Clinical Trials /

Phase I-II, FIH, TROP2 ADC, Advanced Unresectable/Metastatic Solid Tumors, Refractory to Standard Therapies

NCT04152499

Description:

A Phase I-II, First-in-Human Study of SKB264 in Patients with Locally Advanced Unresectable/Metastatic Solid Tumors who are refractory to Available Standard Therapies. Patient must have historically documented, incurable, locally advanced or metastatic cancer that are refractory to standard therapies of one of the following types: i. Ovarian epithelial cancer (Phase I only) ii. Gastric adenocarcinoma (Phase I-II) iii. Pancreatic adenocarcinoma (Phase I-II) iv. Triple negative breast cancer (Phase I only) v. Bladder cancer (Phase I-II)

Related Conditions:
  • Bladder Carcinoma
  • Breast Carcinoma
  • Gastric Adenocarcinoma
  • Malignant Ovarian Epithelial Tumor
  • Pancreatic Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase I-II, FIH, TROP2 ADC, Advanced Unresectable/Metastatic Solid Tumors, Refractory to Standard Therapies
  • Official Title: A Phase I-II, First-in-Human Study of SKB264 in Patients With Locally Advanced Unresectable /Metastatic Solid Tumors Who Are Refractory to Available Standard Therapies

Clinical Trial IDs

  • ORG STUDY ID: KL264-01
  • NCT ID: NCT04152499

Conditions

  • Ovarian Epithelial Cancer
  • Gastric Adenocarcinoma
  • Pancreas Adenocarcinoma
  • Triple Negative Breast Cancer
  • Bladder Cancer

Interventions

DrugSynonymsArms
SKB264Phase I: Dose Escalation

Purpose

A Phase I-II, First-in-Human Study of SKB264 in Patients with Locally Advanced Unresectable/Metastatic Solid Tumors who are refractory to Available Standard Therapies. Patient must have historically documented, incurable, locally advanced or metastatic cancer that are refractory to standard therapies of one of the following types: i. Ovarian epithelial cancer (Phase I only) ii. Gastric adenocarcinoma (Phase I-II) iii. Pancreatic adenocarcinoma (Phase I-II) iv. Triple negative breast cancer (Phase I only) v. Bladder cancer (Phase I-II)

Detailed Description

      This is an open label, Phase I-II, first in human (FIH) study for SKB264 as monotherapy in
      patients who have locally advanced unresectable or metastatic solid tumor that is refractory
      to all standard therapies. TROP2 (trophoblast antigen 2) assessments will not be performed
      prior to enrollment but it will be assessed retrospectively. Confirmation of TROP2
      (trophoblast antigen 2) expression by immunohistology or other means is not required, but the
      Sponsor will request fresh tumor biopsy or tissue specimens from archived materials for
      determination of TROP2 (trophoblast antigen 2) expression retrospectively. The patient must
      be, in the judgment of the investigator, an appropriate candidate for experimental therapy
      whose tumor is refractory to standard therapies. Patients will receive study drug as a single
      IV infusion at the prescribed dose level at each administration. Cycles will continue until
      disease progression or unacceptable toxicity. The study is divided into 2 parts (Phase I and
      Phase II).
    

Trial Arms

NameTypeDescriptionInterventions
Phase I: Dose EscalationExperimentalFive dose levels have been selected for evaluation in the Phase I part of the study: 2, 4, 6, 9, and 12 mg/kg of SKB264
  • SKB264
Phase II: • Cohort 1ExperimentalHistologically documented, incurable, locally advanced or metastatic Gastric Adenocarcinoma refractory to standard therapies.
  • SKB264
Phase II: • Cohort 2ExperimentalHistologically documented, incurable, locally advanced or metastatic Pancreatic Adenocarcinoma refractory to standard therapies.
  • SKB264
Phase II: • Cohort 3ExperimentalHistologically documented, incurable, locally advanced or metastatic Bladder Cancer refractory to standard therapies.
  • SKB264

Eligibility Criteria

        Inclusion Criteria:

        Phase I:

          1. Patients must be able to provide documented voluntary informed consent.

          2. Male or female patient ≥ 18 years.

          3. Histologically documented, incurable, locally advanced or metastatic cancer that are
             refractory to standard therapies of one of the following types:

             i. Ovarian epithelial cancer ii. Gastric adenocarcinoma iii. Pancreatic adenocarcinoma
             iv. Triple negative breast cancer v. 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 or
             fresh tumor biopsy for determination of TROP2 expression retrospectively.

          4. Measurable or evaluable disease by CT/MRI during dose escalation.

          5. Patients should have an unresectable locally advanced or metastatic solid tumor that
             is refractory to all standard therapies.

          6. Granulocyte count ≥ 1.5×109/L, platelet count ≥ 100×109/L, and hemoglobin ≥ 9 g/dL.

          7. Serum bilirubin ≤ 1.5 mg/dL (Patients with known Gilbert disease who have serum
             bilirubin level ≤ 3 ×ULN may be enrolled)., 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).

          8. 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.

          9. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.

         10. 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.

         11. 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:

          1. Patients must be able to provide documented voluntary informed consent.

          2. Male or female patient ≥ 18 years.

          3. Histologically documented, incurable, locally advanced or metastatic cancer refractory
             to standard therapies as follows:

             i. Cohort 1: Gastric adenocarcinoma ii. Cohort 2: Pancreatic adenocarcinoma iii.
             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 or
             fresh tumor biopsy for determination of TROP2 expression retrospectively.

          4. Measurable disease by CT/MRI.

          5. Patients should have an unresectable locally advanced or metastatic solid tumor that
             is refractory to all standard therapies.

          6. Granulocyte count ≥ 1.5×109/L, platelet count ≥ 100×109/L, and hemoglobin ≥ 9 g/dL.

          7. Serum bilirubin ≤ 1.5 mg/dL (Patients with known Gilbert disease who have serum
             bilirubin level ≤ 3 ×ULN may be enrolled)., 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).

          8. Creatinine clearance ≥ 50 mL/min calculated by Cockcroft-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.

          9. ECOG Performance Status 0 or 1.

         10. 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.

         11. 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:

          1. 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).

          2. Symptomatic brain metastases or any radiation or surgery for brain metastases within 3
             months of first infusion of study drug.

          3. Require supplemental oxygen for daily activities.

          4. Documented Grade ≥ 2 peripheral neuropathy.

          5. 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.

          6. 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.

          7. Any experimental therapy within 4 weeks or five half-lives, whichever is shorter, of
             first infusion of study drug.

          8. Any major surgical procedure within 4 weeks of first infusion of study drug.

          9. 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.

         10. Have known prior positive test results for human immunodeficiency virus.

         11. Uncontrolled hypertension or diabetes.

         12. Subjects who require use of strong inhibitors or inducers of CYP3A4 at least 14 days
             prior to and throughout Study. Use of strong inhibitors or inducers of CYP3A4 is not
             allowed in this study. List of representative examples of strong inhibitors or
             inducers of CYP3A4 is provided in Appendix III.

         13. Pregnancy or lactation.

         14. Left ventricular ejection fraction < 45% determined by echocardiogram or multiple
             gated acquisition scan.

         15. Resting QTc (corrected QT interval) > 480 msec at baseline.

         16. Ascites requiring paracentesis ≥1 per week.

         17. Symptomatic pleural effusion.

         18. New thromboembolic events over the last 6 months

        Phase II:

          1. Any patient who was treated in the Phase I part of this study.

          2. 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).

          3. Symptomatic brain metastases or any radiation or surgery for brain metastases within 3
             months of first infusion of study drug.

          4. Require supplemental oxygen for daily activities.

          5. Documented Grade ≥ 2 peripheral neuropathy.

          6. 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.

          7. Any chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or biologic therapy
             treatment within 4 weeks of first infusion of study drug.

          8. Any experimental therapy within 4 weeks or 5 half-lives, whichever is shorter of first
             infusion of study drug.

          9. Any major surgical procedure within 4 weeks of first infusion of study drug.

         10. 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.

         11. Have known prior positive test results for human immunodeficiency virus.

         12. Uncontrolled hypertension or diabetes.

         13. Subjects who require use of strong inhibitors or inducers of CYP3A4 at least 14 days
             prior to and throughout Study. Use of strong inhibitors or inducers of CYP3A4 is not
             allowed in this Study. List of representative examples strong inhibitors or inducers
             of CYP3A4 is provided in Appendix III.

         14. Pregnancy or lactation.

         15. Left ventricular ejection fraction < 45% determined by echocardiogram or multiple
             gated acquisition scan.

         16. Resting QTc (corrected QT interval) > 480 msec at baseline.

         17. Ascites requiring paracentesis ≥1 per week.

         18. Symptomatic pleural effusion.

         19. New thromboembolic events over the last 6 months
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I: Maximum Tolerated Dose (MTD)
Time Frame:A minimum of 28 days after first infusion of study drug
Safety Issue:
Description:Number of patients with dose limiting toxicities

Secondary Outcome Measures

Measure:Phase I: Dose Limiting Toxicities (DLTs)
Time Frame:A minimum of 28 days after first infusion of study drug
Safety Issue:
Description:DLT Reporting at D28
Measure:Phase I:Treatment-related adverse events as assessed by CTCAE v5
Time Frame:Every 2 weeks from date of enrollment until until 30 days after last infusion of study drug or the end of treatment visit, whichever occurs later
Safety Issue:
Description:Treatment-related adverse event reporting
Measure:Phase I:Objective Response Rate (ORR)
Time Frame:From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months
Safety Issue:
Description:As determined by the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1, which will be complete response (CR) + partial response (PR)
Measure:Phase I and II: Duration of response (DOR)
Time Frame:Minimum of 28 days from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months
Safety Issue:
Description:DOR in patients who responded during time frame per protocol
Measure:Phase I and II: Progression Free Survival (PFS)
Time Frame:From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months
Safety Issue:
Description:Kaplan Meier Curve for survival without progression in patients who responded to treatment
Measure:Phase I and II: Overall Survival (OS)
Time Frame:From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months
Safety Issue:
Description:Kaplan Meier Curve for survival in all enrolled patients
Measure:Phase I and II: Anti-drug antibodies (ADA)
Time Frame:Minimum of 28 days from date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months
Safety Issue:
Description:ADA data from Bioanalytical Lab.
Measure:Phase I and II: Maximum observed serum or plasma concentration (Cmax)
Time Frame:Through study completion, an average of 24 months
Safety Issue:
Description:One of the PK (pharmacokinetics) parameters for SKB264
Measure:Phase I and II: Area under the serum or plasma concentration time curve from 0 to infinity (AUC[0-∞])
Time Frame:Through study completion, an average of 24 months
Safety Issue:
Description:One of the PK (pharmacokinetics) parameters for SKB264
Measure:Phase I and II: Clearance (CL)
Time Frame:Through study completion, an average of 24 months
Safety Issue:
Description:One of the PK (pharmacokinetics) parameters for SKB264
Measure:Phase I and II: Terminal phase elimination half life (t½)
Time Frame:Through study completion, an average of 24 months
Safety Issue:
Description:One of the PK (pharmacokinetics) parameters for SKB264
Measure:Phase I and II: Volume of distribution at terminal phase (Vz)
Time Frame:Through study completion, an average of 24 months
Safety Issue:
Description:One of the PK (pharmacokinetics) parameters for SKB264
Measure:Phase I and II: Volume of distribution at steady state (Vss)
Time Frame:Through study completion, an average of 24 months
Safety Issue:
Description:One of the PK (pharmacokinetics) parameters for SKB264
Measure:Phase I and II: Levels of TROP2 (trophoblast antigen 2) expression in tumor tissue
Time Frame:Through study completion, an average of 24 months
Safety Issue:
Description:To investigate any potential correlations of TROP2 (trophoblast antigen 2) levels with responses and toxicity

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Klus Pharma Inc.

Trial Keywords

  • TROP2, ADC

Last Updated

April 23, 2020