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Combination Study of SV-BR-1-GM in Combination With INCMGA00012 and Epacadostat

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ClinicalTrials.gov Identifier: NCT03328026
Recruitment Status : Recruiting
First Posted : November 1, 2017
Last Update Posted : March 11, 2021
Sponsor:
Collaborator:
Cancer Insight, LLC
Information provided by (Responsible Party):
BriaCell Therapeutics Corporation

Tracking Information
First Submitted Date  ICMJE October 23, 2017
First Posted Date  ICMJE November 1, 2017
Last Update Posted Date March 11, 2021
Actual Study Start Date  ICMJE March 16, 2018
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 30, 2019)
  • Evaluate the Adverse Events (AEs), including Serious Adverse Events (SAEs), that occur in patients treated with SV-BR-1-GM administered in combination with INCMGA00012 and epacadostat [Safety] [ Time Frame: Through study completion, an average of 1 year ]
    To evaluate the safety of SV-BR-1-GM as assessed by: o Adverse Events (AEs), including Serious Adverse Events (SAEs)
  • Evaluate the Proportion of Patients with Abnormalities in Safety Laboratory Parameters that occur in patients treated with SV-BR-1-GM administered in combination with INCMGA00012 and epacadostat [Safety] [ Time Frame: Through study completion, an average of 1 year ]
    To evaluate the safety of SV-BR-1-GM as assessed by: o The Proportion of Patients with Abnormalities in Safety Laboratory Parameters
  • Evaluate changes in the electrocardiogram QT interval that occur in patients treated with SV-BR-1-GM administered in combination with INCMGA00012 and epacadostat [Safety] [ Time Frame: Through study completion, an average of 1 year ]
    To evaluate the safety of SV-BR-1-GM as assessed by: o Electrocardiograms (ECG) with measurement of the QT interval
  • Evaluate the changes in weight that occur in patients treated with SV-BR-1-GM administered in combination with INCMGA00012 and epacadostat [Safety] [ Time Frame: Through study completion, an average of 1 year ]
    To evaluate the safety of SV-BR-1-GM as assessed by: o Weight (Kg)
Original Primary Outcome Measures  ICMJE
 (submitted: October 27, 2017)
  • Evaluate the Safety of BriaVax™ (Adverse Events) when administered in combination with ipilimumab (for patients with PD-L1/2- tumors) or pembrolizumab (for patients with PD-L1/2+ tumors) [Safety] [ Time Frame: Through study completion, an average of 1 year ]
    To evaluate the safety of BriaVax™ as assessed by: o Adverse Events (AEs), including Serious Adverse Events (SAEs)
  • Evaluate the Safety of BriaVax™ (Laboratory Parameters) when administered in combination with ipilimumab (for patients with PD-L1/2- tumors) or pembrolizumab (for patients with PD-L1/2+ tumors) [Safety] [ Time Frame: Through study completion, an average of 1 year ]
    To evaluate the safety of BriaVax™ as assessed by: o Safety Laboratory Parameters
  • Evaluate the Safety of BriaVax™ (Physical Examination) when administered in combination with ipilimumab (for patients with PD-L1/2- tumors) or pembrolizumab (for patients with PD-L1/2+ tumors) [Safety] [ Time Frame: Through study completion, an average of 1 year ]
    To evaluate the safety of BriaVax™ as assessed by: o Physical Examination
  • Evaluate the Safety of BriaVax™ (Vital Signs) when administered in combination with ipilimumab (for patients with PD-L1/2- tumors) or pembrolizumab (for patients with PD-L1/2+ tumors) [Safety] [ Time Frame: Through study completion, an average of 1 year ]
    To evaluate the safety of BriaVax™ as assessed by: o Vital Signs
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 27, 2019)
  • Evaluate the tumor response to SV-BR-1-GM (ORR) when administered in combination with INCMGA00012 and epacadostat [ Time Frame: Through study completion, an average of 1 year ]
    Tumor response as assessed by: o Objective response rate (ORR), defined as complete response (CR) or partial response (PR) per RECIST 1.1
  • Evaluate the tumor response to SV-BR-1-GM (Non-progression) when administered in combination with INCMGA00012 and epacadostat [ Time Frame: Through study completion, an average of 1 year ]
    Tumor response as assessed by: o Non-progressive rate, defined as CR, PR or stable disease (SD) per iRECIST
  • Evaluate the tumor response to SV-BR-1-GM (Durability) when administered in combination with INCMGA00012 and epacadostat [ Time Frame: Through study completion, an average of 1 year ]
    Tumor response as assessed by: o Durability of response
Original Secondary Outcome Measures  ICMJE
 (submitted: October 27, 2017)
  • To evaluate the tumor response to BriaVax™ (ORR) when administered in combination with ipilimumab (for patients with PD-L1/2- tumors) or pembrolizumab (for patients with PD L1/2+ tumors) [ Time Frame: Through study completion, an average of 1 year ]
    Tumor response as assessed by: o Objective response rate (ORR), defined as complete response (CR) or partial response (PR) per immune-related response criteria (iRECIST)
  • To evaluate the tumor response to BriaVax™ (Non-progression) when administered in combination with ipilimumab (for patients with PD-L1/2- tumors) or pembrolizumab (for patients with PD L1/2+ tumors) [ Time Frame: Through study completion, an average of 1 year ]
    Tumor response as assessed by: o Non-progressive rate, defined as CR, PR or stable disease (SD) per iRECIST
  • To evaluate the tumor response to BriaVax™ (Durability of response) when administered in combination with ipilimumab (for patients with PD-L1/2- tumors) or pembrolizumab (for patients with PD L1/2+ tumors) [ Time Frame: Through study completion, an average of 1 year ]
    Tumor response as assessed by: o Durability of response, by evaluating those patients eligible to complete the optional treatments from 9-12 months
  • To evaluate the immune responses elicited by BriaVax™ (DTH) when administered in combination with ipilimumab (for patients with PD-L1/2- tumors) or pembrolizumab (for patients with PD-L1/2+ tumors) [ Time Frame: Through study completion, an average of 1 year ]
    Immune responses as assessed by: o Delayed type hypersensitivity (DTH) skin tests
  • To evaluate the immune responses elicited by BriaVax™ (T cell responses) when administered in combination with ipilimumab (for patients with PD-L1/2- tumors) or pembrolizumab (for patients with PD-L1/2+ tumors) [ Time Frame: Through study completion, an average of 1 year ]
    Immune responses as assessed by: o T cell responses to BriaTest™ (SV-BR-1)
  • To evaluate the immune responses elicited by BriaVax™ (other immunological tests) when administered in combination with ipilimumab (for patients with PD-L1/2- tumors) or pembrolizumab (for patients with PD-L1/2+ tumors) [ Time Frame: Through study completion, an average of 1 year ]
    Immune responses as assessed by: o Other immunological tests
  • To evaluate patient characteristics (HLA type) that may be predictive of responses to BriaVax™ when administered in combination with ipilimumab (for patients with PD-L1/2- tumors) or pembrolizumab (for patients with PD-L1/2+ tumors) [ Time Frame: Through study completion, an average of 1 year ]
    Patient characteristics including: o Human Leukocyte Antigen (HLA) type
  • To evaluate tumor characteristics that may be predictive of responses to BriaVax™ when administered in combination with ipilimumab (for patients with PD-L1/2- tumors) or pembrolizumab (for patients with PD-L1/2+ tumors) [ Time Frame: Through study completion, an average of 1 year ]
    Patient and tumor characteristics including: o Tumor expression of PD-L1, PD-L2 and cancer/testis antigens such as PRAME
  • To evaluate Quality of Life (QOL) in patients administered BriaVax™ in combination with ipilimumab (for patients with PD-L1/2- tumors) or pembrolizumab (for patients with PD-L1/2+ tumors) [ Time Frame: Through study completion, an average of 1 year ]
    Quality of Life as assessed by the Short Form 36 (SF36)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Combination Study of SV-BR-1-GM in Combination With INCMGA00012 and Epacadostat
Official Title  ICMJE A Phase I/IIa Study of the SV-BR-1-GM Regimen in Metastatic or Locally Recurrent Breast Cancer Patients in Combination With INCMGA00012 and Epacadostat
Brief Summary This is an open-label study of Study WRI-GEV-007, which evaluates SV-BR-1-GM in metastatic or locally recurrent breast cancer patients, in combination with the PD-1 inhibitor INCMGA00012 and the IDO inhibitor epacadostat. Patients who with advanced breast cancer who have failed prior therapies will be eligible to enroll in this study. The study will evaluate SV-BR-1-GM in combination with INCMGA00012 and epacadostat. Treatment cycles will be every 3 weeks with evaluations for tumor progression or response every 6-12 weeks.
Detailed Description

This is an open-label, single arm study of the SV-BR-1-GM regimen in combination with INCMGA00012 and epacadostat in patients with metastatic or locally recurrent breast cancer who have failed at least two lines of therapy.

