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

• ClinicalTrials.gov Identifier: NCT03328026
• Recruitment Status: Recruiting
• First Posted: November 1, 2017
• Last Update Posted: November 22, 2019
• Sponsor: BriaCell Therapeutics Corporation
• Collaborator: Cancer Insight, LLC
• Information provided by (Responsible Party): BriaCell Therapeutics Corporation

Study Description

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).

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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

Eligibility Criteria

• 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.

Contacts and Locations

Contacts

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

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

• Study Director: George E Peoples, MD, FACS; Cancer Insight, LLC

More Information

Additional Information:

Sponsor Website  CRO Website 

• Responsible Party: BriaCell Therapeutics Corporation
• ClinicalTrials.gov Identifier: NCT03328026
• Other Study ID Numbers: BRI-ROL-001
• First Posted: November 1, 2017
• Last Update Posted: November 22, 2019
• Last Verified: January 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

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