumab to dual agent treatment following progression.

Evaluated using Kaplan-Meier methodology.

The number of participants who achieved a confirmed response is defined as the number of patients having a best objective tumor status of complete response (CR) or partial response (PR) lasting at least 4 weeks as determined using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. (CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites).

The number of participants who experienced at least one grade 3 or higher adverse event (AE) regardless of attribution. AEs are graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (version 5.0 beginning April 1, 2018).

Duration of response is defined for all evaluable patients who have achieved a confirmed response as the date at which the patient's objective status is first noted to be a CR or PR to the earliest date progression (PD) is documented. The distribution of duration of response will be estimated using the method of Kaplan-Meier. (CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites, PD: Any new lesion or increase by \>= 50% of previously involved sites from nadir).

The 6-month clinical benefit rate is defined as the percentage of participants with a response or stable disease (CR, PR, or SD) at 6 months. (CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites, PD: Any new lesion or increase by \>= 50% of previously involved sites from nadir, SD: Not CR/PR or PD).

Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression (PD) is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator. (PD: Any new lesion or increase by \>= 50% of previously involved sites from nadir).

Overall survival time is defined as the time from randomization to death due to any cause. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.

Serious AEs and Other (Not Including Serious) AEs summary tables summarizes AEs assessed for participants who started treatment and were evaluable for AEs. All-cause mortality is assessed for all enrolled participants. Adverse events are described and graded using the terminology and grading categories defined in the NCI's Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. However, CTCAE v5.0 is used for serious AE reporting through CTEP-AERS as of April 1, 2018.

Patients receive 3mg/kg nivolumab IV over 30 minutes once every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity.

Initial Single

Patients receive 3mg/kg nivolumab IV over 30 minutes and 1mg/kg ipilimumab IV over 90 minutes once every 3 weeks for 12 weeks. Patients then receive 3mg/kg nivolumab IV over 30 minutes every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity.

Initial Dual

Dedifferentiated liposarcoma (LPS) Cohort Patients receive 3mg/kg nivolumab IV over 30 minutes once every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity.

LPS Single

Dedifferentiated liposarcoma (LPS) Cohort Patients receive 3mg/kg nivolumab IV over 30 minutes and 1mg/kg ipilimumab IV over 90 minutes once every 3 weeks for 12 weeks. Patients then receive 3mg/kg nivolumab IV over 30 minutes every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress by imaging during the first 12 weeks of therapy may continue treatment, at the discretion of the patient and treating investigator.

LPS Dual

Undifferentiated Pleomorphic Sarcoma \& Malignant Fibrous Histiocytoma (UPS/MFH) Cohort Patients receive 3mg/kg nivolumab IV over 30 minutes once every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity.

UPS/MFH Single

Undifferentiated Pleomorphic Sarcoma \& Malignant Fibrous Histiocytoma (UPS/MFH) Cohort Patients receive 3mg/kg nivolumab IV over 30 minutes and 1mg/kg ipilimumab IV over 90 minutes once every 3 weeks for 12 weeks. Patients then receive 3mg/kg nivolumab IV over 30 minutes every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress by imaging during the first 12 weeks of therapy may continue treatment, at the discretion of the patient and treating investigator.

UPS/MFH Dual

Gastrointestinal stromal tumor (GIST) Cohort Patients receive 3mg/kg nivolumab IV over 30 minutes once every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity.

GIST Single

Gastrointestinal stromal tumor (GIST) Cohort Patients receive 3mg/kg nivolumab IV over 30 minutes and 1mg/kg ipilimumab IV over 90 minutes once every 3 weeks for 12 weeks. Patients then receive 3mg/kg nivolumab IV over 30 minutes every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress by imaging during the first 12 weeks of therapy may continue treatment, at the discretion of the patient and treating investigator.

GIST Dual

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Eastern Cooperative Oncology Group PS Scale: 0)Fully active, able to carry on all pre-disease performance without restriction; 1)Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2)Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours; 3)Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; 4)Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair.

ECOG Performance Status

Randomized patients are included in this analysis.

Sandra P. D'Angelo, M.D.

Participants who completed the study and were evaluable for the primary endpoint are included in this analysis.

