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Nab-Paclitaxel and Durvalumab With or Without Neoantigen Vaccine in Treating Patients With Metastatic Triple Negative Breast Cancer

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ClinicalTrials.gov Identifier: NCT03606967
Recruitment Status : Not yet recruiting
First Posted : July 31, 2018
Last Update Posted : October 16, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase II trial studies how well nab-paclitaxel and durvalumab with or without personalized synthetic long peptide vaccine (neoantigen vaccine) work in treating participants with triple negative breast cancer that has spread to other places in the body. Drugs used in chemotherapy, such as nab-paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as durvalumab, may interfere with the ability of tumor cells to grow and spread. Vaccines made from peptides may help the body build an effective immune response to kill tumor cells. It is not yet known whether giving nab-paclitaxel and durvalumab with or without neoantigen vaccine will work better in treating participants with triple negative breast cancer.

Condition or disease Intervention/treatment Phase
Anatomic Stage IV Breast Cancer AJCC v8 Estrogen Receptor Negative HER2/Neu Negative Metastatic Triple-Negative Breast Carcinoma Progesterone Receptor Negative Prognostic Stage IV Breast Cancer AJCC v8 Drug: Carboplatin Biological: Durvalumab Drug: Gemcitabine Hydrochloride Drug: Nab-paclitaxel Biological: Personalized Synthetic Long Peptide Vaccine Drug: Poly ICLC Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. Evaluate the clinical response to nab-paclitaxel + MEDI4736 (durvalumab) + neoantigen vaccine (Arm 1) versus (vs.) nab-paclitaxel + MEDI4736 (durvalumab) (Arm 2) in patients with metastatic triple negative breast cancer (TNBC).

SECONDARY OBJECTIVES:

I. Evaluate the safety of nab-paclitaxel + MEDI4736 (durvalumab) + neoantigen vaccine vs. nab-paclitaxel + MEDI4736 (durvalumab) in patients with metastatic TNBC.

EXPLORATORY OBJECTIVES:

I. Assess the immune response induced by nab-paclitaxel + MEDI4736 (durvalumab) + neoantigen vaccine vs. nab-paclitaxel + MEDI4736 (durvalumab) in patients with metastatic TNBC.

II. Biomarkers of response to therapy will be assessed based on the research biopsies performed at baseline, following the chemotherapy run-in (Part A) and following nab-paclitaxel + MEDI4736 +/- neoantigen vaccine (Part B).

OUTLINE:

PART A: Participants receive gemcitabine hydrochloride intravenously (IV) over 30 minutes and carboplatin IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Participants with progression of disease within the first 18 weeks may switch and receive nab-paclitaxel IV over 30 minutes on days 1, 8, and 15 of each remaining course.

PART B: Participants are randomized to 1 of 2 arms.

ARM I: Participants receive personalized synthetic long peptide vaccine and poly-ICLC subcutaneously (SC) on days 1, 4, 8, 15, 22, 50, and 78 in the absence of disease progression or unacceptable toxicity. Participants also receive durvalumab IV over 60 minutes on day 1 and nab-paclitaxel IV over 30 minutes on days 1, 8, and 15. courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Participants receive durvalumab IV over 60 minutes on day 1 and nab-paclitaxel IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up for 52 weeks.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomized Phase 2 Clinical Trial of Nab-Paclitaxel + MEDI4736 (Durvalumab) + Neoantigen Vaccine vs. Nab-Paclitaxel + MEDI4736 (Durvalumab) in Patients With Metastatic Triple Negative Breast Cancer
Estimated Study Start Date : December 15, 2018
Estimated Primary Completion Date : July 31, 2019
Estimated Study Completion Date : July 31, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Active Comparator: Arm II (durvalumab, nab-paclitaxel)

PART A: Participants receive gemcitabine hydrochloride IV over 30 minutes and carboplatin IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Participants with progression of disease within the first 18 weeks may switch and receive nab-paclitaxel IV over 30 minutes on days 1, 8, and 15 of each remaining course.

PART B: Participants receive durvalumab IV over 60 minutes on day 1 and nab-paclitaxel IV over 30 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo

Biological: Durvalumab
Given IV
Other Names:
  • Imfinzi
  • Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer
  • MEDI-4736
  • MEDI4736

Drug: Gemcitabine Hydrochloride
Given IV
Other Names:
  • dFdCyd
  • Difluorodeoxycytidine Hydrochloride
  • Gemzar
  • LY-188011
  • LY188011

Drug: Nab-paclitaxel
Given IV
Other Names:
  • ABI 007
  • ABI-007
  • Abraxane
  • Albumin-bound Paclitaxel
  • Albumin-Stabilized Nanoparticle Paclitaxel
  • Nanoparticle Albumin-bound Paclitaxel
  • Nanoparticle Paclitaxel
  • paclitaxel albumin-stabilized nanoparticle formulation
  • Protein-bound Paclitaxel

Experimental: Treatment (neoantigen vaccine, durvalumab, nab-paclitaxel)

PART A: Participants receive gemcitabine hydrochloride IV over 30 minutes and carboplatin IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. Participants with progression of disease within the first 18 weeks may switch and receive nab-paclitaxel IV over 30 minutes on days 1, 8, and 15 of each remaining course.

