Pembrolizumab and Radiation Therapy in Treating Patients With Intermediate or High-Grade Soft Tissue Sarcoma

Phase 1

Completed

Conditions: Soft Tissue Sarcoma
Recurrent Soft Tissue Sarcoma

Interventions: Biological: Pembrolizumab
Radiation: Radiation Therapy

Registration Number: NCT03338959

Lead Sponsor: Fred Hutchinson Cancer Center

Brief Summary: This phase I/II trial studies pembrolizumab and radiation therapy in treating patients with intermediate or high-grade soft tissue sarcoma. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving pembrolizumab and radiation therapy may work better in treating patients with soft tissue sarcoma.

Detailed Description: OUTLINE:

Patients receive pembrolizumab intravenously (IV) per institutional standard at the Seattle Cancer Care Alliance as an outpatient therapy. Cycles repeat every 3 weeks, up to a maximum of three doses, for 3 months in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy daily for 5-6 weeks beginning on Day 1 of Week 2.

After completion of study treatment, patients are followed up at 30 days after last dose, 90 days after last dose, 30 days after post-operative visit (wound care follow-up), and then every 12 weeks for up to 1 year, then every 6 months up to 5 years.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 27

Inclusion Criteria

Be willing and able to provide written informed consent for the trial
Be ≥18 years of age on day of signing informed consent documents
Have measurable disease based on RECIST 1.1
Have newly diagnosed disease or localized recurrent or oligometastatic lesions that are candidates for radiation
- NOTE: Subjects may not have any prior systemic therapy or radiation for this sarcoma. They may have received systemic therapy and/or radiation for a different cancer
- NOTE: Oligometastatic disease will be defined as 3 or fewer detectable lesions with plans to radiate all detectable disease with conventionally fractionated radiation prior to resection
Have an intermediate- or high-grade soft tissue sarcoma at the discretion of the reviewing Sarcoma pathologist
The tumor must be at least 3 cm in maximum dimension for intermediate-grade tumors, or 1.5 cm in maximum dimension for high-grade tumors
Have plans to undergo neo-adjuvant radiation and surgery with curative intent. A minimum of 45 Gy is necessary, planned to be administered over a minimum of 25 fractions
Be willing to provide tissue from a newly obtained core incisional or excisional biopsy of a tumor lesion. Archival tissue from a recent clinical or research biopsy (within 90 days prior to Week 1 treatment) may be used in place of a fresh tissue biopsy
Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale or > 70% on the Karnofsky scale. Evaluation of performance status is to be performed within 7 days prior to the date of enrollment
Absolute neutrophil count (ANC) >= 1,500/mcL (performed within 28 days of enrollment)
Platelets >= 100,000/mcL (performed within 28 days of enrollment)
Hemoglobin >= 9 g/dL or >= 5.6 mmol/L (performed within 28 days of enrollment)

* Criteria must be met without erythropoeiten dependency and without packed red blood cell (pRBC) transfusion within last two weeks
Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (performed within 28 days of enrollment)

* Creatinine clearance should be calculated per institutional standard
Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (performed within 28 days of enrollment)
Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN (performed within 28 days of enrollment)
Albumin >= 2.5 mg/dL (performed within 28 days of enrollment)
International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (performed within 28 days of enrollment)
Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (performed within 28 days of enrollment)
Female subjects of childbearing potential should have a negative serum pregnancy within 72 hours prior to receiving the first dose of study medication
All individuals of child-bearing potential must be willing to use an adequate method of contraception, from the first dose of the study medication through 120 days after the last dose of study medication

Exclusion Criteria

Has had prior radiation to affected area
Has one of the following sarcoma subtypes where neoadjuvant chemotherapy is established as practice at our institution: extra-skeletal Ewing's sarcoma, embryonal rhabdomyosarcoma, alveolar rhabdomyosarcoma

* NOTE: Pleomorphic rhabdomyosarcoma is allowed. Bone sarcomas including osteosarcoma, Ewing's sarcoma and chondrosarcoma are not allowed. Extra-skeletal Osteosarcoma is considered a soft tissue sarcoma and is allowed.
Has a diagnosis of immunodeficiency or has an active autoimmune disease that has required systemic treatment in the past 2 years except replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid)
Is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
Has a known history of active TB (Bacillus tuberculosis)
Hypersensitivity (>= grade 3) to pembrolizumab and/or any of its excipients
Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years

* NOTE: The time requirement does not apply to participants who underwent successful definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, or other in-situ cancers
Has current or a history of any distant metastatic disease (including brain)

*NOTE: An isolated or oligo-metastatic regional recurrence may be allowed if all other criteria are met, curative attempt is being pursued
Has known history of (non-infectious) pneumonitis that required steroids, or has current evidence of pneumonitis
Has an active infection requiring systemic therapy
Has known psychiatric or substance abuse disorders that would interfere with adherence to the requirements of the trial
Is pregnant (positive urine pregnancy test within 72 hours prior to enrollment) or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. If a urine pregnancy test is positive or cannot be confirmed negative, a serum pregnancy test will be required
Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-CTLA4 or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory 1-cell receptor (eg, CTLA-4, OX 40, CD137)
Has a known history of human immunodeficiency virus (HIV) infection
Has a known history of Hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or Hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) infection
Has received a live vaccine or live-attenuated vaccine within 30 days of planned start of study therapy. Administration of killed vaccines is allowed. Note: Any licensed coronavirus (COVID-19) vaccine (including for emergency use) is allowed in the study as long as they are messenger ribonucleic acid (mRNA) vaccines, adenoviral vaccines, or inactivated vaccines. These vaccines will be treated just as any other concomitant therapy. Investigational vaccines (i.e., those not licensed or approved for emergency use) are not allowed.
Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
Has a history or current evidence of any condition, therapy, or laboratory abnormality or other circumstance that might confound the results of the study, interfere with the subject's participation for the full duration of the study, such that it is not in the best interest of the subject to participate, in the opinion of the treating investigator or has not adequately recovered from any major surgery or has ongoing surgical complications
Has had an allogenic tissue/solid organ transplant

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (pembrolizumab, radiation therapy)	Radiation Therapy	Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 3 weeks for 3 months in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy daily for 5-6 weeks.
Treatment (pembrolizumab, radiation therapy)	Pembrolizumab	Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 3 weeks for 3 months in the absence of disease progression or unacceptable toxicity. Patients also undergo radiation therapy daily for 5-6 weeks.

Primary Outcome Measures

Name	Time	Method
Rate of Complete Tumor Necrosis	From baseline through wound care follow-up visit (up to 8 months)	Necrosis greater than or equal to 90% at pathologic assessment at time of surgery

Secondary Outcome Measures

Name	Time	Method
Complete Response Rate	From baseline through wound care follow-up visit (up to 8 months)	Rate of disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10mm as defined per RECIST v1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters; Overall Response (OR) = CR + PR.
Incidence of Adverse Events	Through the wound care follow-up visit (up to 8 months)	Treatment-related adverse events (AEs) experienced by participants evaluated by Common Terminology Criteria for Adverse Events (CTCAE) 5.0 and determined to be possibly related, probably related, or definitely related to either pembrolizumab therapy, radiation therapy, or both.
Partial Response Rate	From baseline through wound care follow-up visit (up to 8 months)	Proportion of patients who achieved a partial response based on modified Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters; Overall Response (OR) = CR + PR.
Overall Response Rate	From baseline through wound care follow-up visit (up to 8 months)	Rate of participants who experienced a Complete Response (CR) + Partial Reponse (PR) as defined per RECIST v1.1 criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters; Overall Response (OR) = CR + PR.