Number of Participants Who Achieved a Confirmed Response

Grade 3 Event

Grade 4 Event

Grade 5 Event

Patients receive 3mg/kg nivolumab IV over 30 minutes once every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress on single agent nivolumab may elect to cross over to Initial Cohort - Arm II.

Randomized patients who received treatment (i.e. exclude cancel patients).

Number of Participants Who Experienced at Least One Grade 3 or Higher Adverse Event Regardless of Attribution

Participants who achieved a confirmed response are included in this analysis.

Duration of Response

Randomized Initial Cohort participants who received treatment (i.e. exclude cancel patients) Only.

6-Month Clinical Benefit Rate [Initial Cohort]

Randomized Expansion LPS and UPS/MFH Cohorts Participants who received treatment Only

6-Month Clinical Benefit Rate [Expansion LPS and UPS/MFH Cohorts Only]

Randomized Expansion GIST Cohort Participants who received treatment Only.

6-Month Clinical Benefit Rate [Expansion GIST Cohort Only]

Progression-free Survival (PFS)

Overall Survival (OS)

PD-L1 Expression Assessed Using Immunohistochemistry (IHC)

Change in Selected Biomarkers Measured in Serial Peripheral Blood

Selected Biomarkers Measured in Tumor Tissue

Confirmed Response in Patients Who Crossover From Single Agent Nivolumab to Dual Agent Treatment Following Progression

Duration of Response in Patients Who Crossover From Single Agent Nivolumab to Dual Agent Treatment Following Progression

PFS in Patients Who Crossover From Single Agent Nivolumab to Dual Agent Treatment Following Progression

OS in Patients Who Crossover From Single Agent Nivolumab to Dual Agent Treatment Following Progression

Initial Cohort - Arm I (Nivolumab)

Initial Cohort - Arm II (Nivolumab, Ipilimumab)

Dedifferentiated liposarcoma (LPS) Cohort Patients receive 3mg/kg nivolumab IV over 30 minutes once every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress after 10 weeks on single agent nivolumab may elect to cross over to LPS Cohort - Arm II.

Expansion LPS Cohort - Arm I (Nivolumab)

Expansion LPS Cohort - Arm II (Nivolumab, Ipilimumab)

Undifferentiated Pleomorphic Sarcoma \& Malignant Fibrous Histiocytoma (UPS/MFH) Cohort Patients receive 3mg/kg nivolumab IV over 30 minutes once every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress after 10 weeks on single agent nivolumab may elect to cross over to UPS/MFH Cohort - Arm II.

Expansion UPS/MFH Cohort - Arm I (Nivolumab)

Expansion UPS/MFH Cohort - Arm II (Nivolumab, Ipilimumab)

Gastrointestinal stromal tumor (GIST) Cohort Patients receive 3mg/kg nivolumab IV over 30 minutes once every 2 weeks. Cycles repeat every 42 days for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients who progress after 10 weeks on single agent nivolumab may elect to cross over to GIST Cohort - Arm II.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Testing the Addition of Cemiplimab to Palbociclib for the Treatment of Advanced Dedifferentiated Liposarcoma	NCT05694871	Advanced Dediff... Locally Advance... Metastatic Dedi... Stage III Soft ... Stage IV Soft T... Unresectable De...	Palbociclib Cemiplimab Magnetic Resona... Computed Tomogr... Biospecimen col... Questionnaire A...	18 Years -	Alliance for Clinical Trials in Oncology
Nivolumab With or Without Ipilimumab in Treating Patients With Metastatic Sarcoma That Cannot Be Removed by Surgery	NCT02500797	Locally Advance... Locally Advance... Locally Advance... Locally Advance... Metastatic Bone... Metastatic Lipo... Metastatic Soft... Metastatic Undi... Metastatic Unre... Pleomorphic Lip... Stage III Bone ... Stage III Soft ... Stage IV Bone S... Stage IV Soft T... Stage IVA Bone ... Stage IVB Bone ... Unresectable Bo... Unresectable De... Unresectable Li... Unresectable Ma... Unresectable So...	Ipilimumab Laboratory Biom... Nivolumab Quality-of-Life...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for locally advanced dedifferentiated liposarcoma