Patients will receive the SV-BR-1-GM regimen with combination immunotherapy. There will be an initial evaluation of the combination of the SV-BR-1-GM regimen with INCMGA00012 every 3 weeks. If this is found to be safe and well tolerated in a cohort of at least 6 patients (dose-limiting toxicities (DLTs) in less than 30% of the patients evaluated), then a triple combination of the SV-BR-1-GM regimen with INCMGA00012 and epacadostat will be evaluated in a cohort of 6 patients. If the DLT rate remains below 30%, additional higher dose levels of epacadostat will be explored. Once a dose of epacadostat has been determined that is safe and reliably normalizes plasma kynurenine levels, the study will expand to treat an additional 36 patients. If DLTs are seen in 30% or more of patients, the dose of epacadostat will be further reduced and an additional cohort of 6 patients evaluated in a stepwise fashion until a safe dose level is determined. Once the recommended phase II dose is determined, the study will expand to treat an additional 36 patients.

The SV-BR-1-GM regimen consists of:

  1. Pre- SV-BR-1-GM cyclophosphamide 2-3 days prior to SV-BR-1-GM inoculation
  2. SV-BR-1-GM inoculation
  3. Interferon-alpha-2b - at the inoculation sites 2 (±1 day) post-SV-BR-1-GM
  4. Interferon-alpha-2b - at the inoculation sites 4 (±1 day) post-SV-BR-1-GM

The SV-BR-1-GM regimen will be administered with the following combination immunotherapy regimen:

  1. Combination therapy with INCMGA00012 (anti-PD-1)
  2. Combination therapy with epacadostat (IDO inhibitor)

The SV-BR-1-GM regimen with INCMGA00012 will be administered every 21 days (± 3 days), except when approved by the Investigator in consultation with the medical monitor. Epacadostat will be dosed twice daily and will continue through each cycle. Note that hormonal therapy (e.g., aromatase inhibitors) is permitted if ongoing, but may be added while the patient is on this study only with the medical monitor's approval (e.g. for hormone receptor positive patients who are deriving clinical benefit but have not achieved a CR after >6 cycles of therapy).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Breast Cancer Female
  • Breast Neoplasm Female
Intervention  ICMJE
  • Biological: SV-BR-1-GM
    SV-BR-1-GM inoculation intradermally in 4 sites on the upper back (x2) and thighs (x2).
  • Biological: INCMGA00012
    INCMGA00012 will be given 375 mg intravenously either ~2 or ~4 days after SV-BR-1-GM inoculation for up to 24 infusions. Cycles will be every 3 weeks.
  • Drug: Low dose cyclophosphamide
    Pretreatment with low dose cyclophosphamide 2-3 days prior to SV-BR-1-GM inoculation.
    Other Name: Cytoxan
  • Biological: Interferon Inoculation
    Post-inoculation low dose Interferon-alpha-2b into the vaccination sites ~2 and ~4 days after SV-BR-1-GM inoculation.
    Other Name: Intron A
  • Drug: Epacadostat 600 mg BID
    Epacadostat 600 mg twice daily given orally
    Other Name: INCB024360
Study Arms  ICMJE
  • Experimental: INCMGA00012, SV-BR-1-GM combination
    Patients will be treated with the SV-BR-1-GM regimen (including pre-treatment with low dose cyclophosphamide and post-treatment Interferon inoculation) in combination with INCMGA00012 with cycles every 3 weeks
    Interventions:
    • Biological: SV-BR-1-GM
    • Biological: INCMGA00012
    • Drug: Low dose cyclophosphamide
    • Biological: Interferon Inoculation
  • Experimental: INCMGA00012, Epacadostat 600 mg BID, SV-BR-1-GM combination
    Patients will be treated with the SV-BR-1-GM regimen (including pre-treatment with low dose cyclophosphamide and post-treatment Interferon inoculation) in combination with INCMGA00012 and epacadostat 600 mg BID with cycles every 3 weeks
    Interventions:
    • Biological: SV-BR-1-GM
    • Biological: INCMGA00012
    • Drug: Low dose cyclophosphamide
    • Biological: Interferon Inoculation
    • Drug: Epacadostat 600 mg BID
  • Experimental: INCMGA00012, Epacadostat, SV-BR-1-GM combination expansion
    Patients will be treated with the SV-BR-1-GM regimen (including pre-treatment with low dose cyclophosphamide and post-treatment Interferon inoculation) in combination with INCMGA00012 and epacadostat (dose to be determined) with cycles every 3 weeks
    Interventions:
    • Biological: SV-BR-1-GM
    • Biological: INCMGA00012
    • Drug: Low dose cyclophosphamide
    • Biological: Interferon Inoculation
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 27, 2019)
60
Original Estimated Enrollment  ICMJE
 (submitted: October 27, 2017)
40
Estimated Study Completion Date  ICMJE December 31, 2022
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Have histological confirmation of breast cancer with recurrent and/or metastatic lesions, as per the investigational site, and have failed prior therapy.
  2. Patients with persistent disease and local recurrence must not be amenable to local treatment.
  3. For patients with metastatic disease:

    1. Human epidermal growth factor 2 (HER2) positive and estrogen receptor (ER) or progesterone receptor (PR) positive tumors: must be refractory to hormonal therapy (e.g., aromatase inhibitor, tamoxifen or fluvestrant) and previously treated with at least 2 regimens including at least two anti-HER2 agents (e.g., trastuzumab and pertuzumab).
    2. HER2 negative and either ER or PR positive tumors: must be refractory to hormonal therapy (e.g. aromatase inhibitor, tamoxifen or fluvestrant) and previously treated with at least 2 chemotherapy containing regimens.
    3. HER2 positive and ER and PR negative tumors: must have failed at least 2 regimens including at least two anti-HER2 agents (e.g., trastuzumab and pertuzumab).
    4. Triple Negative tumors: Must have exhausted other available therapies including prior treatment with a taxane and carboplatin.

    Patients with new or progressive breast cancer metastatic to the brain will be eligible provided:

    1. The brain metastases must be clinically stable (without evidence of progressive disease by imaging) for at least 4 weeks prior to first dose
    2. Must have received prior radiation therapy for brain metastases or be ineligible for radiation therapy
    3. There is no need for steroids and patients have not had steroids for at least 2 weeks
    4. No individual tumor size is >50 mm
    5. Tumor is not impinging on Middle Cerebral Artery/speech-motor strip
    6. If surgically debulked, must be healed from surgery and at least 3 weeks have elapsed since general anesthesia
    7. Patients consent to MRI studies at 3-4 week intervals until evidence of tumor regression on at least 2 imaging studies. In no case, will the interval between MRI studies be longer than 3 months. MRI studies may be introduced at any time should the patients develop new or clearly worsening symptoms and/or introduction of steroids
  4. Be 18 years of age or older and female
  5. Have expected survival of at least 4 months
  6. Have adequate performance status (ECOG 0-1)
  7. Have provided written informed consent

Exclusion Criteria:

  1. Concurrent or recent chemotherapy, immunotherapy (except the SV-BR-1-GM regimen), or general anesthesia/major surgery within 21 days. Patients must have recovered from all known or expected toxicities from previous treatment and passed a treatment-free "washout" period of 3 weeks before starting this program (8 weeks for patients receiving nitrosourea or mitomycin). Prior immune related toxicity should not have exceeded Grade 2 (with exception of endocrinopathy).
  2. Radiotherapy within 14 days of first dose of study treatment with the following caveats:

    1. 28 days for pelvic radiotherapy.
    2. 8 weeks for brain metastases
    3. 6 months for thoracic region radiotherapy that is > 30 Gy in 2 Gy fractions.
  3. Toxicity of prior therapy that has not recovered to ≤ Grade 1 or baseline (with the exception of any grade of alopecia and anemia not requiring transfusion support). Endocrinopathy, if well-managed, is not exclusionary and should be discussed with medical monitor.
  4. Participant has not recovered adequately from toxicities and/or complications from surgical intervention before starting study drug.
  5. History of clinical hypersensitivity to the designated combination immunotherapy, GM-CSF, Interferon-alpha-2b (Merck), yeast, beef, or to any components used in the preparation of SV-BR-1-GM.
  6. History of clinical hypersensitivity to any of the immunotherapies proposed for combination treatment or their excipients.
  7. Known hypersensitivity to another monoclonal antibody that cannot be controlled with standard measures (e.g., antihistamines and corticosteroids) or known allergy or hypersensitivity to any component of INCMGA00012 or formulation components.
  8. Serum creatinine OR Measured or calculated Creatinine Clearance (CrCl) (GFR can also be used in place of creatinine or CrCl) >1.5 × ULN OR <30 mL/min for participants with creatinine levels >1.5 × institutional ULN.
  9. Absolute granulocyte count <1500; platelets <100,000; hemoglobin ≤ 9 g/L.
  10. Bilirubin ≥ 1.5 × ULN unless conjugated bilirubin ≤ ULN; alkaline phosphatase >5x upper limit of normal (ULN); ALT/AST >2x ULN. For patients with hepatic metastases, ALT/AST >5x ULN is exclusionary.
  11. INR or PT or aPTT > 1.5 × ULN, unless the participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants. Note: See the restricted medications list in protocol section 5.9. If an alternative cannot be found, the participant cannot be enrolled.
  12. Receiving any medication listed in the prohibited medication (section 5.10 of the protocol).
  13. Participants may not have a history of serotonin syndrome after receiving 1 or more serotonergic drugs.
  14. Proteinuria >1+ on urinalysis or >1 gm/24hr.
  15. Have a history or presence of an abnormal electrocardiogram (ECG) that, in the investigator's opinion, is clinically meaningful. Screening corrected QT interval (QTc) interval >480 milliseconds is excluded (corrected by Fridericia or Bazett formula). In the event that a single QTc is >480 milliseconds, the participant may enroll if the average QTc for the 3 ECGs is <480 milliseconds.
  16. Left ventricular ejection fraction (LVEF as determined by cardiac echo or MUGA scan) below the normal limits of the institutions' specific testing range. This assessment may be repeated once at the discretion of the Investigator with the approval of the Sponsor.
  17. New York Heart Association stage 3 or 4 cardiac disease.
  18. A pericardial effusion of moderate severity or worse.
  19. Symptomatic pleural effusion or ascites. A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
  20. Any woman of childbearing potential (i.e., has had a menstrual cycle within the past year and has not been surgically sterilized), unless she: agrees to take appropriate precautions to avoid becoming pregnant during the study (with at least 99% certainty, see Appendix A for permitted methods) and has a negative serum pregnancy test within 7 days prior to starting treatment.
  21. Women who are pregnant or nursing.
  22. Known additional malignancy that is progressing or requires active treatment, or history of other malignancy within 3 years of study entry with the exception of cured basal cell or squamous cell carcinoma of the skin, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or indolent malignancy, or cancers from which the participant has been disease-free for > 1 year, after treatment with curative intent.
  23. Patients who are HIV positive (by self-report) or have clinical or laboratory features indicative of AIDS.
  24. Have a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study treatment.

    a. Beta-blocker therapy, while not exclusionary, is discouraged and alternatives should be sought if possible. The beta-blocker might compromise use of epinephrine for the rare possibility of anaphylaxis.

  25. Has had an allogeneic tissue/solid organ transplant.
  26. Have an active autoimmune disease that has required systemic treatment in 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 allowed.
  27. Patients with a history of colitis.
  28. Has a history of (non-infectious) pneumonitis that required systemic steroids or current pneumonitis/interstitial lung disease.
  29. Known active HBA, HBV, or HCV infection, as defined by elevated transaminases with the following serology: positivity for HAV IgM antibody, anti-HCV, anti-HBc IgG or IgM, or HBsAg (in the absence of prior immunization).
  30. Active infections requiring systemic therapy.

    a. All antibiotic therapy within 28 days of initiating treatment must be recorded

  31. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
  32. Patients with severe psychiatric (e.g., schizophrenia, bipolar, or borderline personality disorder) or other clinically progressive major medical problems, unless approved by the Investigator in consultation with the medical monitor.
  33. Has received a live vaccine within 28 days of the planned start of study drug. Note: examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox/zoster, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live-attenuated vaccines and are not allowed.
  34. Male breast cancer patients.
  35. Patients may not be on a concurrent clinical trial, unless approved by the Investigator.
  36. Has a history of a gastrointestinal condition or procedure that in the opinion of the Investigator may affect oral drug absorption.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Katie L Lyon, MS, CCRP 210-952-6301 Klyon@cancerinsight.com
Contact: Sherri Thomas, RN BSN CCRP (210) 844-5861 sthomas@cancerinsight.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03328026
Other Study ID Numbers  ICMJE BRI-ROL-001
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party BriaCell Therapeutics Corporation
Study Sponsor  ICMJE BriaCell Therapeutics Corporation
Collaborators  ICMJE Cancer Insight, LLC
Investigators  ICMJE
Study Director: George E Peoples, MD, FACS Cancer Insight, LLC
PRS Account BriaCell Therapeutics Corporation
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP