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Phase I-II, FIH, TROP2 ADC, Advanced Unresectable/Metastatic Solid Tumors, Refractory to Standard Therapies (A264)

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ClinicalTrials.gov Identifier: NCT04152499
Recruitment Status : Recruiting
First Posted : November 5, 2019
Last Update Posted : June 25, 2021
Sponsor:
Information provided by (Responsible Party):
Klus Pharma Inc.

Brief Summary:

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:

  1. Triple negative breast cancer
  2. Epithelial ovarian cancer
  3. Non-small cell lung cancer
  4. Gastric adenocarcinoma
  5. Small cell lung cancer
  6. Urothelial carcinoma

Condition or disease Intervention/treatment Phase
Ovarian Epithelial Cancer Gastric Adenocarcinoma Breast Cancer Urothelial Carcinoma Non-Small Cell Lung Cancer Small-Cell Lung Cancer Drug: SKB264 Phase 1 Phase 2

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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 250 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : February 28, 2020
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : December 2022


Arm Intervention/treatment
Experimental: Phase I: Dose Escalation
Five 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
Drug: SKB264
SKB264 is an Antibody Drug Conjugate (ADC) targeting TROP2 expressing cancer cells.

Experimental: Phase II: Triple Negative Breast cancer
Histologically documented, incurable, locally advanced or metastatic cancer
Drug: SKB264
SKB264 is an Antibody Drug Conjugate (ADC) targeting TROP2 expressing cancer cells.

Experimental: Phase II: Ovarian Epithelial cancer
Histologically documented, incurable, locally advanced or metastatic cancer
Drug: SKB264
SKB264 is an Antibody Drug Conjugate (ADC) targeting TROP2 expressing cancer cells.

Experimental: Phase II: Non-Small Cell Lung Cancer
Histologically documented, incurable, locally advanced or metastatic cancer
Drug: SKB264
SKB264 is an Antibody Drug Conjugate (ADC) targeting TROP2 expressing cancer cells.

Experimental: Phase II: Gastric Adenocarcinoma
Histologically documented, incurable, locally advanced or metastatic cancer
Drug: SKB264
SKB264 is an Antibody Drug Conjugate (ADC) targeting TROP2 expressing cancer cells.

Experimental: Phase II: Small Cell Lung Cancer
Histologically documented, incurable, locally advanced or metastatic cancer
Drug: SKB264
SKB264 is an Antibody Drug Conjugate (ADC) targeting TROP2 expressing cancer cells.

Experimental: Phase II: Urothelial Carcinoma
Histologically documented, incurable, locally advanced or metastatic cancer
Drug: SKB264
SKB264 is an Antibody Drug Conjugate (ADC) targeting TROP2 expressing cancer cells.




Primary Outcome Measures :
  1. Phase I: Maximum Tolerated Dose (MTD) and Recommended Doses for Expansion (RDEs) [ Time Frame: Assess up to 12 months ]
    To determine the maximum tolerated dose (MTD) and/or recommended doses for expansion (RDEs). RDEs will not exceed MTD.

  2. Phase II: Objective Response Rate (ORR) [ Time Frame: 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 12 months ]
    To evaluate the objective response rate (ORR) [Complete Response (CR) + Partial Response (PR)] of SKB264 when administered intravenously (IV) as monotherapy at the RDEs to patients with metastatic or locally advanced unresectable tumors.


Secondary Outcome Measures :
  1. Phase I: Dose Limiting Toxicities (DLTs) [ Time Frame: Day 28 days after first infusion of study drug ]
    To determine the dose limiting toxicities (DLTs) of SKB264 when administered IV twice (on Days 1 and 15) every 2 weeks in 4 weeks (28 days) cycles as monotherapy to patients with metastatic or locally advanced unresectable tumors.

  2. Phase I: Overall safety and tolerability profile [ Time Frame: Assessed up to end of study, approximately 12 months ]
    To determine the treatment emergent adverse events by severity and by dose level of SKB264 when administered IV twice (on Days 1 and 15) every 2 weeks in 4 weeks (28 days) cycles as monotherapy to patients with metastatic or locally advanced unresectable tumors.

  3. Phase I: Preliminary efficacy based on ORR (Objective Response Rate) [ Time Frame: From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, approximately 12 months ]
    ORR (Objective Response Rate) as determined by the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1, which will be complete response (CR) + partial response (PR)

  4. Phase I: Preliminary efficacy based on DOR(Duration of Response) [ Time Frame: From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, approximately 12 months ]
    To evaluate preliminary efficacy in patients treated with SKB264 as monotherapy based on DOR(Duration of Response).

  5. Phase I: Preliminary efficacy based on PFS(Progression-Free Survival) [ Time Frame: From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, approximately 12 months ]
    To evaluate preliminary efficacy in patients treated with SKB264 as monotherapy based on PFS(Progression-Free Survival).

  6. Phase I: Preliminary efficacy based on OS(Overall Survival) [ Time Frame: From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, approximately 12 months ]
    To evaluate preliminary efficacy in patients treated with SKB264 as monotherapy based on OS(Overall Survival)

  7. Phase I and II: Anti-drug Antibodies (ADA) [ Time Frame: From Cycle 1 to Cycle 6 and End of Treatment(EOT), approximately 12 months ]
    To assess the incidence of anti-drug antibody (ADA) formation to SKB264.

  8. Phase I and II: Levels of TROP2 expression in tumor tissue [ Time Frame: Screening and End of Treatment(EOT), approximately 12 months ]
    To assess levels of TROP2 expression in tumor tissue and correlation of those levels with responses and toxicity.

