MC# 19-36 - A Phase I-II, First-in-Human Study of SKB264 in Patients with Locally Advanced/Metastatic Solid Tumors who are refractory to Available Standard Therapies

  • Agent(s): SKB264
  • Disease Type(s): Bladder, Gastric, Ovarian, Pancreatic, Breast- Triple Negative
  • Phase(s): I, II
  • Drug Classification(s): Antibody Drug Conjugate
  • Molecular Target(s): TROP2

Mechanism of Action

SKB264 is an antibody drug conjugate targeting human trophoblast cell surface antigen 2 (TROP2)

Purpose

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

  • About the safety and tolerability of SKB264
  • How proteins that indicate the status of your disease are affected with use of SKB264
  • If SKB264 prevents or delays tumor growth or shrinks existing tumors
  • How much of SKB264 is absorbed into the blood and how fast it is removed
Inclusion Criteria

Phase I

  • Patients must be able to provide documented voluntary informed consent
  • Male or female patient ≥ 18 years
  • Histologically documented, incurable, locally advanced or metastatic cancer of one of the following types:
    • Ovarian epithelial cancer
    • Gastric adenocarcinoma
    • Pancreatic adenocarcinoma
    • Triple negative breast cancer
    • Bladder cancer
  • Note: Confirmation of TROP2 expression by immunohistology or other means is not required, but the Sponsor will request tissue specimens from archived materials for determination of TROP2 expression
  • Measurable or evaluable disease by CT/MRI during dose escalation
  • Patients should have an unresectable locally advanced or metastatic solid tumor that is refractory to all standard therapies
  • Granulocyte count ≥ 1.5×109/L, platelet count ≥ 100×109/L, and hemoglobin ≥ 9 g/dL
  • Serum bilirubin ≤ 1.5 mg/dL, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≤ 2.5 × upper limit of normal (ULN), with the exception of patients with hepatic metastases (ALT and AST ≤ 5 × ULN) and patients with hepatic and/or bone metastases (alkaline phosphatase ≤ 5 × ULN)
  • Creatinine clearance ≥ 50 mL/min calculated by Cockcroft-Gault, Chronic Kidney Disease Epidemiology Collaboration, or Modification of Diet in Renal Disease formulas. Note that 24-hour urine collection is not required but is allowed
  • Eastern Cooperative Oncology Group Performance Status ≤ 1
  • For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception during study treatment that results in a low failure rate of <1% per year when used consistently and correctly.  Female and male patient treated with SKB264 should continue contraception use for 7 months after the last dose.  Such methods include combined (estrogen and progestogen containing) hormonal contraception, progestogen- only hormonal contraception associated with inhibition of ovulation together with another additional barrier method always containing a spermicide, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion or vasectomized partner (on the understanding that this is the only one partner during the whole study duration), and sexual abstinence.
  • Oral contraception should always be combined with an additional contraceptive method because of a potential interaction with the study drug.  The same rules are valid for male patients involved in this clinical trial if they have a partner of childbirth potential.  Male patients must always use a condom.
  • Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 14 days prior to initiation of study drug
  • Women are excluded from birth control if they had had tubal ligation or a hysterectomy
  • Patients must have recovered (i.e., improvement to Grade 1 or better) from all acute toxicities from previous therapy, excluding alopecia and vitiligo

Phase II:

  • Patients must be able to provide documented voluntary informed consent
  • Male or female patient ≥ 18 years
  • Histologically documented, incurable, locally advanced or metastatic cancer as follows:
    • Cohort 1: Gastric adenocarcinoma
    • Cohort 2: Pancreatic adenocarcinoma
    • Cohort 3: Bladder cancer
      • Note: Confirmation of TROP2 expression by immunohistology or other means is not required, but the Sponsor will request tissue specimens from archived materials for determination of Trop-2 expression
  • Measurable disease by CT/MRI
  • Granulocyte count ≥ 1.5×109/L, platelet count ≥ 100×109/L, and hemoglobin ≥ 9 g/dL
  • Serum bilirubin ≤ 1.5 mg/dL, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≤ 2.5 × upper limit of normal (ULN), with the exception of patients with hepatic metastases (ALT and AST ≤ 5 × ULN) and patients with hepatic and/or bone metastases (alkaline phosphatase ≤ 5 × ULN)
  • Creatinine clearance ≥ 50 mL/min calculated by Cockroft-Gault, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), or Modification of Diet in Renal Disease (MDRD) formulas.  Note that 24-hour urine collection is not required but is allowed.
  • ECOG Performance Status ≤ 1
  • For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception during study treatment that results in a low failure rate of <1% per year when used consistently and correctly.  Female and male patient treated with SKB264 should continue contraception use for 7 months after the last dose.  Such methods include combined (estrogen and progestogen containing) hormonal contraception, progestogen- only hormonal contraception associated with inhibition of ovulation together with another additional barrier method always containing a spermicide, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion or vasectomized partner (on the understanding that this is the only one partner during the whole study duration), and sexual abstinence.
  • Oral contraception should always be combined with an additional contraceptive method because of a potential interaction with the study drug.  The same rules are valid for male patients involved in this clinical trial if they have a partner of childbirth potential. Male patients must always use a condom.
  • Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 14 days prior to initiation of study drug
  • Women are excluded from birth control if they had had tubal ligation or a hysterectomy
  • Patients must have recovered (i.e., improvement to Grade 1 or better) from all acute toxicities from previous therapy, excluding alopecia and vitiligo
Exclusion Criteria

Phase I:

  • Severe or uncontrolled cardiac disease requiring treatment, congestive heart failure (New York Heart Association) III or IV, unstable angina pectoris even if medically controlled, history of myocardial infarction during the last 6 months, serious arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal supraventricular tachycardia)
  • Symptomatic brain metastases or any radiation or surgery for brain metastases within 3 months of first infusion of study drug
  • Require supplemental oxygen for daily activities
  • Documented Grade ≥ 2 peripheral neuropathy
  • Documented moderate to severe dry eye syndrome, moderate to severe Meibomian gland disease and/or blepharitis, keratoconjunctivitis sicca (KSC), history of corneal ulcers and/or corneal pathology that would predispose the subjects to worsening dry eye and/or the inability to heal the cornea, keratoconjunctivitis and/or corneal ulcer established by targeted ophthalmologic exam and not responsive to ophthalmic management recommended in this protocol during screening period
  • Any condition, environmental exposure or concomitant medication known to increase susceptibility of corneas to epithelial erosion (e.g. LASIK surgery, rheumatoid arthritis, Sjogren’s)
  • Any chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or biologic therapy treatment within 4 weeks or five half-lives, whichever is shorter, of first infusion of study drug
  • Any experimental therapy within 4 weeks or five half-lives, whichever is shorter, of first infusion of study drug
  • Any major surgical procedure within 4 weeks of first infusion of study drug
  • Diagnosed active liver disease, including viral or other hepatitis, current or history of alcoholism, or cirrhosis.  Patients who have positive hepatitis B virus test results due to having been previously vaccinated against hepatitis B, as evidenced by negative hepatitis B surface antigen (HBsAg), negative anti-hepatitis B core protein, and positive antibody to the HBsAg (anti-HBs) are not excluded.
  • Have known prior positive test results for human immunodeficiency virus
  • Uncontrolled hypertension or diabetes
  • Subjects who require use of strong inhibitors or inducers of CYP3A4 at least 14 days prior and throughout Study.  Use of strong inhibitors or inducers of CYP3A4 is not allowed in this Study.
  • Pregnancy or lactation
  • Left ventricular ejection fraction < 45% determined by echocardiogram or multiple-gated acquisition scan
  • Resting QTc > 480 msec at baseline
  • Ascites requiring paracentesis ≥1 per week
  • Symptomatic pleural effusion
  • New thromboembolic events over the last 6 months

Phase II:

  • Any patient who was treated in the Phase I part of this study
  • Severe or uncontrolled cardiac disease requiring treatment, congestive heart failure (New York Heart Association) III or IV, unstable angina pectoris even if medically controlled, history of myocardial infarction during the last 6 months, serious arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal supraventricular tachycardia)
  • Symptomatic brain metastases or any radiation or surgery for brain metastases within 3 months of first infusion of study drug.
  • Require supplemental oxygen for daily activities
  • Documented Grade ≥ 2 peripheral neuropathy
  • Documented moderate to severe dry eye syndrome, moderate to severe Meibomian gland disease and/or blepharitis, keratoconjunctivitis sicca (KSC), history of corneal ulcers and/or corneal pathology that would predispose the subjects to worsening dry eye and/or the inability to heal the cornea, keratoconjunctivitis and/or corneal ulcer established by targeted ophthalmologic exam and not responsive to ophthalmic management recommended in this protocol during screening period
  • Any condition, environmental exposure or concomitant medication known to increase susceptibility of corneas to epithelial erosion (e.g. LASIK surgery, rheumatoid arthritis, Sjogren’s)
  • Any chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or biologic therapy treatment within 4 weeks or 5 half-lives, whichever is shorter, of first infusion of study drug
  • Any experimental therapy within 4 weeks or 5 half-lives, whichever is shorter, of first infusion of study drug
  • Any major surgical procedure within 4 weeks of first infusion of study drug
  • Diagnosed active liver disease, including viral or other hepatitis, current or history of alcoholism, or cirrhosis.  Patients who have positive hepatitis B virus test results due to having been previously vaccinated against hepatitis B, as evidenced by negative hepatitis B surface antigen (HBsAg), negative anti-hepatitis B core protein, and positive antibody to the HBsAg (anti-HBs) are not excluded.
  • Have known prior positive test results for human immunodeficiency virus
  • Uncontrolled hypertension or diabetes
  • Subjects who require use of strong inhibitors or inducers of CYP3A4 at least 14 days prior and throughout Study.  Use of strong inhibitors or inducers of CYP3A4 is not allowed in this Study.
  • Pregnancy or lactation
  • Left ventricular ejection fraction < 45% determined by echocardiogram or multiple-gated acquisition scan
  • Resting QTc > 480 msec at baseline
  • Ascites requiring paracentesis ≥1 per week
  • Symptomatic pleural effusion
  • New thromboembolic events over the last 6 months

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT04152499

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Re: MC# 19-36