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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)

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ClinicalTrials.gov Identifier: NCT04574583
Recruitment Status : Not yet recruiting
First Posted : October 5, 2020
Last Update Posted : October 27, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Metastatic Cancer Solid Tumors Drug: SX-682 Drug: M7824 Biological: MVA-BN-CV301 Biological: FPV-CV301 Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 105 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Estimated Study Start Date : October 30, 2020
Estimated Primary Completion Date : December 31, 2025
Estimated Study Completion Date : June 30, 2026

Arm Intervention/treatment
Experimental: 1/Sequential Dose Escalation
Escalating doses of SX-682 for 2 weeks THEN M7824 +CV301
Drug: SX-682
SX-682 will be given orally at designated dose twice a day every day

Drug: M7824
Subjects will receive M7824 at a flat dose of 1,200 mg intravenously on Days 1 and 15 of each cycle.

Biological: MVA-BN-CV301
MVA-BN-CV301 will be given as four subcutaneous injections (4x108 Inf. U/0.5ml twice during Cycle 1 (Days 1 and 15),

Biological: FPV-CV301
FPV-CV301 will be given as one subcutaneous injection (1x109 Inf. U/0.5ml) on Day 1starting at cycle 2 through cycle 5 (every 4 weeks) then on Day 1 of every 3 cycles (Cycles 8 and Cycle 11).

Experimental: 2/Combination Dose Escalation
Escalating doses of SX-682 for 2 weeks THEN Escalating doses of SX-682 + M7824 + CV301
Drug: SX-682
SX-682 will be given orally at designated dose twice a day every day

Drug: M7824
Subjects will receive M7824 at a flat dose of 1,200 mg intravenously on Days 1 and 15 of each cycle.

Biological: MVA-BN-CV301
MVA-BN-CV301 will be given as four subcutaneous injections (4x108 Inf. U/0.5ml twice during Cycle 1 (Days 1 and 15),

Biological: FPV-CV301
FPV-CV301 will be given as one subcutaneous injection (1x109 Inf. U/0.5ml) on Day 1starting at cycle 2 through cycle 5 (every 4 weeks) then on Day 1 of every 3 cycles (Cycles 8 and Cycle 11).

Experimental: 3/Disease-Specific Expansion
RP2D of SX-682 + M7824 + CV301
Drug: SX-682
SX-682 will be given orally at designated dose twice a day every day

Drug: M7824
Subjects will receive M7824 at a flat dose of 1,200 mg intravenously on Days 1 and 15 of each cycle.

Biological: MVA-BN-CV301
MVA-BN-CV301 will be given as four subcutaneous injections (4x108 Inf. U/0.5ml twice during Cycle 1 (Days 1 and 15),

Biological: FPV-CV301
FPV-CV301 will be given as one subcutaneous injection (1x109 Inf. U/0.5ml) on Day 1starting at cycle 2 through cycle 5 (every 4 weeks) then on Day 1 of every 3 cycles (Cycles 8 and Cycle 11).




Primary Outcome Measures :
  1. To evaluate the safety and tolerability of single agent SX-682. [ Time Frame: DLT observation period (first 4 weeks) ]
    Dose limiting toxicities and the list of adverse event frequencies

  2. To determine the MTD of SX-682 followed by M7824 and CV301 vaccines in patients with advanced or metastatic solid tumors. [ Time Frame: Period of Safety lead-in (monotherapy) ]
    dose at which no more than 1 of 6 subjects taking SX-682 followed by M7824 and CV301 vaccines experience DLT

  3. To determine the RP2D of SX-682 with M7824 and CV301 vaccines in patients with advanced or metastatic solid tumors. [ Time Frame: 1-2 years ]
    Recommended Phase II dose

  4. To evaluate preliminary efficacy based on objective response rate (ORR), in each disease cohort separately. [ Time Frame: 1-2 years ]
    The fraction of patients who experience a response in each disease-specific cohort will be reported along with 95% two-sided confidenceintervals


Secondary Outcome Measures :
  1. To evaluate preliminary efficacy: disease control rate (DCR; CR+PR+SD) and progression-free survival (PFS) using RECIST1.1. [ Time Frame: 4-5 years ]
    Disease control rate (DCR; CR+PR+SD) and Progression free survival (PFS)

  2. 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) ]
    Drug level in blood



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04574583


Contacts
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Contact: Elizabeth A Lamping (240) 760-6083 elizabeth.lamping@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: James L Gulley, M.D. National Cancer Institute (NCI)
Additional Information:
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT04574583    
Other Study ID Numbers: 200155
20-C-0155
First Posted: October 5, 2020    Key Record Dates
Last Update Posted: October 27, 2020
Last Verified: September 28, 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) ):
Immunotherapy
Checkpoint Inhibitor
Vaccine
Combination Therapy
Metastatic Cancer
Additional relevant MeSH terms:
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Neoplasm Metastasis
Neoplasms
Neoplastic Processes
Pathologic Processes