Retifanlimab with or without Gemcitabine and Docetaxel in Patients with Advanced, Unresectable or Metastatic Soft Tissue Sarcoma

Inclusion Criteria

• PRE-SCREENING: All patients with unresectable or metastatic sarcoma will be eligible to pre-screen for Arm 2 of this study
• ARM 1: Diagnosis of metastatic or locally advanced and unresectable high-grade soft tissue sarcoma. Unresectable is defined as: * Primary tumor cannot be safely removed surgically, or * Primary tumor would benefit from systemic therapy prior to a surgical approach
• ARM 1: Must consent to mandatory tumor biopsy (if deemed safe and feasible) for research studies at screening, if archival tissue is not available, and at cycle (C)1 day (D)15, C3D15
• ARM 1: No prior systemic therapy * Adjuvant or neoadjuvant therapies received ≥ 1 year prior to enrollment are permitted
• ARM 2: Diagnosis of metastatic or locally advanced and unresectable sarcoma with an immune-enriched/non-fibrotic microenvironment as determined by BostonGene’s Tumor Portrait^TM test. Unresectable is defined as: * Primary tumor cannot be safely removed surgically, or * Primary tumor would benefit from systemic therapy prior to a surgical approach
• ARM 2: Must consent to mandatory tumor biopsy for research at baseline and after cycle 1
• ARM 2: All patients must have either received ≥ 1 line of prior systemic therapy or refused standard of care chemotherapy * Patients may not have received more than 3 prior lines of systemic therapy * Patients who are treated with doxorubicin followed by liposomal doxorubicin (or vice versa) will be considered to have had only 1 prior line * Patients who received neoadjuvant or adjuvant chemotherapy within one year are considered to have received prior systemic therapy * Patients who refuse standard of care chemotherapy will be eligible
• Be willing and able to provide written informed consent
• Age >= 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1
• Presence of measurable disease per RECIST v1.1 * Target lesions must not be chosen from a previously irradiated field unless there has been radiographically and/or pathologically documented tumor progression in that lesion prior to enrollment.
• Negative serum pregnancy test in women of childbearing potential
• Patients with chronic hepatitis B virus (HBV) (hepatitis B surface antigen [HBsAg]-positive with undetectable or low HBV deoxyribonucleic acid [DNA] and normal alanine aminotransferase [ALT], or HBsAg-negative with anti-hepatitis B core [HBc]-positive serology) and hepatitis C virus (HCV) (completed curative antiviral treatment with HCV viral load below the limit of quantification) may be eligible * Patients with HBV should be treated with suppressive antiviral therapy prior to enrollment * Patients with HCV must have completed curative therapy and have negative HCV viral load
• Absolute neutrophil count (ANC) >= 1,500 /mcL
• Platelets >= 75,000 / mcL
• Hemoglobin >= 9 g/dL or >= 5.6 mmol/L
• Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance >= 60 mL/min for patient with creatinine levels > 1.5 X institutional ULN (GFR can also be used in place of creatinine or creatinine clearance [CrCl])
• Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for patients with total bilirubin levels > 1.5 ULN except patients with Gilbert’s disease (=< 3 x ULN)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and ALT (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for patients with liver metastases

Exclusion Criteria

• Unstable or deteriorating cardiovascular disease within the previous 6 months, including: * Unstable angina or myocardial infarction * Cerebrovascular accident (CVA)/stroke * New York Heart Association (NYHA) class III or IV congestive heart failure * Uncontrolled clinically significant arrhythmias
• Current use of immunosuppressive medication, EXCEPT for the following: * Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection) * Systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone or equivalent * Steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication)
• Evidence of clinically significant immunosuppression such as the following: * Primary immunodeficiency state such as severe combined immunodeficiency disease * Concurrent opportunistic infection * Receiving systemic immunosuppressive therapy (> 2 weeks) including oral steroid doses > 10 mg/day of prednisone or equivalent within 2 months prior to enrollment
• History or evidence of symptomatic autoimmune disease in past 2 years prior to enrollment * Replacement therapy (e.g., thyroxine for hypothyroidism, insulin for diabetes or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment for autoimmune disease
• Uncontrolled human immunodeficiency virus (HIV) infection, as defined by one or more of the following: * Patients with CD4+ T-cell (CD4+) counts < 350 cells/uL * Patients with a history of an opportunistic infection secondary to acquired immunodeficiency syndrome (AIDS) * Patients on anti-microbials with drug-drug interactions with the study drugs on this protocol, who cannot be switched to alternative anti-microbials * Patients on antiretroviral therapy < 4 weeks * Patients with HIV viral load > 400 copies/mL
• Active hepatitis B or hepatitis C
• Patients who have received a live vaccine within 30 days of the start date of the planned study therapy (with the exception of COVID-19 vaccines)
• History of active TB (Bacillus tuberculosis)
• Radiation therapy within 2 weeks prior to study day 1
• If patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
• Women who are pregnant or breast feeding
• Patients expecting to conceive or father children within the projected duration of the trial, starting with the visit through 180 days after the last dose of study treatment(s)
• Prior organ transplantation including allogenic stem-cell transplantation
• Active infection requiring systemic therapy
• Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v5.0 grade >= 3)
• Patients with prior history of interstitial lung disease and clinically significant pulmonary compromise, including those who have a requirement for supplemental oxygen use to maintain adequate oxygenation