Clinical Trials /

Testing the Addition of an Individualized Vaccine to Nab-Paclitaxel, Durvalumab and Tremelimumab and Chemotherapy in Patients With Metastatic Triple Negative Breast Cancer

NCT03606967

Description:

This phase II trial studies how well nab-paclitaxel, durvalumab, and tremelimumab with or without personalized synthetic long peptide vaccine (neoantigen vaccine) works in treating patients with triple negative breast cancer that has spread to other places in the body (metastatic). 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. Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may induce changes in body's immune system and 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, durvalumab, and tremelimumab with or without neoantigen vaccine will work better in treating patients with triple negative breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of an Individualized Vaccine to Nab-Paclitaxel, Durvalumab and Tremelimumab and Chemotherapy in Patients With Metastatic Triple Negative Breast Cancer
  • Official Title: Randomized Phase 2 Clinical Trial of Nab-Paclitaxel + Durvalumab (MEDI4736) + Tremelimumab + Neoantigen Vaccine vs. Nab-Paclitaxel + Durvalumab (MEDI4736) + Tremelimumab in Patients With Metastatic Triple Negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2018-01581
  • SECONDARY ID: NCI-2018-01581
  • SECONDARY ID: 10146
  • SECONDARY ID: 10146
  • SECONDARY ID: UM1CA186704
  • NCT ID: NCT03606967

Conditions

  • Anatomic Stage IV Breast Cancer AJCC v8
  • Invasive Breast Carcinoma
  • Metastatic Triple-Negative Breast Carcinoma
  • Prognostic Stage IV Breast Cancer AJCC v8

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboArm I (neoantigen vaccine, durvalumab, nab-paclitaxel)
DurvalumabImfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736Arm I (neoantigen vaccine, durvalumab, nab-paclitaxel)
Gemcitabine HydrochloridedFdCyd, Difluorodeoxycytidine Hydrochloride, FF 10832, FF-10832, FF10832, Gemcitabine HCI, Gemzar, LY-188011, LY188011Arm I (neoantigen vaccine, durvalumab, nab-paclitaxel)
Nab-paclitaxelABI 007, ABI-007, Abraxane, Albumin-bound Paclitaxel, Albumin-Stabilized Nanoparticle Paclitaxel, Nanoparticle Albumin-bound Paclitaxel, Nanoparticle Paclitaxel, Paclitaxel Albumin, paclitaxel albumin-stabilized nanoparticle formulation, Protein-bound PaclitaxelArm I (neoantigen vaccine, durvalumab, nab-paclitaxel)
Personalized Synthetic Long Peptide VaccinePersonalized SLP Vaccine, TSMA-based SLP Vaccine, TSMA-based Synthetic Long Peptide Vaccine, Tumor Specific Mutant Antigen-based Synthetic Long Peptide VaccineArm I (neoantigen vaccine, durvalumab, nab-paclitaxel)
Poly ICLCHiltonol, 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 AcidArm I (neoantigen vaccine, durvalumab, nab-paclitaxel)
TremelimumabAnti-CTLA4 Human Monoclonal Antibody CP-675,206, CP-675, CP-675,206, CP-675206, TicilimumabArm I (neoantigen vaccine, durvalumab, nab-paclitaxel)

Purpose

This phase II trial studies how well nab-paclitaxel, durvalumab, and tremelimumab with or without personalized synthetic long peptide vaccine (neoantigen vaccine) works in treating patients with triple negative breast cancer that has spread to other places in the body (metastatic). 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. Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may induce changes in body's immune system and 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, durvalumab, and tremelimumab with or without neoantigen vaccine will work better in treating patients with triple negative breast cancer.

Detailed Description

      PRIMARY OBJECTIVE:

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

      SECONDARY OBJECTIVE:

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

      EXPLORATORY OBJECTIVES:

      I. Assess the immune response induced by nab-paclitaxel + durvalumab (MEDI4736) +
      tremelimumab + neoantigen vaccine vs. nab-paclitaxel + durvalumab (MEDI4736) + tremelimumab
      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 + durvalumab (MEDI4736) + tremelimumab +/- neoantigen vaccine (Part B).

      OUTLINE:

      PART A: Patients 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 cycles
      in the absence of disease progression or unacceptable toxicity. Beginning cycle 4, patients
      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 for 2 cycles at the discretion of the treating
      physician.

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

      ARM I: Patients 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. Patients also receive tremelimumab IV over 60 minutes on day 1 of
      cycles 1-4, durvalumab IV over 60 minutes on day 1 and nab-paclitaxel IV over 30 minutes on
      days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or
      unacceptable toxicity.

