PRIMARY OBJECTIVE:
I. To explore the safety of BO-112 in combination with nivolumab in soft tissue sarcoma
patients undergoing preoperative radiotherapy, as assessed by the frequency and severity of
adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) version
(v)4.0 toxicity criteria.
SECONDARY OBJECTIVES:
I. Determine the change in T cell infiltration at surgical resection from baseline as
measured by immunohistochemistry.
II. Assess treatment effect (necrosis score) of BO-112 in combination with nivolumab in soft
tissue sarcoma patients receiving preoperative hypofractionated radiotherapy, compared to
patients treated on a recently completed phase 2 study of preoperative hypofractionated
radiotherapy alone.
III. Evaluate the 2-year rate of local and distant metastasis of BO-112 in combination with
nivolumab in patients with localized resectable soft tissue sarcoma receiving preoperative
hypofractionated radiotherapy, as compared to historical patients receiving preoperative
radiotherapy alone.
EXPLORATORY OBJECTIVES:
I. Evaluate the dynamics of the intratumoral T cell phenotype. II. Assess the capacity to
grow ex vivo tumor infiltrating lymphocytes from patients treated with BO-112 in combination
with nivolumab.
III. Analyze changes in T-cell receptor (TCR) repertoire in tumor infiltrating lymphocytes
and peripheral blood mononuclear cells (PBMCs) between baseline, post-treatment, and ex vivo
cultured tumor infiltrating lymphocyte (TIL) samples.
OUTLINE:
Patients receive BO-112 intratumorally on days 1, 8, and 15 and nivolumab intravenously (IV)
over 30-60 minutes on days 8 and 22 in the absence of disease progression or unacceptable
toxicity. Patients also undergo standard of care radiation therapy on days 8-12 for a total
of 5 fractions. Patients then undergo standard of care definitive surgical resection on day
26 to 50.
After completion of study treatment, patients are followed up at 2 weeks, 3 months, and
between 6-12, 12-18, and 18-24 months.
Inclusion Criteria:
- Written informed consent, and assent where appropriate, must be obtained from the
subject prior to performing any protocol-related procedures, including screening
evaluations
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
- Resectable, biopsy proven soft tissue sarcoma of the extremity, trunk or
retroperitoneum including undifferentiated pleomorphic sarcoma, myxofibrosarcoma,
leiomyosarcoma, dedifferentiated liposarcoma, and synovial sarcoma. Undifferentiated
pleomorphic sarcoma encompasses any of the following histologies:
- Pleomorphic undifferentiated sarcoma
- Unclassified spindle cell sarcoma
- Spindle cell sarcoma not otherwise specified
- Pleomorphic spindle cell sarcoma
- Pleomorphic fibroblastic sarcoma
- Undifferentiated high-grade pleomorphic sarcoma
- Pleomorphic sarcoma with prominent inflammation
- Pleomorphic sarcoma with giant cells
- Malignant fibrous histiocytoma (including storiform-pleomorphic and inflammatory
subtypes)
- Fibrosarcoma
- Tumor that is injectable
- Hemoglobin >= 9 g/dL
- Absolute neutrophil count >= 1,000/mm^3
- Platelet count >= 100,000/mm^3 and transfusion independent
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x
institutional upper limit of normal (ULN)
- Bilirubin =< 1.5 x ULN; for subjects with documented/suspected Gilbert's disease,
bilirubin =< 3 x ULN
- Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin
time (PTT) =< 1.5 x institutional upper limit of normal unless the patient is on
anticoagulant therapy within 28 days prior to enrollment (if the patient is receiving
anticoagulant therapy, PT, and a PTT must be within therapeutic range of intended use
of anticoagulants)
- Patients must be willing to submit blood and tissue specimens for translational
medicine studies
- Patients must be offered the opportunity to participate in specimen banking for future
research
- Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
[HCG]) within 24 hours prior to the start of study drug
- Women must not be breastfeeding
- Women of childbearing potential (WOCBP) must be willing to use either two adequate
barrier methods or a barrier method plus a hormonal method of contraception to prevent
pregnancy, or to abstain from heterosexual activity (complete abstinence) throughout
the study, starting with visit 1 through 5 months after the last dose of study
therapy. Approved contraceptive methods include intrauterine device, diaphragm with
spermicide, cervical cap with spermicide, male condoms, female condoms with
spermicide, or oral contraceptives. Spermicides alone are not an acceptable method of
contraception. Should a woman become pregnant or suspect she is pregnant while she or
her partner is participating in this study, she should inform her treating physician
immediately
- Men receiving nivolumab and who are sexually active with WOCBP will be instructed to
adhere to highly effective contraception during active participation in study
treatment and for a period of 7 months after the last dose of nivolumab
- HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
- Highly effective methods of contraception have a failure rate of < 1% when used
consistently and correctly. WOCBP and female partners of male subjects, who are
WOCBP, are expected to use one of the highly effective methods of contraception
listed below. Male subjects must inform their female partners who are WOCBP of
the contraceptive requirements of the protocol and are expected to adhere to
using contraception with their partner. Contraception methods are as follows:
- Progestogen only hormonal contraception associated with inhibition of ovulation
- Hormonal methods of contraception including oral contraceptive pills containing
combined estrogen + progesterone, vaginal ring, injectables, implants and
intrauterine devices (IUDs) such as Mirena
- Nonhormonal IUDs, such as ParaGard
- Bilateral tubal occlusion
- Vasectomized partner with documented azoospermia 90 days after procedure
- Vasectomized partner is a highly effective birth control method provided
that partner is the sole sexual partner of the WOCBP trial participant and
that the vasectomized partner has received medical assessment of the
surgical success
- Intrauterine hormone-releasing system (IUS)
- Complete abstinence
- Complete abstinence is defined as the complete avoidance of heterosexual
intercourse
- Complete abstinence is an acceptable form of contraception for all study
drugs and must be used throughout the duration of the study treatment (plus
5 half-lives of the investigational drug plus 30 days)
- It is not necessary to use any other method of contraception when complete
abstinence is elected
- Subjects who choose complete abstinence must continue to have pregnancy
tests, as specified
- Acceptable alternate methods of highly effective contraception must be
discussed in the event that the subject chooses to forego complete
abstinence
- The reliability of sexual abstinence needs to be evaluated in relation to
the duration of the clinical trial and the preferred and usual lifestyle of
the subject
- LESS EFFECTIVE METHODS OF CONTRACEPTION
- Diaphragm with spermicide
- Cervical cap with spermicide
- Vaginal sponge with spermicide
- Male or female condom with or without spermicide
- A male and a female condom must not be used together
- Progestogen-only oral hormonal contraception, where inhibition of ovulation is
not the primary mode of action
- UNACCEPTABLE METHODS OF CONTRACEPTION
- Periodic abstinence (calendar, symptothermal, post-ovulation methods)
- Withdrawal (coitus interruptus)
- Spermicide only
- Lactation amenorrhea method (LAM)
Exclusion Criteria:
- Contraindications to tumor biopsy and injections (coagulopathy, known history of
keloid formation, etc.)
- Women who are pregnant or breastfeeding
- Inability to give informed consent
- History of other malignancy that can interfere with interpretation of the results
- Prior irradiation in the area to be treated with preoperative radiation
- Any condition that might interfere with the subject's participation in the study,
safety, or in the evaluation of the study results
- Concurrent enrollment in another clinical study, unless it is an observational
(non-interventional) clinical study or the follow-up period of an interventional study
- Prior exposure to any Programmed death-ligand 1 (anti-PD-1 or anti-PD-L1 antibody), or
any Cytotoxic T lymphocyte-associated antigen (anti-CTLA 4) antibodies
- Patients must not have received any live vaccine within 30 days prior to registration.
Seasonal flu vaccines and other vaccines that do not contain live virus are permitted
- Any concurrent chemotherapy, immunotherapy, or biologic therapy for cancer treatment.
Concurrent use of hormones is acceptable
- Patient must not have evidence of any clinically significant immunosuppression such as
the following: primary immunodeficiency state such as severe combined immunodeficiency
disease; concurrent opportunistic infection; receiving systemic immunosuppressive
therapy within 28 days before enrollment with the exceptions of intranasal, topical,
and inhaled corticosteroids or oral corticosteroids at physiologic doses not to exceed
10 mg/day of prednisone or equivalent
- Active or prior documented autoimmune disease within the past 3 years
- NOTE: Subjects with active, known or suspected autoimmune disease such as
vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune
condition only requiring hormone replacement, psoriasis not requiring systemic
treatment, or conditions not expected to recur in the absence of an external
trigger are permitted to enroll
- Active or prior documented inflammatory bowel disease
- History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required
steroids or has current ILD/pneumonitis or where suspected ILD/pneumonitis cannot be
ruled out by imaging at screening
- Exposure to any investigational drug within 7 days prior to screening visit or for
which 5 half-lives have not elapsed
- Prisoners or subjects who are involuntarily incarcerated
- Note: under certain specific circumstances a person who has been imprisoned may
be included or permitted to continue as a subject
- Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (e.g., infectious disease) illness
