Clinical Trial 23250

• Overview

  Study 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

  Objective:

  Primary Objective: The primary objective is to evaluate the clinical response to nab-paclitaxel + Durvalumab (MEDI4736) + tremelimumab + neoantigen vaccine (Arm 1) vs. nab-paclitaxel + Durvalumab (MEDI4736) + tremelimumab (Arm 2) in patients with metastatic TNBC. The primary endpoint is progression-free survival (PFS) which is defined as time from the initiation of Part B to progression or death. Secondary Objective: The secondary objective is to evaluate the safety of nab-paclitaxel + Durvalumab (MEDI4736) + tremelimumab + neoantigen vaccine vs. nab-paclitaxel + Durvalumab (MEDI4736) + tremelimumab in patients with metastatic TNBC. Safety will be assessed by clinical evaluation (CTCAE v. 5.0). Other secondary endpoints include clinical response (RECIST 1.1), clinical benefit rate (CR, PR, or SD at ≥ 3 months), and overall survival (OS).

• Treatments

  Therapies:

  Chemotherapy (NOS); Immunotherapy; Therapy (NOS); Vaccine

  Medications:

  AMP-514 (Durvalumab); CP-675,206 (tremelimumab); Durvalumab (); Gemzar (gemcitabine); MEDI4736 (Durvalumab); Nab-paclitaxel (Abraxane); Neoantigen (); Paraplatin (carboplatin); Sacituzumab Govitecan (); carboplatin (); gemcitabine (); tremelimumab ()

• Inclusion Criteria

  Key Inclusion Criteria:
  • Patients must have a histologically confirmed diagnosis of metastatic invasive triple negative breast cancer. Patients with clinical and/or radiologic suspicion of metastatic TNBC can be consented prior to this confirmation.
  • ER and PR less than Allred score of 3 OR less than 1% positive staining cells in the invasive component of the tumor.
  • HER2 negative by FISH or IHC staining 0 or 1+.
  • PD-L1 negative by any FDA approved test.
  • Patients may have measurable or evaluable disease.
  • 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. 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.
  • At least age 18 years. Because no dosing or adverse event data are currently available on the use of durvalumab (MEDI4736) and tremelimumab in combination with neoantigen vaccine in patients > ECOG performance status 0-1 (Karnofsky greater than or equal to 60%, see Appendix A).
  • Body weight > 30 kg.
  • Must have a life expectancy of at least 12 weeks.
  • Patients must have normal organ and marrow function as defined by the protocol.
  • 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 under 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 or older 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 tremelimumab 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 completion of durvalumab (MEDI4736) and tremelimumab. 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.
  • Other inclusion criteria may apply.

• Exclusion Criteria

  Key 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.
  • Patients who have not recovered from Grade 2 or higher adverse events due to prior anti-cancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria.
  • 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.
  • 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.
  • 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 Fridericias formula (QTcF) greater than or equal to 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.
  • Other exclusion criteria may apply.

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