      ARM II: Patients receive tremelimumab IV over 60 minutes on day 1 of cycles 1-4, durvalumab
      IV over 60 minutes on day 1 and nab-paclitaxel IV over 30 minutes on days 1, 8, and 15.
      Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 1 year, then
      annually thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (neoantigen vaccine, durvalumab, nab-paclitaxel)ExperimentalPART A: Patients 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 cycles in the absence of disease progression or unacceptable toxicity. Beginning cycle 4, patients 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 for 2 cycles at the discretion of the treating physician. PART B: Patients 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. Patients also receive tremelimumab IV over 60 minutes on day 1 of cycles 1-4, durvalumab IV over 60 minutes on day 1 and nab-paclitaxel IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Carboplatin
  • Durvalumab
  • Gemcitabine Hydrochloride
  • Nab-paclitaxel
  • Personalized Synthetic Long Peptide Vaccine
  • Poly ICLC
  • Tremelimumab
Arm II (durvalumab, nab-paclitaxel)Active ComparatorPART A: Patients 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 cycles in the absence of disease progression or unacceptable toxicity. Patients 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 cycle. PART B: Patients receive tremelimumab IV over 60 minutes on day 1 of cycles 1-4, durvalumab IV over 60 minutes on day 1 and nab-paclitaxel IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Carboplatin
  • Durvalumab
  • Gemcitabine Hydrochloride
  • Nab-paclitaxel
  • Tremelimumab

Eligibility 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+.

          -  PD-L1 negative by any Food and Drug Administration (FDA) approved test.

          -  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 durvalumab (MEDI4736) 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.

          -  Human immunodeficiency virus (HIV)-positive patients are eligible provided they have a
             negative viral load, CD4 count > 250, and are on a stable antiretroviral regimen.

          -  Ability to understand and the willingness to sign a written informed consent document.
             Patients with impaired decision-making capacity who have a close caregiver or legal
             guardian are also eligible with the consent of the caregiver/guardian.

        Exclusion Criteria:

          -  Patients who are not considered to be candidates for carboplatin + gemcitabine for
             first line therapy of their metastatic triple negative breast cancer are not eligible.

          -  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 durvalumab (MEDI4736)
             or tremelimumab.

          -  Patients who have not recovered from grade >= 2 adverse events due to prior
             anti-cancer therapy with the exception of alopecia, vitiligo, and the laboratory
             values defined in the inclusion criteria.

               -  Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis
                  after consultation with the study physician.

          -  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 durvalumab (MEDI4736) and tremelimumab.

               -  Note: Patients, if enrolled, should not receive live vaccine whilst receiving
                  study treatment and up to 30 days after the last dose of study treatment.

          -  Major surgical procedure within 28 days prior to the first dose of durvalumab
             (MEDI4736) and tremelimumab. Local surgery of isolated lesions for palliative intent
             is acceptable.

          -  Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab (MEDI4736) or tremelimumab. The following are exceptions to this
             criterion:

               -  Intranasal, inhaled, topical steroids or local steroid injections (e.g.
                  intra-articular injection)

               -  Systemic corticosteroids at physiological doses which are not to exceed 10 mg/day
                  of prednisone or an equivalent corticosteroid

               -  Steroids as premedication for hypersensitivity reactions (e.g. CT scan
                  premedication).

          -  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 or history of leptomeningeal carcinomatosis.

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to durvalumab (MEDI4736) and tremelimumab. 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 durvalumab (MEDI4736) and
             tremelimumab 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 durvalumab (MEDI4736) and tremelimumab, breastfeeding
             should be discontinued if the mother is treated with durvalumab (MEDI4736) and
             tremelimumab. 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.

          -  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 (known positive hepatitis B virus [HBV] surface antigen
             [HBsAg] result), or hepatitis C. Patients with a past or resolved HBV infection
             (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg)
             are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if
             polymerase chain reaction is negative for HCV ribonucleic acid (RNA).

          -  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.

          -  History of allogeneic organ transplantation.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:From initiation of Part B to progression or death, assessed at 6 and 12 months
Safety Issue:
Description: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

Measure:Incidence of adverse events
Time Frame:Up to day 22
Safety Issue:
Description:Will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5. 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.
Measure:Clinical response rate
Time Frame:Up to 52 weeks
Safety Issue:
Description:Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Will be assessed and their 95% confidence intervals will be calculated.
Measure:Clinical benefit rate (complete response, partial response, stable disease)
Time Frame:Up to 52 weeks
Safety Issue:
Description:Will be assessed by RECIST 1.1. Will be assessed and their 95% confidence intervals will be calculated.
Measure:Overall survival (OS)
Time Frame:Up to 52 weeks
Safety Issue:
Description:The median OS and 95% confidence interval will also be assessed using Kaplan-Meier product limit methods and compared by log-rank test.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

May 21, 2021