Clinical Trials /

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

NCT03328026

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Combination Study of SV-BR-1-GM in Combination With INCMGA00012 and Epacadostat
  • 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

Clinical Trial IDs

  • ORG STUDY ID: BRI-ROL-001
  • NCT ID: NCT03328026

Conditions

  • Breast Cancer Female
  • Breast Neoplasm Female

Interventions

DrugSynonymsArms
SV-BR-1-GMINCMGA00012, SV-BR-1-GM combination
INCMGA00012INCMGA00012, SV-BR-1-GM combination
Low dose cyclophosphamideCytoxanINCMGA00012, SV-BR-1-GM combination
Interferon InoculationIntron AINCMGA00012, SV-BR-1-GM combination
Epacadostat 600 mg BIDINCB024360INCMGA00012, Epacadostat 600 mg BID, SV-BR-1-GM combination

Purpose

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).
    

Trial Arms

NameTypeDescriptionInterventions
INCMGA00012, SV-BR-1-GM combinationExperimentalPatients 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
  • SV-BR-1-GM
  • INCMGA00012
  • Low dose cyclophosphamide
  • Interferon Inoculation
INCMGA00012, Epacadostat 600 mg BID, SV-BR-1-GM combinationExperimentalPatients 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
  • SV-BR-1-GM
  • INCMGA00012
  • Low dose cyclophosphamide
  • Interferon Inoculation
  • Epacadostat 600 mg BID
INCMGA00012, Epacadostat, SV-BR-1-GM combination expansionExperimentalPatients 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
  • SV-BR-1-GM
  • INCMGA00012
  • Low dose cyclophosphamide
  • Interferon Inoculation

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:To evaluate the safety of SV-BR-1-GM as assessed by: o Adverse Events (AEs), including Serious Adverse Events (SAEs)

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:Tumor response as assessed by: o Objective response rate (ORR), defined as complete response (CR) or partial response (PR) per RECIST 1.1
Measure: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
Safety Issue:
Description:Tumor response as assessed by: o Non-progressive rate, defined as CR, PR or stable disease (SD) per iRECIST
Measure: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
Safety Issue:
Description:Tumor response as assessed by: o Durability of response

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:BriaCell Therapeutics Corporation

Last Updated

November 20, 2019