Rollover Study of SV-BR-1-GM in Combination With Ipilimumab or Pembrolizumab

Study Description

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Brief Summary:

This is an open-label rollover study of Study WRI-GEV-007, which evaluates SV-BR-1-GM in metastatic or locally recurrent breast cancer patients. Patients who demonstrate progressive disease on Study WRI-GEV-007 will be eligible to enroll in this study, which will evaluate SV-BR-1-GM in combination with pembrolizumab (Keytruda) if their tumors express PD-L1 or PD-L2, or in combination with ipilimumab (Yervoy) if their tumors do not express PD-L1 or PD-L2. Treatment cycles will be every 3 weeks with evaluations for tumor progression or response every 8-12 weeks.

Condition or disease	Intervention/treatment	Phase
Breast Cancer Female; Breast Neoplasm Female	Biological: SV-BR-1-GM; Biological: Pembrolizumab; Biological: Ipilimumab; Drug: Low dose cyclophosphamide; Biological: Interferon Inoculation	Phase 1; Phase 2

Detailed Description:

This is an open-label, single arm roll-over study of Study WRI-GEV-007, "A Phase I/IIa Study of SV-BR-1-GM in Metastatic or Locally Recurrent Breast Cancer Patients". Those patients who have exhibited disease progression according to iRECIST criteria will be eligible to roll over into this study, at the Investigator's discretion. Following discussion with the Sponsor, the Investigator can have the patient treated with one of the following regimens:

1. Combination therapy with pembrolizumab (KEYTRUDA®, anti-PD-1) - for patients with PD-L1 or PD-L2 positive tumors (defined as at least 1% of tumor cells on biopsy or archival material, or 1% of circulating tumor cells, staining positive for PD-L1 or PD-L2).
2. Combination therapy with ipilimumab (YERVOY®, anti-CTLA-4) - for patients with PD-L1 and PD-L2 negative tumors (defined as at less than 1% of tumor cells on biopsy or archival material, or 1% of circulating tumor cells, staining positive for PD-L1 or PD-L2).

The SV-BR-1-GM regimen will be tailored to accommodate the dosing regimen of the immunotherapy, but cannot be more frequent than every 2 weeks, except when approved by the Investigator in consultation with the Sponsor. After the first year of therapy, consideration should be given to decreasing the frequency of therapy (monthly, every 6 weeks, etc.) by the PI in consultation with the Sponsor. 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 Sponsor's approval.

Patients rolling over from Study WRI-GEV-007 will be screened to assure they fulfill the enrollment criteria. Screening must be performed within 30 days of initiating therapy, and imaging studies must be performed within 2 weeks of initiating therapy. Patients will be evaluated every 3 weeks during the study, including all safety assessments. Imaging studies will be performed every 2-3 months (8 - 12 weeks) during study participation. Pharmacodynamic assessments, including evaluation of the immune response to SV-BR-1-GM will also be performed every 3 months. Patients who develop progressive disease may remain on the study if the Investigator feels they are deriving clinical benefit. For patients who come off the study, a final assessment will be carried out 2-4 weeks following the final treatment, including all safety assessments. Subjects will continue to be followed for survival analysis by phone call every 6 months.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	40 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase I/IIa Rollover Study of the Whole-Cell Vaccine SV-BR-1-GM in Metastatic or Locally Recurrent Breast Cancer Patients in Combination With Ipilimumab or Pembrolizumab
Actual Study Start Date :	March 16, 2018
Estimated Primary Completion Date :	December 31, 2020
Estimated Study Completion Date :	December 31, 2020

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Pembrolizumab SV-BR-1-GM combination; Patients with tumors that express PD-L1 or PD-L2 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 pembrolizumab 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: Pembrolizumab; Pembrolizumab will be given 200 mg intravenously either ~2 or ~4 days after SV-BR-1-GM inoculation for up to 24 infusions. Cycles will be every 3 weeks.; Other Name: Keytruda 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: Ipilimumab SV-BR-1-GM combination; Patients with tumors that do not express PD-L1 or PD-L2 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 ipilimumab 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: Ipilimumab; Ipilimumab will be given 3 mg/kg intravenously either ~2 or ~4 days after SV-BR-1-GM inoculation for up to 4 infusions. Cycles will be every 3 weeks.; Other Name: Yervoy 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

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Primary Outcome Measures :

1. Evaluate the Safety of SV-BR-1-GM (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 SV-BR-1-GM as assessed by:

   o Adverse Events (AEs), including Serious Adverse Events (SAEs)

Secondary Outcome Measures :

1. Evaluate the Safety of SV-BR-1-GM (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 SV-BR-1-GM as assessed by:

   o Safety Laboratory Parameters

2. Evaluate the tumor response to SV-BR-1-GM (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)

3. Evaluate the tumor response to SV-BR-1-GM (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

4. Evaluate the tumor response to SV-BR-1-GM (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

5. Evaluate the immune responses elicited by SV-BR-1-GM (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

6. Evaluate the immune responses elicited by SV-BR-1-GM (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 SV-BR-1

7. Evaluate the immune responses elicited by SV-BR-1-GM (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

8. Evaluate patient characteristics (HLA type) that may be predictive of responses to SV-BR-1-GM 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

9. Evaluate tumor characteristics that may be predictive of responses to SV-BR-1-GM 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

10. Evaluate Quality of Life (QOL) in patients administered SV-BR-1-GM 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)

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Has been a participant in Study WRI-GEV-007, "A Phase I/IIa Study of SV-BR-1-GM in Metastatic or Locally Recurrent Breast Cancer Patients"

2. Have histological confirmation of breast cancer with recurrent and/or metastatic lesions via investigational site which has failed prior therapy.

   • Patients with persistent disease and local recurrence must not be amenable to local treatment.

   • For patients with metastatic disease:

     • 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 containing at least two anti-HER2 agents (e.g. trastuzumab and pertuzumab).
     • HER2 negative and either ER or PR positive tumors: must be refractory to hormonal therapy (e.g. aromatase inhibitor, tamoxifen or fulvestrant) and previously treated with at least 2 chemotherapy containing regimens.
     • HER2 positive and ER and PR negative tumors: must have failed at least 2 regimens containing at least two anti-HER2 agents (e.g. trastuzumab and pertuzumab).
     • 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 brain will be eligible provided:

   1. Must have received prior radiation therapy for brain metastases or be ineligible for radiation therapy
   2. There is no need for steroids and patients have not had steroids at least 2 weeks
   3. No individual tumor size is >50 mm3
   4. ECOG status <3
   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 study may be introduced at any time should the patients develop new or clearly worsening symptoms and/or introduction of steroids
3. Have evidence of persistent, recurrent, or progressive disease for which there is no known or established treatment available with curative intent, after failing at least one course of community standard systemic treatment with chemotherapy (and endocrine therapy if appropriate)
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 0-2)
7. Have provided written informed consent

Exclusion Criteria:

1. Concurrent or recent chemotherapy, radiotherapy, or general anesthesia/major surgery within 3 weeks. 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 persons receiving nitrosourea or mitomycin).
2. 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 the experimental vaccine.
3. History of clinical hypersensitivity to the immunotherapy proposed for combination treatment.
4. BUN >30 in conjunction with a creatinine >2.
5. Absolute granulocyte count < 1000; platelets <100,000.
6. Bilirubin >2.0; alkaline phosphatase >5x upper limit of normal (ULN); ALT/AST >2x ULN. For patients with hepatic metastases, ALT/AST >5x ULN is exclusionary.
7. 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.
8. New York Heart Association stage 3 or 4 cardiac disease.
9. A pleural effusion of moderate severity or worse.
10. Proteinuria >1+ on urinalysis or >1 gm/24hr.
11. Any woman of childbearing potential, unless she: Agrees to take appropriate precautions to avoid becoming pregnant (with at least 99% certainty) during the study and has a negative serum pregnancy test within 7 days prior to starting treatment.
12. Women who are pregnant or nursing.
13. Patients with concurrent second malignancy. Persons with previous malignancies effectively treated and not requiring treatment for >24 months are eligible, provided there is unambiguous documentation that current local recurrence or metastatic site represents recurrence of the primary breast malignancy.
14. Patients who are HIV positive (by self-report) or have clinical or laboratory features indicative of AIDS.
15. Patients who require anticoagulation or systemic steroids at doses >10 mg daily of prednisone or equivalent or any immunosuppressive drugs. 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.
16. Patients who are on treatment for an autoimmune disease, unless specifically approved by the Investigator and the Sponsor.
17. Patients with a history of colitis.
18. Patients with severe psychiatric (i.e. schizophrenia, bipolar, or borderline personality disorder) or other clinically progressive major medical problems, unless approved by the Investigator.

18. Male breast cancer patients. 19. Patients may not be on a concurrent clinical trial, unless approved by Investigator.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Karen Arrington, RN BSN CCRP	210-243-5711	karrington@cancerinsight.com
Contact: George E Peoples, MD, FACS	210.557.4291	gpeoples@cancerinsight.com

Locations

United States, California
St. Joseph Heritage Healthcare	Recruiting
Santa Rosa, California, United States, 95403
Contact: Jennafer Carlin-Rosset, MPH 707-521-3830 Jennafer.Carlin@stjoe.org
Contact: Kim Young, RN, CCRC 707-521-3830 Kimberly.Young@stjoe.org
Principal Investigator: Jarrod P Holmes, M.D.

Sponsors and Collaborators

BriaCell Therapeutics Corporation

Cancer Insight, LLC

Investigators

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

More Information

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Additional Information:

Sponsor Website 

CRO Website 

Responsible Party:	BriaCell Therapeutics Corporation
ClinicalTrials.gov Identifier:	NCT03328026 History of Changes
Other Study ID Numbers:	BRI-ROL-001
First Posted:	November 1, 2017
Last Update Posted:	March 20, 2018
Last Verified:	March 2018
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; Cyclophosphamide; Pembrolizumab; Interferons; Antibodies, Monoclonal; 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