Clinical Trials /

Nivolumab and BO-112 Before Surgery for the Treatment of Resectable Soft Tissue Sarcoma

NCT04420975

Description:

This phase I trial studies the side effects of BO-112 when given together with nivolumab before surgery in treating patients with soft tissue sarcoma that can be removed by surgery (resectable). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Immunotherapy with BO-112, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab and BO-112 before surgery may work better in treating patients with soft tissue sarcoma compared to nivolumab alone.

Related Conditions:
  • Dedifferentiated Liposarcoma
  • Fibroblastic Liposarcoma
  • Fibroblastic Osteosarcoma
  • Fibrosarcoma
  • Leiomyosarcoma
  • Myxofibrosarcoma
  • Retroperitoneal Sarcoma
  • Soft Tissue Sarcoma
  • Spindle Cell Sarcoma
  • Synovial Sarcoma
  • Undifferentiated High Grade Pleomorphic Sarcoma of Bone
  • Undifferentiated Pleomorphic Sarcoma
  • Undifferentiated Pleomorphic Sarcoma with Osteoclast-Like Giant Cells
  • Undifferentiated Pleomorphic Sarcoma, Inflammatory Variant
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab and BO-112 Before Surgery for the Treatment of Resectable Soft Tissue Sarcoma
  • Official Title: A Phase I Study of Nivolumab and Intratumoral BO 112 for Resectable Soft Tissue Sarcoma

Clinical Trial IDs

  • ORG STUDY ID: 19-000419
  • SECONDARY ID: NCI-2019-08556
  • SECONDARY ID: 19-000419
  • SECONDARY ID: P30CA016042
  • NCT ID: NCT04420975

Conditions

  • Leiomyosarcoma
  • Myxofibrosarcoma
  • Resectable Dedifferentiated Liposarcoma
  • Resectable Soft Tissue Sarcoma
  • Resectable Undifferentiated Pleomorphic Sarcoma
  • Soft Tissue Fibrosarcoma
  • Spindle Cell Sarcoma
  • Stage I Retroperitoneal Sarcoma American Joint Committee on Cancer (AJCC) v8
  • Stage I Soft Tissue Sarcoma of the Trunk and Extremities AJCC v8
  • Stage IA Retroperitoneal Sarcoma AJCC v8
  • Stage IA Soft Tissue Sarcoma of the Trunk and Extremities AJCC v8
  • Stage IB Retroperitoneal Sarcoma AJCC v8
  • Stage IB Soft Tissue Sarcoma of the Trunk and Extremities AJCC v8
  • Stage II Retroperitoneal Sarcoma AJCC v8
  • Stage II Soft Tissue Sarcoma of the Trunk and Extremities AJCC v8
  • Storiform-Pleomorphic Malignant Fibrous Histiocytoma
  • Synovial Sarcoma
  • Undifferentiated Pleomorphic Sarcoma With Osteoclast-Like Giant Cells
  • Undifferentiated Pleomorphic Sarcoma, Inflammatory Variant

Interventions

DrugSynonymsArms
Immunotherapeutic AgentBiological Response Modifier, Biomodulators, BRM, Immune Mediators, Immune Modulators, Immune Regulators, Immunomodulating Agent, Immunomodulators, Immunomodulatory Agent, Immunopotentiators, Immunotherapy AgentTreatment (BO-112, nivolumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (BO-112, nivolumab)

Purpose

This phase I trial studies the side effects of BO-112 when given together with nivolumab before surgery in treating patients with soft tissue sarcoma that can be removed by surgery (resectable). Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Immunotherapy with BO-112, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab and BO-112 before surgery may work better in treating patients with soft tissue sarcoma compared to nivolumab alone.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (BO-112, nivolumab)ExperimentalPatients receive BO-112 intratumorally on days 1, 8, and 15 and nivolumab 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.
  • Immunotherapeutic Agent
  • Nivolumab

Eligibility Criteria

        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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Frequency and severity of adverse events (AEs) and dose limiting toxicities (DLTs)
Time Frame:Before-surgery
Safety Issue:
Description:AEs will be tabulated by type, severity, and the proportion of subject experiencing the event.

Secondary Outcome Measures

Measure:Immune-oncologic impact of the combined regimen of nivolumab and BO-112
Time Frame:Before-surgery
Safety Issue:
Description:Statistical analysis of immune-oncologic changes will be performed by comparing results from surgical specimens with baseline biopsy specimens. For immunohistochemical parameters, the percentage of Cluster of Differentiation 4+ or Cluster of Differentiation 8+ (CD4+ or CD8+) cells will be compared between biopsy and surgical specimens using a paired two-tailed ratio T-test comparing means.
Measure:Pathologic treatment effect
Time Frame:through study completion, an average of 1 year
Safety Issue:
Description:Will be compared to historical samples receiving preoperative radiotherapy alone. Will use a two-sample paired T-test comparing means.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Jonsson Comprehensive Cancer Center

Last Updated

June 10, 2020