MC# 19-25 - A Phase Ib Open-label, Multicenter Dose Escalation and Expansion Study of MT-5111 in Subjects with Previously Treated Advanced HER2-positive Solid Tumors

  • Agent(s): MT-5111
  • Disease Type(s): Breast, Solid Tumor
  • Phase(s): I
  • Drug Classification(s): Antibody Drug Conjugate
  • Molecular Target(s): ERBB2 (HER2)

Mechanism of Action

MT-5111 specifically binds to HER2 expressing cells in a manner consistent with Shiga-like toxin-A subunit mediated cellular cytotoxicity by enzymatic ribosome inhibition and cell death.


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

  • How much of MT-5111 can be given with an acceptable level of side effects
  • The effects of MT-5111 (good and bad)
  • How fast MT-5111 is removed from the body
  • About the safety and tolerability of MT-5111
  • How proteins that indicate the status of your disease are affected with use of MT-5111
  • If MT-5111 prevents or delays tumor growth or shrinks an existing tumor
Inclusion Criteria
  • Subject must sign the written informed consent form before any screening procedure
  • Subject must be aged ≥ 18 years on the date of signing the informed consent
  • Subject must have histologically confirmed, unresectable, locally advanced or metastatic solid cancers
    • In Part 1, all HER2-positive solid cancers are eligible
    • In Part 2, HER2-positive breast, GEA and other HER2-positive solid cancers are eligible for the respective expansion cohorts
  • All subjects in both parts of the study must be HER2-positive in the latest tumor sample tested for HER2 (it is required that testing is done on a metastatic lesion in cases of metastatic cancers), according to standard testing procedures. For the purpose of this study, HER2-positivity is defined as:
    • Tumors tested by immunohistochemistry (IHC): must have an IHC status of 2+ or 3+, regardless of ISH result
    • Tumors tested by ISH only (no IHC available): must be HER2-positive according to the applicable disease specific ASCO-CAP guideline (for breast and GEA). Note: other cancers for which a disease-specific guideline is not available must be tested via IHC and must have a status of 2+ or 3+, regardless of ISH result.
  • Subject should be relapsed or refractory to existing therapy(ies) known to provide clinical benefit for the underlying cancer or have been intolerant of such therapies
    • Subjects with HER2-positive breast cancer should have received at least two lines of HER2-directed therapy in the advanced setting and should have received pertuzumab and trastuzumab emtansine in either the early-stage or advanced setting
    • Subjects with HER2-positive gastric cancer must have previously received trastuzumab or have been intolerant of such therapy
  • Subject must have at least 1 measurable tumor lesion according to RECIST 1.1
    • Subjects with evaluable disease only may be included in the dose escalation phase
  • Subject must have Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1
  • Subject must have a life expectancy of at least 3 months
  • Subject must have adequate bone marrow function, as determined by:
    • Absolute neutrophil count (ANC) ≥1,000/mm3
    • Platelet count ≥75,000 mm³ and
    • Hemoglobin ≥ 8.0 g/dL. No red blood cell transfusion within 4 weeks of study treatment start is allowed.
  • Subject must have adequate kidney function, assessed by the estimated glomerular filtration rate (eGFR) ≥50 mL/min calculated by the Cockroft-Gault formula (APPENDIX C)
    • At the Investigator’s discretion, the eGFR result <50 mL/min will be verified by measurement of creatinine clearance (CLcr) based on the 24-hour urine collection.  Subjects with CLcr ≥50 mL/min will be eligible irrespective of the eGFR result.
  • Subject must have adequate hepatic function, as determined by:
    • Total bilirubin ≤ 1.5 x ULN, or ≤ 3 x ULN for subjects with Gilbert's Syndrome and
    • AST ≤ 3 x ULN (or ≤ 5 x ULN if liver metastasis) and
    • ALT ≤ 3 x ULN (or ≤ 5 x ULN if liver metastasis)
  • Subject must have adequate serum albumin, as determined by:
    • Albumin ≥ 2.5 g/dL
  • Subject must have adequate coagulation, as determined by:
    • International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN (unless on therapeutic anticoagulants and the dose is stable over at least 4 weeks and the INR is < 3.5), and
    • Partial thromboplastin time (PTT) ≤ 1.5 x ULN (unless on therapeutic anticoagulants)
  • Subject must have adequate cardiac function, as determined by:
    • Left ventricular ejection fraction (LVEF) ≥ 55% on the multigated acquisition (MUGA) scan (preferred) or echocardiogram (ECHO) assessment, and
    • QTcF ≤ 480 ms for women and QTcF ≤450 ms for men [average from three QTcF values on the triplicate 12- lead electrocardiogram (ECG)] at baseline
  • Women of reproductive potential must have a negative pregnancy test during the screening period within 72 hours before the start of treatment.  Women not of reproductive potential are female subjects who are postmenopausal or permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy).
  • Subjects of reproductive potential must agree to either abstain continuously from heterosexual intercourse or to use a highly effective method of birth control between signing the informed consent until 90 days after last study treatment.  The Investigator or Delegate should advise the subject to use a double barrier method to achieve adequate contraception.  The following birth control methods will be considered as adequate:
    • Condoms (male or female) with a spermicidal agent;
    • Diaphragm or cervical cap with spermicide;
    • Condom with diaphragm;
    • Intrauterine device;
    • Hormone-based contraception: Established use of oral, injected, or implanted hormonal methods of contraception;
    • Vasectomy (for a male subject or male partner of a female subject)
Exclusion Criteria
  • History or current evidence of neoplastic disease that is histologically distinct from the tumor under study, except cervical carcinoma in situ, superficial noninvasive bladder tumors, curatively treated Stage I-II non-melanoma skin cancer, or any other previous cancer curatively treated more than 2 years prior to enrollment in this study.  Subjects with any other active malignancy may only be enrolled after discussion and approval by the Sponsor.
  • Current evidence of new or growing CNS metastases during screening.  Subjects with known CNS metastases will be eligible if they meet all the following criteria:
    • Had radiotherapy or another appropriate therapy for the brain or spinal metastases
    • Have no neurological symptoms (excluding Grade ≤ 2 neuropathy)
    • Have stable CNS disease on the Computed tomography (CT) or magnetic resonance imaging (MRI) scan within 4 weeks before signing the informed consent compared with prior neuro-imaging.
    • Do not require steroid therapy
  • Current evidence of CTCAE Grade > 1 toxicity before the start of treatment, except for hair loss and those Grade 2 toxicities listed as permitted in other eligibility criteria.  Subjects with Grade 2 neuropathy or other toxicities that are asymptomatic or adequately managed with stable medication may be eligible with approval by the Sponsor.
  • Current evidence of incomplete recovery from surgery or radiotherapy at screening, or planned surgery or radiotherapy from the start of treatment until the post-study follow-up Visit, except minor elective surgery deemed acceptable by the Investigator
  • History or current evidence of significant (CTCAE Grade ≥ 2) infection or wound within 2 weeks before the start of treatment
  • History or current evidence of significant cardiovascular disease before the start of treatment, but not limited to the following conditions:
    • (hs)Troponin I or T > ULN at screening
    • Angina pectoris requiring anti-anginal medication, (chest pain: CTCAE Grade ≥ 2) or clinically significant valvular disease
    • Myocardial infarction within 12 months prior to the start of treatment
    • Arterial thrombosis or pulmonary embolism within ≤ 6 months before the start of treatment
    • Pericarditis (any CTCAE grade), pericardial effusion (CTCAE Grade ≥ 2), non-malignant pleural effusion (CTCAE Grade ≥ 2) or malignant pleural effusion (CTCAE Grade ≥ 3) (subjects with pleural effusion that is manageable and stable >3 months prior to study are eligible)
    • LVEF < 55%, assessed by MUGA scan (preferred) or echocardiography within 1 month before starting study treatment
    • History of Grade ≥ 2 symptomatic congestive heart failure (CHF) or New York Heart Association (NYHA) criteria Class ≥ II (APPENDIX A)
    • High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate > 100/min at rest, significant ventricular arrhythmia (CTCAE Grade ≥ 2) [ventricular tachycardia], or higher-grade atrioventricular (AV)-block [second degree AV-block Type 2 [Mobitz 2] or third degree AV-block]
  • Current evidence of active, uncontrolled hepatitis B virus, hepatitis C virus, human immunodeficiency virus (HIV) (evidenced by detectable viral load by PCR) or acquired immunodeficiency syndrome (AIDS) related illness
    • Serology and virology measurements are not required to be performed at screening, but any previously-reported results should be used for eligibility purposes.  Investigators will test per their discretion.
    • Subjects with a history of treated hepatitis C and nonquantifiable HCV-RNA may be enrolled
    • Subjects on treatment for hepatitis B and/or HIV will be eligible if they have undetectable viral load
      • Subjects with CD4+ T-cell (CD4+) counts ≥ 350 cells/microliter may be enrolled
      • Subjects taking atazanavir should be considered for alternate therapy given the risk of cardiac conduction abnormalities
  • Known or suspected hypersensitivity to the study drug or excipients contained in the study drug formulation
  • Current evidence of hypersensitivity requiring systemic steroids at doses > 20 mg/day prednisone equivalent
  • History or current evidence of any other medical or psychiatric condition or addictive disorder, or laboratory abnormality that, in the opinion of the Investigator, will increase the risks associated with study participation, or require treatments that will interfere with the conduct of the study or the interpretation of study results
  • Current evidence of ≥ Grade 2 underlying pulmonary disease
  • Women who are pregnant or breastfeeding
  • Subjects with unintentional weight loss greater than 10% of their body weight over the preceding 3 months or less
  • Received systemic therapy for the cancer under study or any investigational drug within 4 weeks before the start of treatment
  • Received immunosuppressive agents or other prescribed corticosteroids at doses ≥ 20 mg prednisone equivalent per day within 2 weeks before the start of treatment
  • For Part 1 (dose escalation phase): Received chemotherapy with doxorubicin (or another anthracycline) at any time
  • For Part 2 (dose expansion phase): Received chemotherapy with anthracycline or anthracenedione agents at the doxorubicin equivalent cumulative dose (sum total for all agents combined) of 550 mg/m2 body surface area (BSA), or a lower total doxorubicin equivalent cumulative dose that, in the opinion of the Investigator, would increase the risk of cardiomyopathy in this study, or subjects who have received mitoxantrone at cumulative doses considered to increase the risk of cardiomyopathy.  For subjects who have received a cumulative dose of an anthracycline of more than 300 mg/m2, approval must first be obtained from the Medical Monitor.
  • Received granulocyte colony–stimulating factor (G-CSF) or granulocyte-macrophage colony–stimulating factor (GM-CSF) for the treatment of leukopenia within 2 weeks before the start of treatment


  • Dallas, TX - Mary Crowley Cancer Research - Medical City
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Re: MC# 19-25