The AVIATOR Study: Trastuzumab and Vinorelbine With Avelumab OR Avelumab & Utomilumab in Advanced HER2+ Breast Cancer

Sponsor

Adrienne G. Waks (Other)

Overall Status

Recruiting

CT.gov ID

NCT03414658

Collaborator

Pfizer (Industry), Breast Cancer Research Foundation (Other), Johns Hopkins University (Other)

100

Enrollment

Locations

Arms

83.3

Anticipated Duration (Months)

5.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This research study is studying a combination of drugs as a possible treatment for breast cancer.

The drugs involved in this study are:

Group A: Trastuzumab (Herceptin) + Vinorelbine (Navelbine)
Group B: Trastuzumab + Vinorelbine + Avelumab
Group C: Trastuzumab + Vinorelbine + Avelumab + Utomilumab (PF-05082566)

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Vinorelbine Drug: Trastuzumab Drug: Avelumab Drug: Utomilumab	Phase 2

Detailed Description

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug combination to learn whether the drug combination works in treating a specific disease. "Investigational" means that drug combination is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved Utomilumab as a treatment for any disease.

The FDA (the U.S. Food and Drug Administration) has approved Avelumab as a treatment for other diseases.

The FDA (the U.S. Food and Drug Administration) has approved trastuzumab as a treatment option for this disease.

The FDA (the U.S. Food and Drug Administration) has approved vinorelbine as a treatment for other diseases and is commonly used as a treatment option for this disease.

The immune system is the body's natural defense against disease. The immune system sends a type of cells called T cells throughout the body to detect and fight infections and diseases-including cancers. One way the immune system controls the activity of T cells is through the PD-1 (programmed cell death protein-1) pathway. However, some cancer cells hide from T-cell attack by taking control of the PD-1 pathway and this stops T cells from attacking cancer cells. Avelumab is a type of drug, known as an antibody which is designed to block the PD-1 pathway and helps the immune system in detecting and fighting cancer cells. An antibody is a protein produced by the body's immune system when it detects harmful substances. Previous studies show that the administration of antibodies which block the PD-1 pathway can lead to tumor destruction.

Utomilumab is an antibody designed to stimulate the body's immune system to fight cancer cells. Previous studies have shown that the administration of this type of antibody may help to prevent tumors from growing.

In the laboratory, adding avelumab and Utomilumab to trastuzumab appears to improve effectiveness. It is not known whether this is true in humans.

In this research study, the investigators are evaluating the activity of 3 different combinations: (a)trastuzumab and vinorelbine combined, (b) trastuzumab, vinorelbine and avelumab combined, and (c) trastuzumab, vinorelbine, avelumab and utomilumab combined in participants with metastatic HER2- positive breast cancer.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

100 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomized, Phase II Study Comparing Trastuzumab and Vinorelbine in Combination With Avelumab or Avelumab and Utomilumab (41BB/CD137 Agonist), in Patients With HER2-positive Metastatic Breast Cancer Who Have Progressed on Prior Trastuzumab and Pertuzumab

Actual Study Start Date :

Jun 21, 2018

Anticipated Primary Completion Date :

Jul 1, 2023

Anticipated Study Completion Date :

