MC# 20-10 - An Open-Label, Multicenter, Multi-Cohort, Phase II Study to Evaluate Enfortumab Vedotin in Subjects with Previously Treated Locally Advanced or Metastatic Malignant Solid Tumors

  • Agent(s): Enfortumab Vedotin
  • Disease Type(s): Breast, Esophageal, Gastric, Head and Neck, Lung-NSCLC, Breast- Triple Negative
  • Phase(s): II
  • Drug Classification(s): Antibody Drug Conjugate
  • Molecular Target(s): Nectin-4

Mechanism of Action

AGS-22CE is an antibody drug conjugate that selectively binds to nectin-4.  After internalization and proteolytic cleavage, MMAE binds to tubulin and inhibits its polymerization, which results in G2/M phase arrest and induces apoptosis in nectin-4 overexpressing tumor cells.

Purpose

In this study, the sponsor and investigators want to learn:

  • About the safety and tolerability of Enfortumab Vedotin based on your disease type
  • How proteins that indicate the status of your disease are affected with use of Enfortumab Vedotin
  • If Enfortumab Vedotin prevents or delays tumor growth or shrinks existing tumors
  • How quickly Enfortumab Vedotin is removed from the blood stream
Inclusion Criteria
  • Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent and privacy language as per national regulations (e.g., Health Insurance Portability and Accountability Act Authorization for US study sites) must be obtained from the subject prior to any study-related procedures (including withdrawal of prohibited medication, if applicable)
  • Subject is considered an adult according to local regulation at the time of signing the informed consent form (ICF)
  • Subject has measurable disease by RECIST Version 1.1
  • Subject has accessible archival tumor tissue from either the primary tumor or a metastatic site, for which source and availability have been confirmed prior to study treatment.  If no archival tumor tissue is available, the subject will have a biopsy to obtain tumor tissue prior to study treatment. If the subject is unable to undergo a biopsy due to safety concerns, enrollment into the study must be discussed with the medical monitor.
  • Subject has ECOG performance status of 0 or 1
  • Subject has the following baseline laboratory data.  If a subject has received a recent blood transfusion, the hematology tests must be obtained ≥ 28 days after any blood transfusion.
    • absolute neutrophil count (ANC) ≥ 1.0 × 109/L
    • platelet count ≥ 100 × 109/L
    • hemoglobin ≥ 9 g/dL
    • serum total bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for subjects with Gilbert’s disease
    • creatinine clearance (CrCl) ≥ 30 mL/min as estimated per institutional standards or as measured by 24-hour urine collection (glomerular filtration rate [GFR] can also be used instead of CrCl)
    • alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN
  • Female subject is not pregnant and at least 1 of the following conditions apply:
    • Not a woman of childbearing potential (WOCBP) (see [Appendix 12.3 Contraception Requirements])
    • WOCBP who agrees to follow the contraceptive guidance (see [Appendix 12.3 Contraception Requirements]) from the time of informed consent through at least 6 months after the last dose of study treatment administration
  • Female subject must agree not to breastfeed starting at screening and throughout the study period and for 6 months after the last dose of study treatment administration
  • Female subject must not donate ova starting at first dose of study treatment and throughout the study period and for 6 months after the last dose of study treatment administration
  • Male subject with female partner(s) of childbearing potential (including breastfeeding partner) must agree to use contraception throughout the treatment period and for 6 months after the last dose of study treatment administration
  • Male subject must not donate sperm during the treatment period and for 6 months after the last dose of study treatment administration
  • Male subject with pregnant partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy throughout the study period and for 6 months after the last dose of study treatment administration
  • Subject agrees not to participate in another interventional study while receiving study treatment in the present study
  • Cohort 1: HR+/HER2- breast cancer
    • Subject has evidence of progression on or after the last regimen received
    • Subject has histologically or cytologically-confirmed HR+/HER2- (estrogen receptor [ER] positive and/or progesterone receptor [PR] positive, and HER2 negative) breast cancers and are not considered a candidate for further hormonal therapy.  Subject will be considered HR+ if biopsies show ≥ 1% expression of ER or PR as per current American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines.
    • Subject has locally advanced or metastatic disease that is not amenable to curative intent treatment
    • Subject has progressed, relapsed, or discontinued for toxicity during or after at least 1 prior cytotoxic regimen, either a taxane or anthracycline in the incurable, unresectable locally advanced or metastatic setting, and has not received > 2 prior lines of cytotoxic therapy in the locally advanced or metastatic setting.  No limit applies to endocrine therapies.
      • Prior cytotoxic regimen received in the neoadjuvant or adjuvant setting will count as a prior cytotoxic regimen if disease recurrence occurred during or within 6 months of completing the regimen
      • Subject has progressed, relapsed, or discontinued for toxicity during or after receiving endocrine or hormonally-directed therapy with cyclin-dependent kinase (CDK) inhibitors
  • Cohort 2: triple negative breast cancer
    • Subject has evidence of progression on or after the last regimen received
    • Subject has histologically or cytologically-confirmed TNBC; defined as unequivocal TNBC histology (ER-negative/PR-negative/HER2-negative).  This is defined by < 1% expression of ER and PR by immunohistochemistry (IHC), and that are, for HER2, either 0 to 1+ by IHC, or IHC 2+ and fluorescence in situ hybridization (FISH) negative (not amplified) as per current ASCO/CAP guidelines.
    • Subject has locally advanced or metastatic disease that is not amenable to curative intent treatment
    • Subject has progressed, relapsed, or discontinued for toxicity during or after at least 1 prior cytotoxic regimen, either a taxane or anthracycline in the incurable, unresectable locally advanced or metatstatic setting, and has not received > 2 prior lines of cytotoxic therapy in the locally advanced or metastatic setting
      • Prior cytotoxic regimen received in the neoadjuvant or adjuvant setting will count as a prior cytotoxic regimen if disease recurrence occurred during or within 6 months of completing the regimen
    • Subject has received prior therapy with an anti-programmed cell death protein-1 (PD-1) or an anti-programmed cell death-ligand 1 (PD-L1) based on subject’s tumor PD-1 or PD-L1 expression and local treatment guidelines and has progressed or discontinued treatment due to toxicity, or therapy is contraindicated for subject
  • Cohort 3: squamous non-small cell lung cancer
    • Subject has evidence of progression on or after the last regimen received
    • Subject has histologically- or cytologically-confirmed squamous NSCLC
      • Subjects with mixed histology NSCLC are eligible provided there is not any component of neuroendocrine histology
      • Subjects with known epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), reactive oxygen species (ROS), BRAF, or other actionable mutations are eligible if treated with mutation targeted therapy and have progressed, relapsed, or discontinued treatment due to toxicity
    • Subject has locally advanced or metastatic disease that is not amenable to curative intent treatment.
    • Subject has either:
      • Progressed, relapsed, or discontinued treatment due to toxicity after 1 platinum-based therapy for locally advanced or metastatic disease, and has not received > 2 prior lines of cytotoxic therapy in the locally advanced or metastatic setting
        • Maintenance therapy does not constitute a new chemotherapy regimen provided there was no progression after the initial platinum-based regimen
        • Changing chemotherapy agents during platinum-based treatment for the management of toxicities does not constitute a new chemotherapy regimen provided no progression had occurred while on the initial therapy
      • OR
      • Progressed or relapsed within 6 months of last dose of platinum-based adjuvant, neoadjuvant, or concomitant chemoradiation regimen for early stage or locally advanced stage disease
    • Subject has received prior therapy with an anti-programmed cell death protein-1 (PD-1) or anti- programmed cell death-ligand 1 (PD-L1) based on subject’s tumor PD-1 or PD-L1 expression and local treatment guidelines and has progressed, relapsed, or discontinued treatment due to toxicity, or therapy is contraindicated for subject
  • Cohort 4: non-squamous non-small cell lung cancer
    • Subject has evidence of progression on or after the last regimen received
    • Subject has histologically or cytologically-confirmed non-squamous NSCLC
      • Subjects with mixed histology NSCLC are eligible provided there is not any component of neuroendocrine histology
      • Subjects with known EGFR, ALK, ROS, BRAF, or other actionable mutations are eligible if treated with mutation targeted therapy and have progressed, relapsed, or discontinued treatment due to toxicity
    • Subject has locally advanced or metastatic disease that is not amenable to curative intent treatment
    • Subject has either:
      • progressed, relapsed, or discontinued treatment due to toxicity after 1 platinum-based therapy for locally advanced or metastatic disease, and has not received > 2 prior lines of cytotoxic therapy in the locally advanced or metastatic setting
        • Maintenance therapy does not constitute a new chemotherapy regimen provided there was no progression after the initial platinum-based regimen
        • Changing chemotherapy agents during platinum-based treatment for the management of toxicities does not constitute a new chemotherapy regimen provided no progression has occurred while on the initial therapy
      • OR
      • progressed or relapsed within 6 months of last dose of platinum-based adjuvant, neoadjuvant, or concomitant chemoradiation regimen for early stage or locally advanced stage disease
    • Subject has received prior therapy with an anti-PD-1 or anti-PD-L1 based on subject’s tumor PD- 1 or PD-L1 expression and local treatment guidelines and has progressed, relapsed, or discontinued treatment due to toxicity, or therapy is contraindicated for subject
  • Cohort 5: head and neck cancer
    • Subject has evidence of progression on or after the last regimen received
    • Subject has histologically- or cytologically-confirmed head and neck cancer
      • Primary tumor site must arise from the oral cavity, oropharynx, hypopharynx, and larynx; tumors arising from the nasopharynx are excluded
