Palbociclib and Pembrolizumab in Undifferentiated Pleomorphic Sarcoma (UPS)

Study Overview
=================
Brief Summary
-----------------
This is a single-arm open-label window of opportunity clinical study assessing the impact of pre- treatment with palbociclib

Detailed Description
-----------------
This is a single-arm open-label window of opportunity clinical study assessing the impact of pre- treatment with palbociclib. Patients with be given palbociclib for 2 weeks following a pre-treatment ultrasound guided biopsy used to establish an immunological baseline of the tumor microenvironment. After the conclusion of palbociclib therapy, a post-treatment biopsy will be performed to assess the impact of palbociclib on the tumor microenvironment; pembrolizumab will be started the same day as the second biopsy. After 2 doses of pembrolizumab, a third (optional) biopsy could be performed. At 8 weeks of therapy disease response will be assessed as per standard of care.

Official Title
-----------------
Phase Ib Trial Evaluating the Combination of CDK4 Inhibitor With Immunotherapy in Patients With Undifferentiated Pleomorphic Sarcoma (UPS)

Conditions
-----------------
Undifferentiated Pleomorphic Sarcoma

Intervention / Treatment
-----------------
* Drug: Palbociclib
* Drug: Pembrolizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: A potential subject must meet all the following inclusion criteria to be eligible to participate in the study. Male or female patients aged greater than or equal to 12 years old ECOG Performance Status of less than or equal to 2 Any patient with the diagnosis of locally advanced, unresectable or undifferentiated pleomorphic sarcoma (UPS) who have progressed on at least 1 prior line of therapy and for whom pembrolizumab is an appropriate next standard treatment. Patients with any number of prior lines of therapy including newly diagnosed locally advanced unresectable or metastatic disease. Patients with no known CNS disease, except for treated brain metastasis. Treated brain metastases are defined as having no evidence of progression or hemorrhage after treatment and no ongoing treatment for dexamethasone (as ascertained by clinical examination and brain imaging) during the screening period. Stable dose of anticonvulsants is allowed. Treatment for brain metastases may include whole brain radiotherapy, radiosurgery, or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will be excluded. Ability to understand and the willingness to sign a written informed consent or assent in case of patients less than 18 years old. Exclusion Criteria: A potential subject who meets any of the following exclusion criteria is ineligible to participate in the study. Lab values in the below ranges: Neutrophil count < 1000/mm3 Platelet count < 100,000/mm3 Hemoglobin < 9 g/dL Transfusion to meet eligibility allowed AST/SGOT and ALT/SGPT > 3.0x upper limit of normal (ULN) without disease involvement or > 5.0x ULN if the transaminase elevation is due to disease involvement Alkaline phosphatase > 5.0x ULN without known bony metastases Serum bilirubin > 1.5x ULN Serum creatinine > 1.5x ULN or 24-hour creatinine clearance < 30 mL/min per Cockroft- Gault equation Total serum calcium < lower limit of normal (LLN) or if calcium is below LLN the corrected calcium for serum albumin is greater than or equal to LLN Serum potassium < 3.0 Serum sodium < 130 Serum albumin < 2.5 g/dL History of myocardial infarction. unstable angina, stroke or transient ischemic attack within 6 months prior to Day 1 Prior checkpoint inhibitor or CDK4 inhibitor for advanced UPS. If immunotherapy or CDK4 inhibitor was used as part of neoadjuvant therapy, then 6 months should have elapsed from prior immunotherapy or CDK4i use History or drug induced pneumonitis (both pembrolizumab and Palbociclib can cause pneumonitis) Subjects requiring hemodialysis Patients with severe hepatic impairment (Childs-Pugh Class C). Other concurrent severe and/or uncontrolled medical conditions in the opinion of the investigator which will preclude participation Pregnancy (positive pregnancy test) or lactation If you are a woman who can become pregnant, or a man who is sexually active with a partner who can become pregnant you must use two forms of birth control while on the study and for up to 3 months after the last dose of study drug. Patients who have received chemotherapy or any investigational drug < 4 weeks prior to starting study or who have not recovered from side effects of prior therapy (2 weeks of washout) Concomitant use of any other anti-cancer therapy or radiation therapy of the target lesion. Palliative radiation therapy is permitted to non-target lesions. Patients with any significant history of non-compliance to medical regimens or with inability to grant a reliable informed consent

Ages Eligible for Study
-----------------
Minimum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a single-arm open-label window of opportunity clinical study assessing the impact of pre- treatment with palbociclib
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination of Palbociclib with Pembrolizumab<br>Palbociclib given for 2 weeks following a pre-treatment ultrasound guided biopsy used to establish an immunological baseline of the tumor microenvironment. After the conclusion of palbociclib therapy, a post-treatment biopsy will be performed to assess the impact of palbociclib on the tumor microenvironment; pembrolizumab will be started the same day as the second biopsy. After 2 doses of pembrolizumab, a third (optional) biopsy could be performed. | Drug: Palbociclib<br>* Palbociclib is a CDK4/6 inhibitor. Palbociclib, 125 mg, (pediatric dose 75mg/m2 up to 125mg) daily for 21 days out of every 28 days, PO (orally) starting 14 days prior to Pembrolizumab<br>Drug: Pembrolizumab<br>* Pembrolizumab is a PD-1 blocking antibody. Given 14 days following Palbociclib: Pembrolizumab, 200 mg, once every three weeks, intravenously (IV)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicities (DLTs) and adverse events (AEs) per CTCAE v5 | Confirm the safety of the combination of Palbociclib and Pembrolizumab in UPS as defined by the incidence of DLTs | The dose limiting toxicity period is 4 weeks after starting the first dose of pembrolizumab | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate per RECIST 1.1 criteria | To assess the response (per RECIST 1.1 criteria) of patients with advanced UPS with the combination of CDK4/6 inhibitor and anti-PD-1 immunotherapy | 8 weeks following treatment intiation |