May 31, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Trastuzumab + Vinorelbine Trastuzumab is administered intravenously twice per cycle Vinorelbine is administered intravenously 3 times per cycle	Drug: Vinorelbine work by interfering with cell division, which leaves the tumor unable to grow and spread Drug: Trastuzumab trastuzumab induces an antibody-dependent cell-mediated cytotoxicity against tumor cells that overexpress HER2.
Experimental: Trastuzumab + Vinorelbine + Avelumab Trastuzumab is administered intravenously twice per cycle Vinorelbine is administered intravenously 3 times per cycle Avelumab is administered intravenously twice per cycle Antihistamine and with acetaminophen is mandatory 30 to 60 minutes prior to each dose of avelumab	Drug: Vinorelbine work by interfering with cell division, which leaves the tumor unable to grow and spread Drug: Trastuzumab trastuzumab induces an antibody-dependent cell-mediated cytotoxicity against tumor cells that overexpress HER2. Drug: Avelumab monoclonal antibody directed against the human immunosuppressive ligand programmed death-ligand 1 (PD-L1) protein
Experimental: Trastuzumab + Vinorelbine + Avelumab + Utomilumab Trastuzumab is administered intravenously twice per cycle Vinorelbine is administered intravenously 3 times per cycle Avelumab is administered intravenously twice per cycle Antihistamine and with acetaminophen is mandatory 30 to 60 minutes prior to each dose of avelumab Utomilumab is administered intravenously once per cycle	Drug: Vinorelbine work by interfering with cell division, which leaves the tumor unable to grow and spread Drug: Trastuzumab trastuzumab induces an antibody-dependent cell-mediated cytotoxicity against tumor cells that overexpress HER2. Drug: Avelumab monoclonal antibody directed against the human immunosuppressive ligand programmed death-ligand 1 (PD-L1) protein Drug: Utomilumab Utomilumab is an antibody designed to stimulate the body's immune system to fight cancer cells
Experimental: Trastuzumab + Avelumab + Utomilumab This is a crossover arm Avelumab is administered intravenously twice per cycle Antihistamine and with acetaminophen is mandatory 30 to 60 minutes prior to each dose of avelumab Utomilumab is administered intravenously once per cycle Trastuzumab is administered intravenously twice per cycle	Drug: Trastuzumab trastuzumab induces an antibody-dependent cell-mediated cytotoxicity against tumor cells that overexpress HER2. Drug: Avelumab monoclonal antibody directed against the human immunosuppressive ligand programmed death-ligand 1 (PD-L1) protein Drug: Utomilumab Utomilumab is an antibody designed to stimulate the body's immune system to fight cancer cells

Outcome Measures

Primary Outcome Measures

Progression Free Survival [2 years]
Progression Free Survival is defined from the time from randomization to the first occurrence of disease progression as determined by the investigator using RECIST 1.1 or death from any cause, whichever occurs first.

Secondary Outcome Measures

Objective Response Rate [2 years]
Objective Response Rate is determined by Complete Response or Partial Response by RECIST 1.1
Duration of Response [2 years]
Duration of Response is measured from the time criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented
Overall Survival [2 years]
Overall survival is defined as the time from randomization to death from any cause, or is censored at date last known alive.
Safety and Tolerability [2 years]
Safety and TOlerability will be assessed by the number of participants with adverse events. Adverse events are assessed using NCI-CTCAE version 4.0.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age ≥18 years or older
Histologically confirmed breast adenocarcinoma that is unresectable loco-regionally advanced or metastatic
HER2-positive (immunohistochemistry score 3+) or ERBB2- amplification (Ratio ERBB2/centromeres ≥ 2.0 or mean gene copy number ≥ 6) on primary tumor or of metastatic or unresectable loco-regional biopsy.
Measurable disease per RECIST v1.1 (see Section 11)
Patients must have previous treatment with ado-trastuzumab emtansine (Kadcyla, T-DM1) in any setting. Patients must have previously received trastuzumab and pertuzumab in the metastatic setting or within 12 months of neoadjuvant/adjuvant treatment.
Patient must have progressed on their most recent line of therapy. Progression must have been demonstrated by radiological or clinical assessment.
Left ventricular ejection fraction (LVEF) ≥ 50%
Willingness and availability to submit FFPE tissue for central confirmation of HER2 positivity and central assessment of PD-L1 status. This can be from archival tissue from unresectable loco-regional or metastatic disease obtained ≤ 1 year prior to enrollment or new tissue material from a recently obtained surgical or diagnostic biopsy. Tissue obtained for the biopsy must not have been previously irradiated. If a patient does not have any available archival tissue ≤ 1 year old and the treating investigator does not feel that it would be safe to perform a fresh biopsy, the requirement for a fresh biopsy may be waived after discussion with the Principal Investigator.
Written informed consent for screening and trial participation procedures including biological material transfer and handling.
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Hematopoietic status:
Absolute neutrophil count ≥ 1.0 × 109/L,
Platelet count ≥ 100 × 109/L,
Hemoglobin ≥ 9 g/dL
Hepatic status:
Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN). In the case of known Gilbert's syndrome, a higher serum total bilirubin (< 2 × ULN) is allowed.
AST and ALT ≤ 2.5 × ULN; if the patient has liver metastases, ALT and AST must be ≤ 5 × ULN.
Renal status:
Creatinine ≤ 1.5 ×ULN or creatinine clearance > 60 ml/min
Proteinuria < 1 g/day
International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 × ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulant.
If female of childbearing potential, must have a negative pregnancy test within 7 days of initiating treatment. Childbearing potential is defined by: those who have not been surgically sterilized and/or have had a menstrual period in the past year.
Participants of childbearing potential (as defined above) must be willing to use effective contraception during treatment and up to 7 months after stop of trial treatment. Acceptable methods of contraception are intrauterine devices, bilateral tubal occlusion, vasectomized, or total abstinence. Oral, injectable, or implant hormonal contraceptives are not allowed.
Must not be breastfeeding/lactating.

