SARC028: A Phase II Study of the Anti-PD1 Antibody Pembrolizumab (MK-3475) in Patients With Advanced Sarcomas

Study Overview
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Brief Summary
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The purpose of this study is to determine the efficacy of pembrolizumab in patients with advanced sarcomas.

Detailed Description
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This is a multi-institutional phase II study of pembrolizumab in patients with advanced sarcomas. This study will have two treatment groups, one group for patients with soft tissue sarcoma and one group for patients with bone sarcoma. Initial enrollment for this study included a total of 86 patients with soft tissue sarcoma and bone sarcomas. In the expansion portion, there will be an additional 30 patients with undifferentiated pleomorphic sarcoma (UPS) and 30 patients with dedifferentiated or other high grade liposarcoma (LPS) enrolled into the study.

Official Title
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SARC028: A Phase II Study of the Anti-PD1 Antibody Pembrolizumab (MK-3475) in Patients With Advanced Sarcomas

Conditions
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Soft Tissue Sarcoma, Bone Sarcoma

Intervention / Treatment
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* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years (Age ≥ 12 years for patients with bone sarcomas). Histologically confirmed diagnosis of unresectable, recurrent, and/or metastatic high grade soft-tissue or bone sarcoma of one of the following subtypes: soft tissue sarcomas (leiomyosarcoma, poorly differentiated/de-differentiated liposarcoma, high grade pleomorphic undifferentiated sarcoma/MFH and synovial sarcoma), and bone sarcomas (Ewing sarcoma, osteosarcoma, and chondrosarcoma [de-differentiated or mesenchymal]). ECOG Performance Status of 0 or 1. At least one site of measurable disease on CT/MRI scans as defined by RECIST 1.1. Baseline imaging must be performed within 30 days of dosing. At least one site of accessible disease for pre- and post-treatment core biopsies for at least 20 patients per arm on the expansion cohorts. Patients may have received 1-3 prior systemic therapies in the metastatic setting. Adequate organ function within 14 days of dosing Must be willing to provide and have available archival tissue for PD-L1 testing. Written, voluntary informed consent. Fertile men and women of childbearing potential must agree to use an effective method of birth control from providing signed consent and for 120 days after last study drug administration. Women of childbearing potential include pre-menopausal women and women within the first 2 years of the onset of menopause. Women of childbearing potential must have a negative pregnancy test ≤ 72 hours prior to Day 1 of study. Effective methods of birth control include: surgically sterile, barrier device (condom, diaphragm), contraceptive coil, intrauterine device (IUD), and abstinence. Life expectancy of >12 weeks. Patients with central nervous system disease are eligible for enrollment if they have received prior radiotherapy or surgery to sites of CNS metastatic disease and are without evidence of clinical progression for at least 4 weeks prior to screening, have no evidence of new or enlarging brain metastases, and are off steroids for at least 7 days before first dose of pembrolizumab. Exclusion Criteria: Prior systemic therapy targeting PD-1: PD-L1 axis. Patients who are curable by conventional multidisciplinary management. Patients with severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol. Patients who have received wide field radiotherapy ≤ 4 weeks or limited field radiation for palliation < 2 weeks prior to screening or who have not recovered adequately from side effects of such therapy. Patients who have active infections requiring therapy. Patients that are known to be positive for Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), active Hepatitis B (HBsAg reactive), or Hepatitis C (HCV RNA [qualitative] is detected); patients with negative Hepatitis C antibody testing may not need RNA testing. Patients that have a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the trial. Patients who received systemic anti-cancer treatment prior to the first dose of study drug within the following time frames: Patients with active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or resolved childhood asthma/atopy would be exception to this rule. Patients that require inhaled steroids or local steroid injections would not be excluded from the study. Patients with hypothyroidism not from autoimmune disease that is stable on hormone replacement will not be excluded from the study. Women who are pregnant or nursing/breastfeeding. Known hypersensitivity to pembrolizumab or another mAb. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. Patients with untreated central nervous system disease. Patients with controlled treated CNS lesions who have undergone surgery or stereotactic radiosurgery and stable for 4 weeks are eligible. Inability to comply with protocol required procedures. Patients with medical conditions that require chronic systemic corticosteroid therapy or require any other form of immunosuppressive medication. However, patients using physiologic replacement doses of hydrocortisone, or its equivalent, will be considered eligible for this study: up to 20 mg hydrocortisone (or 5 mg of prednisone) in the morning and 10 mg hydrocortisone (or 2.5 mg prednisone) in the evening. Patients with the risk factors for bowel obstruction or bowel perforation (examples include but not limited to a history of acute diverticulitis, intra-abdominal abscess, abdominal carcinomatosis). Patients who have received a live vaccine within 30 days prior to the first dose of trial treatment.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Soft tissue sarcoma<br>Patients with the following types of soft tissue sarcoma: leiomyosarcoma, poorly differentiated/de-differentiated liposarcoma, high grade pleomorphic undifferentiated sarcoma/MFH, MPNST and synovial sarcoma). Pembrolizumab will be administered at 200 mg intravenously every 3 weeks | Drug: Pembrolizumab<br> <br> * Other names: Mk-3475;|
| Experimental: Bone sarcoma<br>Patients with the following types of bone sarcoma: Ewing sarcoma, osteosarcoma, and chondrosarcoma [de-differentiated or mesenchymal]. Pembrolizumab will be administered at 200 mg intravenously every 3 weeks | Drug: Pembrolizumab<br> <br> * Other names: Mk-3475;|
| Experimental: Expansion<br>Patients with the following types of soft tissue sarcoma: poorly differentiated/de-differentiated liposarcoma, high grade pleomorphic undifferentiated sarcoma. Pembrolizumab was administered at 200 mg intravenously every 3 weeks | Drug: Pembrolizumab<br> <br> * Other names: Mk-3475;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | The Objective Response Rate (ORR) is the percentage of patient's tumor that shrinks or disappears after treatment. ORR will be evaluated according to RECIST (Response Evaluation Criteria In Solid Tumors) 1.1, whereby Complete Response is defined as the disappearance of all target lesions and Partial Response is defined as at least a 30% decrease in the sum of the diameters of target lesions in reference to the baseline diameters. Overall Response (OR) = CR + PR. | Assessments will be conducted at 8 weeks, up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events Related to Pembrolizumab Treatment in Patients With Advanced Sarcoma, by Patient | Related Adverse Event is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a investigational product and related to the investigational product. | Up to 5 years | 
| The Progression-free Survival (PFS) | The progression-free survival is the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse. | up to 5 yrs | 
| Response Rate by Immune-related Response Criteria (Ir-RC) | Immune related response criteria was developed to adequately assess tumor response to immunotherapy.The irRC are based on bidimensional measurements We aimed to assess response by bidimensional measurements in patients with advanced sarcoma. Immune-related Complete Response (irCR) is the complete disappearance of all index lesions. Immune-related Partial Response (irPR) is the decrease by 50% or greater (from Baseline) in the sum of the products of the two largest perpendicular diameters of all index and new measurable lesions | Assessment at 8 weeks, up to 5 years | 
| Overall Survival (OS) | The Overall Survival is the length of time from either the date of diagnosis or the start of treatment for a disease, such as cancer, that patients diagnosed with the disease and are still alive | up to 5 years |