Doxorubicin Plus Dual Checkpoint Blockade for Soft Tissue Sarcomas

Study Overview
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Brief Summary
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This is an open-label, non-randomized, single-institution, single arm Phase II study conducted using a Simon two-stage design with an additional safety lead-in. The overall objective is to determine the efficacy of combination doxorubicin with dual checkpoint blockade with anti-CTLA-4 antibody AGEN1884 and anti-PD-1 antibody AGEN2034. The investigators will estimate the progression-free survival rate at 6 months (PFS6mo) of doxorubicin plus AGEN1884/AGEN2034 in comparison to historical PFS6mo with doxorubicin monotherapy, calculated as the mean from two large randomized Phase 3 clinical trials.

Detailed Description
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The primary endpoint for the study is PFS6mo by RECIST 1.1. The sample size calculation is based on a Simon Two-Stage design with incorporation of early stopping rules for safety and futility (See section 9 for statistical considerations). The Investigators will enroll up to 35 patients on the study to obtain 28 evaluable patients for the primary endpoint. Safety of the combination will be evaluated after the first six patients complete the DLT observation period of 9 weeks. This lengthy DLT period is designed to capture safety and toxicity profile, understanding that immune-related toxicities from checkpoint inhibitors may not emerge immediately. This will also ensure adequate evaluation of potential cardiac and hepatic toxicity from combination doxorubicin and checkpoint inhibitor therapy. If two or more patients experience DLT in the initial safety lead-in cohort, the regimen will be declared intolerable. Any patients who do not complete study therapy through the 9-week DLT observation period for any reasons other than toxicity will be replaced for safety lead-in assessment. If fewer than two patients experience DLT, the investigators will proceed to expansion to complete enrollment of 15 patients in Stage 1. Following enrollment of stage one, accrual will pause for analysis of efficacy. If 6 or fewer of the 15 patients are progression-free at 6 months, the investigators will halt the study for futility. If 7 or more patients are free from progression, then the investigators will proceed with enrollment of 13 additional patients to complete stage 2. the investigators are powered to detect improvement in 6-month PFS rate to 63.4% with the combination over the 43.4% historical PFS6mo.

Official Title
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An Open-Label, Phase II Efficacy Trial of Doxorubicin in Combination With Dual Checkpoint Blockade Using Zalifrelimab (AGEN1884) or Botensilimab (AGEN1181) With Balstilimab (AGEN2034) for Advanced or Metastatic Soft Tissue Sarcomas

Conditions
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Metastatic Soft Tissue Sarcoma, Advanced Soft Tissue Sarcoma

Intervention / Treatment
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* Drug: doxorubicin with AGEN1884 and AGEN2034