    • Subject has locally advanced or metastatic disease that is not amenable to curative intent treatment
    • Subject has progressed, relapsed, or discontinued treatment due to toxicity after 1 platinum-based therapy for locally advanced or metastatic disease, and has not received > 2 prior lines of cytotoxic therapy in the locally advanced or metastatic setting
      • Platinum regimens administered as part of multimodal therapy in the curative setting will count as a regimen if relapse occurred ≤ 6 months after completion
    • Subject has received prior therapy with an anti-PD-1 or anti-PD-L1 based on subject’s tumor PD-1 or PD-L1 expression and local treatment guidelines and has progressed, relapsed, or discontinued treatment due to toxicity, or therapy is contraindicated for subject
  • Cohort 6: gastric or gastroesophageal junction or esophageal cancer
    • Subject has evidence of progression on or after the last regimen received
    • Subject has histologically- or cytologically-confirmed gastric, GEJ, or esophageal cancer
    • Subject has locally advanced or metastatic disease that is not amenable to curative intent treatment
    • Subject has progressed, relapsed, or discontinued due to toxicity after 1 platinum-based therapy for locally advanced or metastatic disease, and has not received > 2 prior lines of cytotoxic therapy in the locally advanced or metastatic setting
      • Neoadjuvant or adjuvant regimens will count as a prior regimen if relapsed or progressed ≤ 6 months after completion
    • Subject must have received a HER2 directed therapy if known to have HER2 positive cancer
Exclusion Criteria
  • Subject has preexisting sensory or motor neuropathy Grade ≥ 2
  • Subject has active central nervous system (CNS) metastases. Subjects with treated CNS metastases are permitted on study if all the following are true:
    • CNS metastases have been clinically stable for ≥ 6 weeks prior to screening
    • If requiring steroid treatment for CNS metastases, the subject is on a stable dose ≤ 20 mg/day of prednisone or equivalent for ≥ 2 weeks
    • Baseline imaging scans show no evidence of new or enlarged brain metastasis
    • Subject does not have leptomeningeal disease
  • Subject has ongoing clinically significant toxicity (Grade 2 or higher with the exception of alopecia) associated with prior treatment (including systemic therapy, radiotherapy or surgery)
  • Subjects with ongoing ≥ Grade 3 immunotherapy-related hypothyroidism or panhypopituitarism are excluded.  Subjects with ongoing immunotherapy-related colitis, uveitis, myocarditis or pneumonitis, or subjects with other immunotherapy-related AEs requiring high doses of steroids (> 20 mg/day of prednisone or equivalent), are excluded.  Subject with ≤ Grade 2 immunotherapy-related hypothyroidism or panhypopituitarism may be enrolled when well- maintained/controlled on a stable dose of hormone replacement therapy (if indicated).
  • Subject has a history of uncontrolled diabetes mellitus within 3 months before the first dose of study treatment.  Uncontrolled diabetes is defined as hemoglobin A1c (HbA1c) ≥ 8% or HbA1c between 7 and < 8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.
  • Subject has prior treatment with enfortumab vedotin or other monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs)
  • Subject has a second malignancy diagnosed within 3 years before first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy.  Subjects with non-melanoma skin cancer, localized prostate cancer treated with curative intent with no evidence of progression, low-risk or very low-risk (per standard guidelines) localized prostate cancer under active surveillance/watchful waiting without intent to treat, or carcinoma in situ of any type (if complete resection was performed) are allowed.
  • Subject is currently receiving systemic antimicrobial treatment for viral, bacterial, or fungal infection at the time of first dose of study treatment.  Routine antimicrobial prophylaxis is permitted.
  • Subject has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or active hepatitis C (e.g., hepatitis C virus [HCV] RNA [qualitative] is detected)
  • Subject has known history of human immunodeficiency virus (HIV) infection (HIV 1 or 2)
  • Subject has documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction or cardiac symptoms (including congestive heart failure) consistent with New York Heart Association Class III-IV within 6 months prior to the first dose of study drug
  • Subject has major surgery within 4 weeks prior to first dose of study drug
  • Subject had radiotherapy, chemotherapy, biologics, investigational agents, and/or antitumor treatment with immunotherapy that is not completed 2 weeks prior to first dose of study drug
  • Subject has known hypersensitivity to enfortumab vedotin or to any excipient contained in the drug formulation of enfortumab vedotin (including histidine, trehalose dihydrate and polysorbate 20) OR subject has known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells
  • Subject has known active keratitis or corneal ulcerations. Subject with superficial punctate keratitis is allowed if the disorder is being adequately treated in the opinion of the investigator
  • Subject has any condition, which, in the investigator’s opinion, makes the subject unsuitable for study participation

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/show/NCT04225117

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Re: MC# 20-10