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CLDX 1114   |   14-506
A Randomized Multicenter Pivotal Study of CDX-011 (CR011-vcMMAE) in Patients with Metastatic, GPNMB Over Expressing, Triple-Negative Breast Cancer (The “METRIC” Study)

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Primary Objective
  • To evaluate the anti-cancer activity of CDX-011 in metastatic, GPNMB over-expressing, triple-negative breast cancer as measured by the objective response rate (ORR) and duration of progression-free survival (PFS)
Secondary Objectives
  • To further assess the anti-cancer activity of CDX-011 in metastatic, GPNMB over-expressing, triple-negative breast cancer, as assessed by duration of response (DOR) and overall survival (OS)
  • To further characterize the safety of CDX-011 in metastatic, GPNMB over-expressing, triple-negative breast cancer
  • To obtain pharmacokinetic parameters and to explore the relationships between patient-specific measures of exposure and safety and activity parameters
Exploratory Objective
  • To assess whether treatment with CDX-011 is associated with improvement in quality of life and/or cancer-related pain as reflected by reduced analgesic use.

Inclusion Criteria
  1. Female or male subjects with metastatic, histologically or cytologically confirmed carcinoma of the breast.
  2. Documented progression of disease , based on radiographic, clinical or pathologic assessment showing increased tumor burden or new site(s) of disease during or subsequent to the last anticancer regimen.
  3. received.
  4. Overexpression of GPNMB (≥ 25% of malignant epithelial cells expressing GPNMB, as determined by a central laboratory using IHC methods) in at least one tumor sample obtained in the advanced (locally advanced, recurrent or metastatic) setting.
  5. Triple-negative status confirmed in a tumor sample obtained in the advanced (locally advanced, recurrent or metastatic) setting, according to the following criteria:
    • Minimal or no expression of estrogen and progesterone receptors (<1% of cells positive by immunohistochemistry (IHC))
    • Minimal or no expression of HER2 (IHC staining of 0 or 1+; ISH single-probe average HER2 copy number < 4.0 signals/cell; or ISH dual-probe HER2/CEP17b ratio < 2.0 with an average HER2 copy number < 4.0 signals/cell). NOTE: laboratory reports will be required to provide quantitative results of sufficient detail to verify the above eligibility for all patients enrolled.
  6. 0 to 2 prior chemotherapy-containing regimens for advanced (locally advanced, recurrent or metastatic) breast cancer. For the purpose of this criterion, a regimen is defined as any combination of therapy, including sequential therapy, received before progression.
  7. 6. Prior receipt of anthracycline-containing chemotherapy in any setting.
    • If received as neoadjuvant/adjuvant therapy, there must have been a progression-free interval of > 6 months after completion of neoadjuvant/adjuvant therapy and no further anthracycline therapy should be indicated.
    • If received in the setting of advanced (locally advanced, recurrent or metastatic) disease, there are no restrictions based on the subsequent progression-free interval; however, any patient who had a progression-free interval of > 6 months after completion of advanced disease therapy should have no further anthracycline therapy indicated.
    • NOTE: Patients in whom no further anthracycline therapy would be indicated include those with contraindicating cardiac conditions, prior intolerance to anthracycline therapy, or those who have received cumulative doses of 240 mg/m2 of doxorubicin or doxorubicin equivalents.
  8. Taxane resistance or intolerance, defined by at least one of the following:
    • If received in the neoadjuvant/adjuvant setting, there must have been a progression-free interval of > 6 months after completion of neo/adjuvant therapy. Furthermore, if the progression-free interval was >12 months after completion of neo/adjuvant therapy, the patient must have received additional taxane-containing therapy (i.e., a taxane-rechallenge) for advanced disease and had progression while receiving or within 6 months of completing the taxane-rechallenge therapy.
    • If received in the setting of advanced (locally advanced, recurrent or metastatic) disease, there must have been progression while receiving or within 6 months of completing advanced disease therapy.
    • No further taxane therapy indicated, due to treatment-limiting toxicity to prior taxane therapy (received in any setting) or persistent comorbidities that contraindicate further therapy, in the opinion of the treating investigator.
  9. Age ≥ 18 years
  10. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1 (Appendix 4).
  11. Life expectancy of ≥ 3 months
  12. Measurable (target) disease by RECIST 1.1 criteria (Eisenhauer, Therasse et al. 2009) (Appendix 3). Target lesions selected for tumor measurements should be those where surgical resection or radiation are not indicated or anticipated.
  13. Resolution of all chemotherapy or radiation-related toxicities ≤ CTCAE v. 4.0 Grade 1 severity, except for alopecia.
  14. Adequate bone marrow function as assessed by absolute neutrophil count (ANC) ≥ 1500/mm3; hemoglobin ≥ 9.0 g/dL, and platelet count ≥ 100,000/mm3.
  15. Adequate renal function as assessed by serum creatinine ≤ 2.0 mg/dL or calculated creatinine clearance > 40 mL/min per the Cockcroft and Gault formula (Appendix 5)
  16. Adequate liver function as assessed by total bilirubin ≤ 1.5 x upper limit of normal (ULN), and alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 3.0 x ULN (≤ 5.0 x ULN in the case of liver metastases). Patients with known Gilbert's syndrome may be enrolled with total bilirubin ≤ 3.0 mg/dL.
  17. Read, understood, and provided written informed consent and, if applicable, HIPAA authorization.