PART B: Participants receive personalized synthetic long peptide vaccine and poly-ICLC SC on days 1, 4, 8, 15, 22, 50, and 78 in the absence of disease progression or unacceptable toxicity. Participants also receive durvalumab IV over 60 minutes on day 1 and nab-paclitaxel IV over 30 minutes on days 1, 8, and 15. courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Carboplatin
Given IV
Other Names:
  • Blastocarb
  • Carboplat
  • Carboplatin Hexal
  • Carboplatino
  • Carbosin
  • Carbosol
  • Carbotec
  • CBDCA
  • Displata
  • Ercar
  • JM-8
  • Nealorin
  • Novoplatinum
  • Paraplatin
  • Paraplatin AQ
  • Paraplatine
  • Platinwas
  • Ribocarbo

Biological: Durvalumab
Given IV
Other Names:
  • Imfinzi
  • Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer
  • MEDI-4736
  • MEDI4736

Drug: Gemcitabine Hydrochloride
Given IV
Other Names:
  • dFdCyd
  • Difluorodeoxycytidine Hydrochloride
  • Gemzar
  • LY-188011
  • LY188011

Drug: Nab-paclitaxel
Given IV
Other Names:
  • ABI 007
  • ABI-007
  • Abraxane
  • Albumin-bound Paclitaxel
  • Albumin-Stabilized Nanoparticle Paclitaxel
  • Nanoparticle Albumin-bound Paclitaxel
  • Nanoparticle Paclitaxel
  • paclitaxel albumin-stabilized nanoparticle formulation
  • Protein-bound Paclitaxel

Biological: Personalized Synthetic Long Peptide Vaccine
Given SC
Other Names:
  • Personalized SLP Vaccine
  • TSMA-based SLP Vaccine
  • TSMA-based Synthetic Long Peptide Vaccine
  • Tumor Specific Mutant Antigen-based Synthetic Long Peptide Vaccine

Drug: Poly ICLC
Given SC
Other Names:
  • Hiltonol
  • Poly I:Poly C with Poly-L-Lysine Stabilizer
  • poly-ICLC
  • PolyI:PolyC with Poly-L-Lysine Stabilizer
  • Polyinosinic-Polycytidylic Acid Stabilized with Polylysine and Carboxymethylcellulose
  • Polyriboinosinic-Polyribocytidylic Acid-Polylysine Carboxymethylcellulose
  • Stabilized Polyriboinosinic/Polyribocytidylic Acid




Primary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: From initiation of Part B to progression or death, assessed at 6 and 12 months ]
    The median PFS in each arm and their 80% confidence intervals will be assessed using Kaplan-Meier product limit methods and compared by log-rank test.


Secondary Outcome Measures :
  1. Incidence of adverse events assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5 [ Time Frame: Up to day 22 ]
    The number and percentage of subjects experiencing each type of adverse event will be tabulated by severity, and relationship to treatment. If appropriate, confidence intervals will be used to characterize the precision of the estimate.

  2. Clinical response rate assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 [ Time Frame: Up to 52 weeks ]
    Will be assessed and their 95% confidence intervals will be calculated.

  3. Clinical benefit rate (complete response, partial response, stable disease) assessed by RECIST 1.1 [ Time Frame: Up to 52 weeks ]
    Will be assessed and their 95% confidence intervals will be calculated.

  4. Overall survival (OS) [ Time Frame: Up to 52 weeks ]
    The median OS and 95% confidence interval will also be assessed using Kaplan-Meier product limit methods and compared by log-rank test.


Other Outcome Measures:
  1. Immune response [ Time Frame: Up to 52 weeks ]
    Serial peripheral blood specimens will be obtained for correlative analyses of the neoantigen-specific T cell response to nab-paclitaxel + MEDI4736 (durvalumab) + neoantigen vaccine vs. nab-paclitaxel + MEDI4736 (durvalumab) therapy. Potential biomarkers that will be assessed include baseline expression of PD-L1 on tumor infiltrating lymphocytes and tumor, TNBC subtype as determined by gene expression, immune signature as determined by gene expression, mutational landscape, presence and phenotype of neoantigen-specific T cells, and neoantigen-specific T cell response as measured by multiparameter flow cytometry. These studies will provide significant insights into how to best combine checkpoint blockade therapy and neoantigen vaccine therapy.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have a histologically confirmed diagnosis of metastatic invasive triple negative breast cancer.
  • Estrogen receptor (ER) and progesterone receptor (PR) less than Allred score of 3 OR less than 1% positive staining cells in the invasive component of the tumor.
  • HER2 negative by fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) staining 0 or 1+.
  • Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for nonnodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest x-ray or as >= 10 mm (>= 1 cm) with computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam.
  • A tumor specimen obtained from relapsed metastatic or locally advanced disease (if applicable) must be submitted. Acceptable samples include core needle biopsies for deep tumor tissue (minimum 4 cores) or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. Formalin-fixed, paraffin-embedded (FFPE) tumor specimens in paraffin blocks are preferred. Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone metastases, and lavage samples are not acceptable.
  • No prior therapy for metastatic TNBC. Patients who have received taxane-based adjuvant therapy are required to have a disease-free interval of at least 12 months after completion of taxane therapy.
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 60%).
  • Body weight > 30 kg.
  • Must have a life expectancy of at least 12 weeks.
  • Absolute neutrophil count >= 1,500/mcL.
  • Platelets >= 100,000/mcL.
  • Hemoglobin >= 9.0 g/dL.
  • Serum bilirubin =< 1.5 x institutional upper limit of normal.
  • Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) =< 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be =< 5 x institutional upper limit of normal.
  • Measured creatinine clearance > 40 mL/min.
  • Calculated creatinine clearance > 40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance.
  • Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

    • Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
    • Women >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
  • The effects of MEDI4736 (durvalumab) and neoantigen vaccine on the developing human fetus are unknown. For this reason and because these agents may be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and through 180 days after the last dose of durvalumab. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
  • Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
  • Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  • Patients who have had chemotherapy, radiotherapy (to more than 30% of the bone marrow), or biologic therapy within 30 days (42 days for nitrosoureas or mitomycin C) prior to entering the study.
  • Patients who have received prior immunotherapy for metastatic disease.
  • Any previous treatment with a PD1 or PD-L1 inhibitor, including MEDI4736 (durvalumab).
  • Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1).
  • Patients who are receiving any other investigational agents or who have received an investigational agent within the last 30 days.
  • Receipt of live attenuated vaccination within 6 months prior to study entry or within 30 days of receiving MEDI4736 (durvalumab).
  • Major surgical procedure within 28 days prior to the first dose of MEDI4736 (durvalumab). Local surgery of isolated lesions for palliative intent is acceptable.
  • Current use or prior use of immunosuppressive medication within 28 days before the first dose of MEDI4736 (durvalumab), with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses which are not to exceed 10 mg/day of prednisone or an equivalent corticosteroid.
  • Known central nervous system (CNS) disease, except for treated asymptomatic CNS metastases. Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
  • Leptomeningeal disease.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to MEDI4736 (durvalumab). Known allergy, or history of serious adverse reaction to vaccines, such as anaphylaxis, hives or respiratory difficulty.
  • Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥ 470 ms calculated from 3 electrocardiograms (ECGs) (within 15 minutes at 5 minutes apart).
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, evidence of any acute or chronic viral illness or disease, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Pregnant women are excluded from this study because MEDI4736 (durvalumab) has the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with MEDI4736 (durvalumab), breastfeeding should be discontinued if the mother is treated with MEDI4736 (durvalumab). These potential risks may also apply to other agents used in this study. A negative serum pregnancy test is required no more than 7 days before study entry.
  • Human immunodeficiency virus (HIV)-positive patients are ineligible because of the potential inability to generate an immune response to vaccines.
  • Active autoimmune disease that has required systemic treatment in the 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 not considered a form of systemic treatment.
  • History of pneumonitis or interstitial lung disease.
  • History of active primary immunodeficiency.
  • Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination, and radiographic findings, and TB testing in line with local practice), hepatitis B (positive test for hepatitis B virus (HBV) surface antigen (HBsAg)), or hepatitis C (positive test for hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection.
  • The patient with a previous history of non-breast malignancy is eligible for this study only if the patient meets the following criteria for a cancer survivor. A cancer survivor is eligible provided the following criteria are met:

    • Patient has undergone potentially curative therapy for all prior malignancies.
    • Patients have been considered disease free for at least 1 year (with the exception of basal cell or squamous cell carcinoma of the skin or carcinoma-in-situ of the cervix).
  • Patients with a strong likelihood of non-adherence (such as difficulties in adhering to follow-up schedule due to geographic distance from the treatment facility) should not be knowingly registered.
  • Patients with a history of prior allogeneic stem cell or solid organ transplantation.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03606967


Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: William Gillanders Duke University - Duke Cancer Institute LAO
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03606967    
Other Study ID Numbers: NCI-2018-01581
NCI-2018-01581 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
10146 ( Other Identifier: Duke University - Duke Cancer Institute LAO )
10146 ( Other Identifier: CTEP )
UM1CA186704 ( U.S. NIH Grant/Contract )
First Posted: July 31, 2018    Key Record Dates
Last Update Posted: October 16, 2018
Last Verified: August 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Gemcitabine
Poly I-C
Paclitaxel
Albumin-Bound Paclitaxel
Carboplatin
Durvalumab
Carboxymethylcellulose Sodium
Vaccines
Immunoglobulins
Antibodies, Monoclonal
Immunoglobulin G
Poly ICLC
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents