Cyclophosphamide and Vaccine Therapy With or Without Trastuzumab in Treating Patients With Metastatic Breast Cancer

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Tracking Information

• First Submitted Date: September 3, 2009
• First Posted Date: September 4, 2009
• Results First Submitted Date: February 15, 2019
• Results First Posted Date: March 12, 2019
• Last Update Posted Date: March 12, 2019
• Study Start Date: July 2009
• Actual Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 15, 2019)

• Toxicity as Assessed by Number of Grade 3 or 4 Adverse Events [ Time Frame: 3 years ]
  Number of grade 3 or 4 nonhematologic toxicity (except alopecia), or any grade 4 hematologic toxicity as defined by NCI CTCAE v3.0
• Clinical Benefit (CB) as Assessed by Progression Free Survival at Six Months [ Time Frame: 6 months post-intervention ]
  Progression-free survival is measured as percentage of participants with stable disease or complete response, as defined by RECIST criteria, six months after receiving last vaccination.
• HER-2/Neu-specific Immune Responses as Measured by Number of Participants With Positive for Delayed-type Hypersensitivity (DTH) Response [ Time Frame: 3 years ]
• Pharmacodynamics of Peripheral CD4+CD25+ Regulatory T Cells [ Time Frame: 3 years ]

Original Primary Outcome Measures (submitted: September 3, 2009)

• Toxicity as assessed by NCI CTCAE v3.0
• Progression-free survival at 6 months
• HER-2/neu-specific immune responses
• Pharmacodynamics of Peripheral CD4+CD25+ Regulatory T Cells

• Change History: Complete list of historical versions of study NCT00971737 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: June 28, 2011)

• Immune Priming in In-vivo Vaccine-site Biopsies [ Time Frame: 3 years ]
• Enumeration of CD8+ T Cells Specific for hTERT by ELISPOT [ Time Frame: 3 years ]
• Characterization of the T-cell Memory Pool Pre- and Post-vaccination [ Time Frame: 3 years ]

Original Secondary Outcome Measures (submitted: September 3, 2009)

• Immune Priming in In-vivo Vaccine-site Biopsies
• Enumeration of CD8+ T Cells Specific for hTERT by ELISPOT
• Characterization of the T-cell Memory Pool Pre- and Post-vaccination

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Cyclophosphamide and Vaccine Therapy With or Without Trastuzumab in Treating Patients With Metastatic Breast Cancer
• Official Title: A Randomized, Open-Label Comparative Study of Combination Therapy With Cyclophosphamide and an Allogeneic GM-CSF-secreting Breast Tumor Vaccine With or Without Trastuzumab for the Treatment of Metastatic Breast Cancer That Does NOT Over-express HER-2/Neu

Brief Summary

RATIONALE: Vaccines made from gene-modified tumor cells may help the body build an effective immune response to kill tumor cells. Biological therapies, such as cyclophosphamide and trastuzumab, may increase the number of immune cells and make the immune response stronger. It is not yet known whether giving cyclophosphamide together with vaccine therapy is more effective with or without trastuzumab in treating patients with metastatic breast cancer.

PURPOSE: This randomized phase II trial is studying the side effects of giving cyclophosphamide together with vaccine therapy and to see how well it works compared with giving cyclophosphamide and vaccine therapy together with trastuzumab in treating patients with metastatic breast cancer.

Detailed Description

OBJECTIVES:

Primary

• To evaluate the safety of cyclophosphamide-modulated vaccination with vs without trastuzumab in patients with breast cancer that does not overexpress HER-2/neu.
• To compare the clinical benefit of cyclophosphamide-modulated vaccination with vs without trastuzumab in these patients.
• To measure HER-2/neu-specific CD4+ and CD8+ T-cell immunity by delayed-type hypersensitivity (DTH) and ELISPOT.
• To measure the pharmacodynamics of CD4+CD25+ regulatory T cells by flow cytometry.

Secondary

• To assess the impact of trastuzumab on immune priming in vivo by immunohistochemistry of vaccine-site biopsies at day +3 and day +7 of courses 1 and 3 on the two study arms, comparing cellular infiltrates to those seen in previous preclinical and clinical models.
• To measure hTERT-specific CD8+ T-cell immunity by ELISPOT.
• To characterize the peripheral-memory T-cell pool.

Tertiary

• To determine baseline and change in vaccine site-draining lymph node immunohistology and gene expression profile.
• To develop the tandem tetramer/CD107a cytotoxicity assay for HER-2/neu-specific CD8+ T cells.
• To measure novel T-cell responses induced by trastuzumab and cyclophosphamide-modulated vaccination.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive cyclophosphamide IV over 30 minutes on day -1 and allogeneic GM-CSF-secreting breast cancer vaccine intradermally on day 0. Courses repeat every 4-6 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive a fourth vaccination at 6-8 months.
• Arm II: Patients receive cyclophosphamide and the vaccine as in arm I and trastuzumab IV over 30-90 minutes on day -1. Courses repeat every 4-6 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive a fourth vaccination at 6-8 months.

Skin punch and lymph node biopsies are collected at baseline and on days +3 and +7 of courses 1 and 3 for biomarker analysis.

After completion of study treatment, patients are followed periodically.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Biological: allogeneic GM-CSF-secreting breast cancer vaccine
  Given intradermally
• Biological: trastuzumab
  Given IV
• Drug: cyclophosphamide
  Given IV

Study Arms

• Active Comparator: Cyclophosphamide and Vaccine only
  Patients receive cyclophosphamide IV over 30 minutes on day -1 and allogeneic GM-CSF-secreting breast cancer vaccine intradermally on day 0. Courses repeat every 4-6 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive a fourth vaccination at 6-8 months.
  Interventions:

  • Biological: allogeneic GM-CSF-secreting breast cancer vaccine
  • Drug: cyclophosphamide
• Experimental: Cyclophosphamide, Vaccine and Trastuzumab
  Patients receive cyclophosphamide and the vaccine as in arm I and trastuzumab IV over 30-90 minutes on day -1. Courses repeat every 4-6 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive a fourth vaccination at 6-8 months.
  Interventions:

  • Biological: allogeneic GM-CSF-secreting breast cancer vaccine
  • Biological: trastuzumab
  • Drug: cyclophosphamide

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 15, 2019): 63
• Original Estimated Enrollment (submitted: September 3, 2009): 60
• Actual Study Completion Date: March 2016
• Actual Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

DISEASE CHARACTERISTICS:

• Histologically confirmed adenocarcinoma of the breast

  • Does not overexpress HER-2/neu, defined as FISH negative or 0, 1+, or 2+ by IHC
  • Stage IV disease
• Must not be eligible for therapy of known curative potential for metastatic breast cancer
• Measurable or evaluable disease
• Stable CNS disease allowed provided that it's adequately treated and not under active treatment
• Hormone receptor status not specified

PATIENT CHARACTERISTICS:

• Menopausal status not specified
• ECOG performance status 0-1
• ANC > 1,000/mm^3
• Platelets > 100,000/mm^3
• Serum bilirubin < 2.0 mg/dL (unless due to Gilbert syndrome)
• AST and ALT < 2 times upper limit of normal (ULN)
• Alkaline phosphatase < 5 times ULN
• Serum creatinine < 2.0 mg/dL
• Ejection fraction normal by MUGA OR ≥ 50% by echocardiogram
• Not pregnant or nursing
• Fertile patients must use effective contraception
• HIV negative
• Asthma or chronic obstructive pulmonary disease that does not require daily systemic corticosteroids allowed

• No prior or concurrent autoimmune disease requiring management with systemic immunosuppression, including any of the following:

  • Inflammatory bowel disease
  • Systemic vasculitis
  • Scleroderma
  • Psoriasis
  • Multiple sclerosis
  • Hemolytic anemia or immune-mediated thrombocytopenia
  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Sjogren syndrome
  • Sarcoidosis
  • Other rheumatologic disease
• No other malignancies within the past 5 years, except carcinoma in situ of the cervix, superficial nonmelanoma skin cancer, superficial bladder cancer, or tamoxifen-related endometrial cancer that has been adequately treated
• No active major medical or psychosocial problems that could be complicated by study participation
• No symptomatic intrinsic lung disease or extensive tumor involvement of the lungs resulting in dyspnea at rest
• No uncontrolled medical problems
• No evidence of active acute or chronic infection
• No known severe hypersensitivity to trastuzumab, except mild to moderate infusion reactions that are easily managed and do not recur
• No allergy to corn

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• More than 28 days since prior and no other concurrent chemotherapy, radiation therapy, or biologic therapy (except trastuzumab)

  • Concurrent endocrine therapy and supportive therapy with bisphosphonates allowed
• More than 28 days since prior and no other concurrent participation in an investigational new drug trial

• More than 28 days since prior and no other concurrent systemic oral steroids

  • Topical, ocular, and nasal steroids allowed
• No prior vaccination with the allogeneic GM-CSF-secreting breast tumor vaccine

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 120 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00971737
• Other Study ID Numbers: J0947; P30CA006973 ( U.S. NIH Grant/Contract ); JHOC-J0947; NA_00024527; GENENTECH-JHOC-J0947; CDR0000653173 ( Other Identifier: other )
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Study Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Leisha A. Emens, MD, PhD; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

• PRS Account: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Verification Date: February 2019