Exclusion Criteria:

Prior therapy with any anti-PD-1, anti-PD-L1, L2, anti-4-1BB (CD137), or anti-CTLA4 therapy
Known Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)
Positive for Hepatitis B (HBsAg reactive) or Hepatitis C (HCV RNA [qualitative]).
History of interstitial lung disease
Active central nervous system metastases, as indicated by clinical symptoms, cerebral edema, and/or progressive growth (patients with history of CNS metastases or spinal cord compression are eligible if they are clinically stable for at least 4 weeks before first dose of investigational product and do not require high-dose steroid treatment).
History of clinically significant or uncontrolled cardiac disease, including congestive heart failure (New York Heart Association functional classification ≥3), angina, myocardial infarction or ventricular arrhythmia.
Previous severe hypersensitivity reaction to treatment with another monoclonal antibody.
Active infection requiring systemic therapy.
Chronic systemic therapy with immunosuppressive agents including corticosteroids.
Active autoimmune disease or a documented history of autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the trial. Patients with hypothyroidism stable on hormone replacement or Sjögren's syndrome will not be excluded from the trial.
Concurrent disease or condition that would make the patient inappropriate for trial participation or any serious medical disorder that would interfere with the patient's safety.
No uncontrolled hypertension (≥180/110), unstable diabetes mellitus, dyspnea at rest, or chronic therapy with oxygen.
Chemotherapy, radiotherapy, and/or biological cancer therapy within 3 weeks prior to the first trial dose or has not recovered to CTCAE v.4 grade 1 or better from adverse events (except alopecia).
Unresolved or unstable, serious adverse events from prior administration of another investigational drug.
Live vaccines within 30 days prior to the first dose of trial therapy and during trial treatment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35249
2	University of California San Francisco	San Francisco	California	United States	94158
3	Georgetown University Medical Center	Washington	District of Columbia	United States	20007
4	University of Chicago Medical Center	Chicago	Illinois	United States	60637
5	Indiana University Health Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
6	Johns Hopkins University	Baltimore	Maryland	United States	21287
7	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02115
8	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
9	Montefiore Medical Center	Bronx	New York	United States	10467
10	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
11	University of Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599-7305
12	Duke University Medical Center	Durham	North Carolina	United States	27710
13	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
14	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
15	Baylor College of Medicine	Houston	Texas	United States	77030
16	MD Anderson Cancer Center	Houston	Texas	United States	77030
17	University of Washington Fred Hutchinson Cancer Care	Seattle	Washington	United States	98109

Sponsors and Collaborators

Adrienne G. Waks
Pfizer
Breast Cancer Research Foundation
Johns Hopkins University

Investigators

Principal Investigator: Adrienne Waks, MD, PhD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Adrienne G. Waks, Principal Investigator, Dana-Farber Cancer Institute

ClinicalTrials.gov Identifier:

NCT03414658

Other Study ID Numbers:

17-455
TBCRC045

First Posted:

Jan 30, 2018

Last Update Posted:

Aug 16, 2022

Last Verified:

Aug 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Keywords provided by Adrienne G. Waks, Principal Investigator, Dana-Farber Cancer Institute

Breast Cancer

Additional relevant MeSH terms:

Study Results

No Results Posted as of Aug 16, 2022