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Phase I/II Trial Investigating the Safety, Tolerability, Pharmacokinetics, Immune and Clinical Activity of SX-682 in Combination With BinTrafusp Alfa (M7824 or TGF-beta "Trap"/PD-L1) With CV301 TRICOM in Advanced Solid Tumors (STAT)

NCT04574583

Description:

Background: Combination immunotherapy techniques are being explored to improve responses and enhance benefits in people with cancer. Researchers want to see if this type of treatment can help people with advanced solid tumors. Objective: To find a safe dose of SX-682 in combined treatment with Bintrafusp alfa and BN-CV301 vaccines and to see if this treatment will cause tumors to shrink. Eligibility: Adults age 18 and older with metastatic cancer may be eligible for the first part of the trial. Adults age 18 and older with metastatic triple negative breast cancer or p16 negative head and neck squamous cell cancer, and who are not candidates for curative surgery may be eligible for the second part of the trial. Design: Participants will be screened under a separate protocol. Participants may have tumor biopsies. They will have physical exams. Their symptoms and medicines will be reviewed. They will have blood tests. They will have electrocardiograms to evaluate their heart. Participants will have imaging scans of the chest, abdomen, and pelvis. They may have a procedure where a small tube with a tiny video camera is put into the nose to look at the throat if they have head and neck cancers. Participants will get bintrafusp alfa through an intravenous catheter. For this, a small tube is put into an arm vein. They will get BN-CV301 vaccines as injections in the arm or thigh. They will take SX-682 by mouth twice a day. They will take the study drugs up to 2 years. They will keep a medicine diary. Participants will have study visits every 2 weeks. They will have 1 or 2 follow-up visits within 30 days after they stop treatment. Then they will be monitored by phone or email for 2 years.

Related Conditions:
  • Breast Carcinoma
  • Head and Neck Squamous Cell Carcinoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase I/II Trial Investigating the Safety, Tolerability, Pharmacokinetics, Immune and Clinical Activity of SX-682 in Combination With TriAdeno Vaccine Regimen and M7824 (TGF-b "Trap/PDLi; Bintrafusp Alpha) in Advanced Solid Tumors (STAT)
  • Official Title: Phase I/II Trial Investigating the Safety, Tolerability, Pharmacokinetics, Immune and Clinical Activity of SX-682 in Combination With TriAdeno Vaccine Regimen and M7824 (TGF-b 'Trap'/PD-Li; Bintrafusp Alpha) in Advanced Solid Tumors (STAT)

Clinical Trial IDs

  • ORG STUDY ID: 200155
  • SECONDARY ID: 20-C-0155
  • NCT ID: NCT04574583

Conditions

  • Metastatic Cancer
  • Solid Tumors

Interventions

DrugSynonymsArms
SX-6821/Sequential Dose Escalation
M78241/Sequential Dose Escalation
MVA-BN-CV3011/Sequential Dose Escalation
FPV-CV3011/Sequential Dose Escalation

Purpose

Background: Combination immunotherapy techniques are being explored to improve responses and enhance benefits in people with cancer. Researchers want to see if this type of treatment can help people with advanced solid tumors. Objective: To find a safe dose of SX-682 in combined treatment with Bintrafusp alfa and BN-CV301 vaccines and to see if this treatment will cause tumors to shrink. Eligibility: Adults age 18 and older with metastatic cancer may be eligible for the first part of the trial. Adults age 18 and older with metastatic triple negative breast cancer or p16 negative head and neck squamous cell cancer, and who are not candidates for curative surgery may be eligible for the second part of the trial. Design: Participants will be screened under a separate protocol. Participants may have tumor biopsies. They will have physical exams. Their symptoms and medicines will be reviewed. They will have blood tests. They will have electrocardiograms to evaluate their heart. Participants will have imaging scans of the chest, abdomen, and pelvis. They may have a procedure where a small tube with a tiny video camera is put into the nose to look at the throat if they have head and neck cancers. Participants will get bintrafusp alfa through an intravenous catheter. For this, a small tube is put into an arm vein. They will get BN-CV301 vaccines as injections in the arm or thigh. They will take SX-682 by mouth twice a day. They will take the study drugs up to 2 years. They will keep a medicine diary. Participants will have study visits every 2 weeks. They will have 1 or 2 follow-up visits within 30 days after they stop treatment. Then they will be monitored by phone or email for 2 years.