Exclusion Criteria
  1. Progression/recurrence of breast cancer during or within 6 months of completion of neoadjuvant or adjuvant chemotherapy.
  2. Investigational therapy within four weeks before planned start of study treatment.
  3. Persistent neuropathy > NCI-CTCAE v. 4.0 Grade 1 (at randomization).
  4. History of allergic reactions attributed to compounds of similar composition to dolastatin or auristatin. Compounds of similar composition include Auristatin PHE as an anti-fungal agent, Auristatin PE (TZT-1027, Soblidotin, NSC-654663) as an anti-tumor agent and symplostatin 1 as an anti-tumor agent.
  5. Known hypersensitivity to 5-flourouracil, capecitabine or any of its components.
  6. Known dihydropyrimidine dehydrogenase (DPD) deficiency.
  7. Known brain metastases, unless previously treated and asymptomatic for 2 months and not progressive in size or number for 2 months prior to randomization. Continued use of steroids and/or anticonvulsants (in the absence of any suspicion of progressive brain metastases) is acceptable.
  8. Subjects unable to provide informed consent and/or unable to comply with the study procedures.
  9. Pregnant or breast-feeding women, and women or men who are not willing to use effective contraception during the time from signing of informed consent through two months after the last dose of study treatment. Effective contraception is defined as double barrier contraception (eg, condom plus spermicide in combination with a female condom, diaphragm, cervical cap, contraceptive sponge or vaginal ring), intra-uterine device (IUD), implants, injectables, combined oral contraceptives, sexual abstinence (total abstinence from sexual intercourse as the preferred lifestyle of the subject; periodic abstinence is not acceptable), or sexual intercourse with only a vasectomized partner. Patients and/or partners who are surgically sterile or postmenopausal are exempt from this requirement.
  10. Significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension, and congestive heart failure (New York Heart Association class 3 or 4), a history of a serious uncontrollable arrhythmia despite treatment, ischemic or severe valvular heart disease, or a myocardial infarction within 6 months prior to the trial entry.
  11. Any underlying medical condition that, in the Investigator's opinion, will make the administration of study treatment (CDX-011 or capecitabine) hazardous to the patient, or would obscure the interpretation of adverse events.
  12. Other malignancy except for adequately treated and cured basal or squamous cell skin cancer, curatively treated in situ disease, or any other cancer from which the patient has been disease-free for ≥ 5 years.

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