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.
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.
Inclusion Criteria:
1. Provision to sign and date the consent form.
2. Stated willingness to comply with all study procedures and be available for the
duration of the study.
3. Be male or female aged 18-100 years at the time of signing informed consent.
4. 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.
5. 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.
6. 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.
7. Have received 0 or 1 prior systemic therapies for metastatic sarcoma and NO prior
anthracyclines or checkpoint inhibitors.
8. Adequate organ function as defined in Table 1.
9. ECOG performance status of 0 or 1 (See Appendix B for scale definitions).
10. 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.
11. 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.
12. 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.
13. 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.
14. Subjects must either possess or undergo placement of central venous catheter,
including pheresis or trifusion catheter, PICC line, or port.
Exclusion Criteria:
1. Prior therapy with anthracycline or checkpoint inhibitors.
2. Hypersensitivity to doxorubicin or any excipients.
3. Patients may not be receiving any other investigational agents (within 4 weeks prior
to Cycle 1, Day 1).
4. 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.
5. 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.
6. 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.
7. Patients with underlying immune deficiency, chronic infections including HIV,
hepatitis, or tuberculosis (TB) or autoimmune disease.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. Any uncontrolled, intercurrent illness including but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia
14. Prolonged QTc interval on Screening EKG >475 ms.
15. Ejection Fraction <50% by 2D ECHO at Screening.
16. 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).
17. 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.
18. Had a previous severe hypersensitivity reaction to another monoclonal antibody.
19. Primary or secondary immunodeficiency (including immunosuppressive disease, autoimmune
disease [excluding hypothyroidism, insulin dependent diabetes mellitus, or vitiligo],
or usage of immunosuppressive medications).