Detailed Description

      Background:

        -  Combination immunotherapy approaches are being actively explored to further improve
           responses, enhance clinical benefit, and overcome resistance to PD(L)-1 agents in cancer
           patients.

        -  Interleukin-8 (IL-8) is a pro-inflammatory chemokine produced by various cell types.
           Overexpression of IL-8 and/or its receptors CXCR1 and CXCR2, is commonly seen in many
           human cancers including breast, cervical, melanoma and prostate.

        -  SX-682 is an oral, small molecule inhibitor of the CXCR1/2 chemokine receptors that are
           believed involved in MDSC-recruitment to tumor and other pro-tumoral mechanisms.

        -  Bintrafusp alfa (M7824 or MSB0011359C) is a bifunctional protein composed of the
           extracellular domain of the TGF-BetaRII receptor (TGF-Beta 'trap') fused to a human
           IgG1. Preclinical data shows bintrafusp alfa treatment increases T-cell trafficking,
           antigenspecific CD8+ T-cell lysis and NK cell activation.

        -  CV301 is a poxviral-based vaccine comprised of recombinant Modified vaccinia Ankara
           (MVA-BN-CV301, prime) and recombinant fowlpox (FPV-CV301, boost). CV301 contains
           transgenes encoding two (2) tumor-associated antigens (TAA), mucin 1 (MUC1) and
           carcinoembryonic antigen (CEA), as well as three costimulatory molecules (B7.1, ICAM-1
           and LFA-3, designated TRICOM). A recent phase 1 clinical trial demonstrated that
           antigen-specific T cells to MUC1 and CEA, as well as to a cascade antigen, brachyury,
           were generated in most patients.

        -  Preclinical studies performed in LTIB with SX-682, M7824 and a CEA-based vaccine showed
           a significant reduction in tumor growth as well as a significant increase in tumor
           infiltration with CD4+ and CD8+ T cells.

      Objectives:

        -  Arm 1 (Sequential Dose Escalation):

             -  To evaluate the safety and tolerability of single agent SX-682.

             -  To determine the MTD of SX-682 followed by M7824 and CV301 vaccines in patients
                with advanced or metastatic solid tumors. If the MTD is not reached the study will
                be focused to describe the safety and tolerability of SX-682 followed by M7824 and
                CV301 vaccines.

        -  Arm 2 (Combination Dose Escalation):

           --To determine the recommended phase 2 dose (RP2D) of SX-682 with M7824 and CV301
           vaccines in patients with advanced or metastatic solid tumors. If the MTD is not reached
           the study will be focused to describe the safety and tolerability of the drug
           combination.

        -  Arm 3 (Expansion):

             -  To evaluate preliminary efficacy based on Objective Response Rate (ORR), in each
                disease cohort separately.

      Eligibility:

        -  Age > 18 years old

        -  Arms 1 and 2 (Dose-Escalation Cohort): Subjects with cytologically or histologically
           confirmed locally advanced or metastatic solid tumors.

        -  Arm 3 (Expansion Cohorts):

             -  TNBC: Subjects with cytologically or histologically confirmed locally advanced or
                metastatic Triple Negative Breast Cancer that has progressed on at least one prior
                treatment in the advanced or in the metastatic setting.

             -  HPV negative HNSCC: Subjects with cytologically or histologically confirmed locally
                advanced or metastatic, HPV negative head and neck squamous cell cancer (p16
                negative for oropharyngeal) that has progressed on at least one prior treatment
                involving a platinum drug or cetuximab in advanced or in the metastatic setting.

        -  Prior first line systemic therapy is required unless there is no standard treatment
           available, the patient cannot tolerate standard first line treatment, or the patient
           declines standard treatment after appropriate counseling has been provided.

        -  ECOG performance status of 0 to 1

        -  Adequate renal, hepatic, and hematologic function

        -  Subjects in Arms 1 and 2 may have disease that is measurable or non-measurable but
           evaluable disease (e.g. present on bone scan, rising tumor markers, non-measurable by
           RECIST but visible on CT scan). Patients with third space fluid (for example pleural
           effusions) as only site of disease will not be eligible. Subjects in Arm 3 must have
           measurable disease according to RECIST 1.1

      Design:

        -  Arm 1 is a phase I, open-label, 3+3 sequential dose escalation trial with short term,
           2-week SX-682 monotherapy lead-in followed by treatment with M7824 and CV301 vaccine
           series in advanced solid tumors (Q2W dosing schedule) for the duration of treatment.

        -  Arm 2 is a phase I, open-label, 3+3 combination dose escalation trial with short term
           SX- 682 monotherapy lead in followed by SX-682 combination with M7824 and CV301 vaccine
           series in advanced solid tumors (Q2W dosing schedule). Each enrolled patient will
           receive SX-682 as monotherapy for 2 weeks then will receive SX-682, M7824 and CV301 for
           the duration of treatment

        -  Arm 3 has two expansion cohorts. Following identification of the MTD or R2PD for the
           combination of SX-682, M7824 and CV301 vaccine, disease-specific phase 2 expansion
           cohorts will open in 1) advanced/metastatic triple negative breast cancer and 2)

      advanced/metastatic, platinum-refractory HPV negative head and neck squamous cell carcinoma.
    

Trial Arms

NameTypeDescriptionInterventions
1/Sequential Dose EscalationExperimentalEscalating doses of SX-682 for 2 weeks THEN M7824 +CV301
  • SX-682
  • M7824
  • MVA-BN-CV301
  • FPV-CV301
2/Combination Dose EscalationExperimentalEscalating doses of SX-682 for 2 weeks THEN Escalating doses of SX-682 + M7824 + CV301
  • SX-682
  • M7824
  • MVA-BN-CV301
  • FPV-CV301
3/Disease-Specific ExpansionExperimentalRP2D of SX-682 + M7824 + CV301
  • SX-682
  • M7824
  • MVA-BN-CV301
  • FPV-CV301

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Patients must have histologically or cytologically confirmed:

               -  Metastatic or locally advanced, Solid tumor (Cohort 1)

        OR

        --Metastatic or locally recurrent, non-resectable Triple Negative Breast Cancer (TNBC),
        defined as ER < 10%, PR < 10% per immunohistochemistry (IHC) and HER 2 negative. HER2
        negative or unamplified breast cancer is defined as IHC 0 or 1+ or IHC 2+ with FISH average
        HER2 copy number < 4.0 signals per cell or HER2/CEP17 < 2.0 with average HER2 copy number <
        4.0 signals per cell.[89] HER2 testing must have been performed in a laboratory accredited
        by the College of American Pathology (CAP) or another accrediting entity (Cohort 2).

        OR

          -  Metastatic or locally recurrent, non-resectable p16 negative Head and Neck Squamous
             Cell Cancer (HNSCC). Oropharyngeal tumors must be negative for p16 overexpression by
             IHC per ASCO/CAP guidelines and in a CAP accredited lab.[90] All other head and neck
             malignancies do not require p16 testing (Cohort 3).

               -  Patients must have histologically or cytologically confirmed metastatic or
                  locally advanced disease. Historical reports from a CAP accredited lab are
                  acceptable.

               -  Subjects in Arms 1 and 2 may have disease that is measurable or non-measurable
                  but evaluable disease (e.g. present on bone scan, rising tumor markers,
                  non-measurable by RECIST but visible on CT scan). Patients with third space fluid
                  (for example pleural effusions) as only site of disease will not be eligible.
                  Subjects in Arm 3 must have measurable disease according to RECIST 1.1

               -  Patients must

          -  have received at least one prior systemic therapy for metastatic or locally advanced
             disease, unless there is no standard treatment available,

        OR

        --not tolerate standard first line treatment,

        OR

        --decline standard treatment after appropriate counseling has been provided.

        Note: Patients in Arm 3, Cohort 3 who have PD-L1 positive TNBC must have progressed on
        atezolizumab + nab-paclitaxel. Patients in Arm 3, Cohort 3 (p16 negative HNSCC) must have
        progressed on or been intolerant to a regimen involving a platinum drug or cetuximab
        monotherapy.

          -  Age greater than or equal to 18 years.

          -  ECOG performance status 0 or 1.

          -  Patients must have adequate organ and marrow function as defined below:

               -  Absolute neutrophil count (ANC) >1,500/mcL

               -  Platelets >100,000/mcL

               -  Hemoglobin > 9 g/dL without a blood transfusion in the 14 days prior to
                  enrollment.

               -  Total bilirubin < 1.5X upper limit of normal (ULN) OR in subjects with Gilbert s
                  Syndrome, a total bilirubin < 3.0 x ULN

               -  AST(SGOT)/ALT(SGPT) <2.5 X institutional upper limit of normal OR in subjects
                  with known liver metastasis, AST/ALT < 3.0 X ULN

               -  An estimated creatinine clearance (CrCl) > 60 mL/min/1.73 m2 using the
                  Cockroft-Gault calculation
                  (https://www.kidney.org/professionals/KDOQI/gfr_calculatorCoc).

          -  The effects of immunotherapies on the developing human fetus are unknown. For this
             reason and because immunotherapy agents as well as other therapeutic agents used in
             this trial are known to be teratogenic, women of child-bearing potential and men must
             agree to use adequate contraception (hormonal or barrier method of birth control;
             abstinence) at the time of study entry, for the duration of study treatment and up to
             6 months after the last dose of the study drug (s). 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.

          -  Patients with well-controlled HIV infection are eligible for trial as long as:

               -  On an effective anti-retroviral therapy (ART) > 4 weeks and with evidence of
                  viral suppression defined as HIV viral load < 400 copies/mL at enrollment

               -  CD4+ count > 200 cells/microL at enrollment

          -  No reported opportunistic infections within 6 months prior to enrollment except for
             the following which will be allowed:

               -  Esophageal candidiasis treated within last 6 months or currently improving with
                  antifungal treatment

               -  Oral and/or genital HSV treated within last 6 months or currently improving with
                  antiviral treatment

               -  Mycobacterium avium infection in last 6 months or that has been treated for at
                  least 1month.

          -  Immunomodulating drugs must be discontinued at least 1 weeks prior to enrollment for
             recent short course use (less than or equal to 14 days) or discontinued at least 4
             weeks prior to enrollment for long term use (> 14 days).

          -  Patients must have a received their last treatment > 4 weeks or 5 half-lives of the
             last treatment drug, whichever is shorter before starting on trial.

          -  Patients with known history of hepatitis B (HBV) infection are eligible for trial as
             long as the HBV viral load is undetectable.

          -  Patients with known history of hepatitis C (HCV) infection must have been treated and
             cured (viral load is undetectable). For patients with HCV infection who are currently
             on treatment, they are eligible if they have an undetectable or unquantifiable HCV RNA
             12 weeks or longer after definitive treatment completion.

          -  Subjects must be able to understand and be willing to sign a written informed consent
             document.

        EXCLUSION CRITERIA:

          -  Patients who are receiving any other investigational agents.

          -  Patients with active brain metastases or central nervous system metastasis (less than
             28 days out from definitive radiotherapy or surgery of brain metastasis) are excluded
             from this clinical trial. However, patients with treated brain metastasis are eligible
             if there is no

        magnetic resonance imaging (MRI) evidence of progression for 6 weeks after treatment is
        complete and the MRI within 28 days prior to enrollment. Patients requiring
        immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalent) for
        palliation are excluded. Patients with evidence of intratumoral or peritumoral brain
        metastasis hemorrhage on screening imaging are also excluded unless the hemorrhage of brain
        metastases is grade < 1 and has been stable on two consecutive imaging scans.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to any of study drugs

          -  Steroid use or active autoimmune disease that might deteriorate when receiving an
             immunostimulatory agent with the exception of:

               -  Diabetes type I, eczema, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid
                  disease or other mild autoimmune disorder not requiring immunosuppressive
                  treatment;

               -  Patients requiring hormone replacement with corticosteroid are eligible if the
                  steroids are administered only for the purpose of adrenal insufficiency and at
                  doses of <10 mg of prednisone or equivalent per day;

               -  Administration of steroids for other conditions through a route known to result
                  in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation)
                  is acceptable;

               -  Patients on physiologic doses of systemic intravenous or oral corticosteroid
                  therapy (greater tahn or equal to the equivalent of prednisone 10 mg/day.

               -  The use of corticosteroids as premedication for contrast-enhanced studies which
                  is allowed prior to enrollment.

          -  Patients with a history of serious intercurrent chronic or acute illness, such as
             cardiac or pulmonary disease, hepatic disease, bleeding diathesis or recent (within 3
             months) clinically significant bleeding events or other illness considered by the
             Investigator as high risk for

        investigational drug treatment.

          -  History of second malignancy within 3 years of enrollment except for the following:
             adequately treated localized skin cancer, ductal carcinoma in situ, cervical carcinoma
             in situ, superficial bladder cancer or other localized malignancy which has been
             adequately treated.

          -  Receipt of any organ transplantation requiring ongoing immunosuppression including
             allogenic stem-cell transplant.

          -  Patients with bone metastases who have initiated denosumab or a bisphosphonate therapy
             within 28 days prior to enrollment. Continuation of prior therapy is allowed.

          -  Patients who have a QTcf interval > 475 msec or > 480 msec with a BBB on screening
             electrocardiogram.

          -  Patients with a personal or family history of long-QT syndrome or are on a concomitant
             drug that is known to cause significant QTc prolongation within 2 weeks of enrollment

          -  Any other condition, which would, in the opinion of the Principal Investigator
             indicated the subject is a poor candidate for the clinical trial or would jeopardize
             the subject or the integrity of the data obtained.

          -  Pregnant women are excluded from this study because study drugs potential for
             teratogenic or abortifacient effects are unknown. Because there is an unknown but
             potential risk for adverse events in nursing infants secondary to treatment of the
             mother with study drugs, breastfeeding should be discontinued if the mother is treated
             with study drugs.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:To evaluate the safety and tolerability of single agent SX-682.
Time Frame:DLT observation period (first 4 weeks)
Safety Issue:
Description:Dose limiting toxicities and the list of adverse event frequencies

Secondary Outcome Measures

Measure:To evaluate preliminary efficacy: disease control rate (DCR; CR+PR+SD) and progression-free survival (PFS) using RECIST1.1.
Time Frame:4-5 years
Safety Issue:
Description:Disease control rate (DCR; CR+PR+SD) and Progression free survival (PFS)
Measure:To characterize the PK/PD profile of SX-682 as a single agent and in combination
Time Frame:30 days after treatment (Study Calendar-Last PK test)
Safety Issue:
Description:Drug level in blood

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Immunotherapy
  • Checkpoint Inhibitor
  • Vaccine
  • Combination Therapy
  • Metastatic Cancer

Last Updated

October 7, 2020