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision to sign and date the consent form. Stated willingness to comply with all study procedures and be available for the duration of the study. Be male or female aged 18-100 years at the time of signing informed consent. Have a histological diagnosis of advanced or metastatic soft tissue sarcoma (STS) (by local pathology review), not curable by surgery, for which treatment with doxorubicin is deemed appropriate by the investigator. Has one of the following histologies: synovial sarcoma, malignant peripheral nerve sheath tumors, dedifferentiated, pleomorphic or myxoid/round cell liposarcoma, uterine or soft tissue leiomyosarcoma, malignant phylloides tumor, high grade undifferentiated pleomorphic sarcomas (HGUPS/MFH), myxofibrosarcoma, fibrosarcoma, angiosarcoma, spindle cell or undifferentiated sarcoma NOS, malignant myoepithelioma, malignant solitary fibrous tumor/hemangiopericytoma, epithelioid hemangioendothelioma, Any other histology or standard of care treatment not specifically addressed will be reviewed by the principal investigator and pathologist for final determination of eligibility. Have measurable or nonmeasurable but evaluable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (Appendix A). Tumors within a previously irradiated field will be designated as nontarget lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiotherapy. Have received 0 or 1 prior systemic therapies for metastatic sarcoma and NO prior anthracyclines or checkpoint inhibitors. Adequate organ function as defined in Table 1. ECOG performance status of 0 or 1 (See Appendix B for scale definitions). Patients must consent and be willing to undergo tumor core needle biopsies at two timepoints: 1. Baseline, 2. Cycle 2 Day 5; a third biopsy for off-study/progression is optional but advised. At least one tumor site must be amenable to biopsy in the judgment of the interventional radiologist. Female subjects of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Females of child bearing potential that are sexually active must agree to either practice 2 medically accepted highly effective methods of contraception at the same time or abstain from heterosexual intercourse from the time of signing the informed consent through 120 days after the last dose of study drug. See Appendix B for protocol-approved highly effective methods of contraceptive combinations. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year. Negative test for pregnancy is required of females of child-bearing potential. A female of child-bearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1. Has not undergone a hysterectomy or bilateral oophorectomy; or 2. Has not been naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months or 730 days.) Conception while on treatment must be avoided. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy. Prior history of vasectomy does NOT replace requirement for contraceptive use. Subjects must either possess or undergo placement of central venous catheter, including pheresis or trifusion catheter, PICC line, or port. Exclusion Criteria: Prior therapy with anthracycline or checkpoint inhibitors. Hypersensitivity to doxorubicin or any excipients. Patients may not be receiving any other investigational agents (within 4 weeks prior to Cycle 1, Day 1). Prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to Cycle 1, Day 1 or has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. Patient has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Cycle 1, Day 1 or has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. Subjects with ≤ Grade 2 neuropathy or alopecia are an exception to this criterion and may qualify for the study. Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. Additional known malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, or squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer. Patients with underlying immune deficiency, chronic infections including HIV, hepatitis, or tuberculosis (TB) or autoimmune disease. Patients with underlying hematologic issues including bleeding diathesis, known previous GI bleeding requiring intervention within the past 6 months. Newly diagnosed pulmonary emboli or deep venous thrombosis must be clinically stable on anticoagulation regimen for ≥ 4 weeks as of Cycle 1 Day 1. Has known history of non-infectious pneumonitis that required oral corticosteroid therapy for resolution within 12 months prior to study entry, or evidence by imaging or symptoms of active non-infectious pneumonitis. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis or leptomeningeal disease. Subjects with previously treated brain metastases may participate provided they are stable based on the following: 1) MRI brain obtained during screening evaluations shows no radiographic evidence of progression or new lesions, 2) any neurologic symptoms have returned to baseline, 3) no requirement for steroids for at least 28 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. Patients without a known history of brain metastases do not require screening brain MRI prior to study enrollment. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed. Is pregnant 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. Any uncontrolled, intercurrent illness including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia Prolonged QTc interval on Screening EKG >475 ms. Ejection Fraction <50% by 2D ECHO at Screening. Any serious medical or psychiatric illness/condition including substance use disorders likely in the judgment of the Investigator(s) to interfere or limit compliance with study requirements/treatment, including NYHA Class II or greater heart disease (see Appendix C for definitions). Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Had a previous severe hypersensitivity reaction to another monoclonal antibody. Primary or secondary immunodeficiency (including immunosuppressive disease, autoimmune disease [excluding hypothyroidism, insulin dependent diabetes mellitus, or vitiligo], or usage of immunosuppressive medications).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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
Intervention Model: Single Group Assignment
Interventional Model Description: This is an open-label, non-randomized, single-institution, single arm Phase II study conducted using a Simon two-stage design with an additional safety lead-in.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: doxorubicin with AGEN1884 and AGEN2034<br>Doxorubicin with dual checkpoint blockade with anti-CTLA-4 antibody AGEN1884 and anti-PD-1 antibody AGEN2034. Doxorubicin dosing is standard at 75 mg/m2 via Bolus with prior Dexrazoxane. AGEN2034 - 300 mg IV over 60min with infusion pump. AGEN1884 - 1 mg/kg IV over 90 min (-10 /+20 min) with infusion pump, within 30 minutes (0 / +20) of completion of AGEN2034. | Drug: doxorubicin with AGEN1884 and AGEN2034<br>* The first cycle of treatment will consist of AGEN2034 and AGEN1884 alone. Beginning with Cycle 2, doxorubicin will be administered every 21 days for a maximum of 6 cycles (Cycles 2-7) with appropriate premedications and pegfilgrastim growth factor support. Doxorubicin will be administered as bolus infusion on day 1 with dexrazoxane cardioprotection. Patients must have central line access for this protocol, including pheresis or trifusion catheter, PICC line, or port. AGEN2034 will be administered every cycle (every 21 days) up to two years. AGEN1884 will be administered every other cycle (Cycle 1, 3, 5, and 7) with maximum of 4 infusions.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the progression-free survival rate | Determine the progression-free survival rate at 6 months of combination therapy with doxorubicin, AGEN1884, and AGEN2034 in anthracycline-naïve patients with advanced or metastatic soft tissue sarcomas. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the overall response rate | Determine the overall response rate of combination therapy with doxorubicin, AGEN1884, and AGEN2034 in anthracycline-naïve patients with advanced or metastatic soft tissue sarcomas. | 3 years | 
| Determine the clinical benefit rate | Determine the clinical benefit rate of combination therapy with doxorubicin, AGEN1884, and AGEN2034 in anthracycline-naïve patients with advanced or metastatic soft tissue sarcomas. | 3 years | 
| Determine the duration of response | Determine the duration of response of combination therapy with doxorubicin, AGEN1884, and AGEN2034 in anthracycline-naïve patients with advanced or metastatic soft tissue sarcomas. | 3 years | 
| Determine the incidence of adverse events | Determine adverse events occurring with combination therapy of doxorubicin, AGEN1884, and AGEN2034 in anthracycline-naïve patients with advanced or metastatic soft tissue sarcomas. | 3 years |