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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 : November 22, 2019
Sponsor:
Collaborator:
Cancer Insight, LLC
Information provided by (Responsible Party):
BriaCell Therapeutics Corporation

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.

Condition or disease Intervention/treatment Phase
Breast Cancer Female Breast Neoplasm Female Biological: SV-BR-1-GM Biological: INCMGA00012 Drug: Low dose cyclophosphamide Biological: Interferon Inoculation Drug: Epacadostat 600 mg BID Phase 1 Phase 2

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).


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : March 16, 2018
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
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
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

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
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

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
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




Primary Outcome Measures :
  1. 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)


  2. 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


  3. 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


  4. 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)



Secondary Outcome Measures :
  1. 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


  2. 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


  3. 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




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:   Female
Accepts Healthy Volunteers:   No
Criteria

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.

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): NCT03328026


Contacts
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Contact: Katie L Lyon, MS, CCRP 210-952-6301 Klyon@cancerinsight.com
Contact: Sherri Thomas, RN BSN CCRP (210) 844-5861 sthomas@cancerinsight.com

Locations
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United States, California
St. Joseph Heritage Healthcare Recruiting
Santa Rosa, California, United States, 95403
Contact: Kimberly Young, BS, RN, CCRC    707-521-3830    kimberly.young@stjoe.org   
Contact: Kayla Cordes    707-521-3829    Kayla.Cordes@stjoe.org   
Principal Investigator: Jarrod P Holmes, M.D.         
United States, Florida
University of Miami/Sylvester at Plantation Recruiting
Plantation, Florida, United States, 33324
Contact: Deborah M Conte, CCRC    954-210-1171    dmc238@med.miami.edu   
Principal Investigator: Carmen J Calfa, MD         
United States, Kansas
Cancer Center of Kansas (CCK) Recruiting
Wichita, Kansas, United States, 67214
Contact: Susan Weber, RN, BSN    316-613-4318    susan.weber@cancercenterofkansas.com   
Contact: John Taylor    316-268-1230    John.Taylor@cancercenterofkansas.com   
Principal Investigator: Shaker Dakhil, MD         
Sponsors and Collaborators
BriaCell Therapeutics Corporation
Cancer Insight, LLC
Investigators
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Study Director: George E Peoples, MD, FACS Cancer Insight, LLC

Additional Information:
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Responsible Party: BriaCell Therapeutics Corporation
ClinicalTrials.gov Identifier: NCT03328026     History of Changes
Other Study ID Numbers: BRI-ROL-001
First Posted: November 1, 2017    Key Record Dates
Last Update Posted: November 22, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Interferons
Cyclophosphamide
Vaccines
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antiviral Agents
Anti-Infective Agents