  9. Phase I and II: Characterization of PK_Cmax [ Time Frame: From Cycle 1 to Cycle 6 and End of Treatment(EOT), approximately 12 months ]
    To characterize the PK of SKB264-TAB, such as Cmax

  10. Phase I and II: Characterization of PK_AUC (Area Under the Curve) [ Time Frame: From Cycle 1 to Cycle 6 and End of Treatment(EOT), approximately 12 months ]
    To characterize the PK of SKB264-TAB, such as AUC (Area Under the Curve)

  11. Phase I and II: Characterization of PK_Half life [ Time Frame: From Cycle 1 to Cycle 6 and End of Treatment(EOT), approximately 12 months ]
    To characterize the PK of SKB264-TAB, such as half life

  12. Phase II: Recommended Doses for Expansion (RDEs) [ Time Frame: After Day 28 from the first infusion at each dose level in Phase Ⅰ ]
    To obtain additional characterization of the safety of SKB264 at the RDEs.

  13. Phase II: Efficacy based on DOR(Duration of Response) [ Time Frame: From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, approximately 12 months. ]
    To evaluate efficacy in patients treated with SKB264 as monotherapy based on DOR(Duration of Response)

  14. Phase II: Efficacy based on PFS (Progression-Free Survival) [ Time Frame: From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, approximately 12 months. ]
    To evaluate efficacy in patients treated with SKB264 as monotherapy based on PFS (Progression-Free Survival)

  15. Phase II: Efficacy based on OS (Overall Survival) [ Time Frame: From date of enrollment until the date of first documented progression or date of death from any cause, whichever came first, approximately 12 months. ]
    To evaluate efficacy in patients treated with SKB264 as monotherapy based on OS (Overall Survival)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Phase I:

  1. Patients must be able to provide documented voluntary informed consent.
  2. Male or female patient aged 18-75 years.
  3. Histologically documented, incurable, locally advanced or metastatic epithelial origin malignant cancer , priority to include but not limited to the following tumor types:

    • Breast cancer
    • Ovarian epithelial cancer
    • Non-small cell lung cancer
    • Gastric adenocarcinoma
    • Small cell lung cancer
    • Urothelial cancers

    Note: Confirmation of TROP2 expression by immunohistology or other means is not required, but the Sponsor will request tissue specimens from fresh or archived materials for determination of TROP2 expression.

  4. Measurable disease by CT/MRI during dose escalation.
  5. Patients should have an unresectable locally advanced or metastatic solid tumor that is refractory to standard therapies, or have no standard therapies, or standard treatment is not applicable at this stage.
  6. Granulocyte count ≥ 1.5×109/L, platelet count ≥ 100×109/L, and hemoglobin ≥ 9 g/dL.
  7. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5×ULN.
  8. 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).
  9. 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.
  10. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1.
  11. 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 . 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 hormonereleasing 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 are excluded from birth control if they had had tubal ligation or a hysterectomy.
  12. Patients must have recovered (i.e., improvement to Grade 1 or better) from all acute toxicities from previous therapy, excluding alopecia and vitiligo.
  13. Expected survival ≥ 3 months.

Phase II:

  1. Patients must be able to provide documented voluntary informed consent.
  2. Male or female patient aged 18-75 years.
  3. Histologically documented, incurable, locally advanced or metastatic cancer, priority to include but not limited to the following tumor types (the sponsor will add or remove indications based on real-time study results):

    • Triple negative breast cancer
    • Epithelial ovarian cancer
    • Non-small cell lung cancer
    • Gastric adenocarcinoma
    • Small cell lung cancer
    • Urothelial carcinoma

    Note: Confirmation of TROP2 expression by immunohistology or other means is not required, but the Sponsor will request tissue specimens from fresh or archived materials for determination of Trop-2 expression

  4. Measurable disease by CT/MRI.
  5. Patients should have an unresectable locally advanced or metastatic solid tumor that is refractory to standard therapies, or have no standard therapies, or standard treatment is not applicable at this stage.
  6. Granulocyte count ≥ 1.5×109/L, platelet count ≥ 100×109/L, and hemoglobin ≥ 9 g/dL.
  7. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5×ULN.
  8. 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).
  9. 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.
  10. ECOG Performance Status 0 or 1.
  11. 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. 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 hormonereleasing 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 are excluded from birth control if they had had tubal ligation or a hysterectomy.
  12. Patients must have recovered (i.e., improvement to Grade 1 or better) from all acute toxicities from previous therapy, excluding alopecia and vitiligo.
  13. Expected survival ≥ 3 months.

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. Subjects with second primary cancers (except for cured in situ non-melanoma skin cancer and in situ cervical cancer with no relapse in the last 3 years).
  4. Require supplemental oxygen for daily activities.
  5. Documented Grade ≥ 2 peripheral neuropathy.
  6. History of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, corneal disease that prevents/delays corneal healing, macular degeneration.
  7. Subjects previously treated with TROP 2 targeted therapies.
  8. Any standard cancer therapy (e.g chemotherapy, hormonal therapy, radiotherapy, immunotherapy, biologic therapy treatment, or therapy with traditional Chinese medicines approved for anti-tumor treatment, etc.) within 4 weeks or five half-lives, whichever is shorter, of first infusion of study drug.
  9. Any experimental therapy within 4 weeks or five half-lives, whichever is shorter, of first infusion of study drug.
  10. Any major surgical procedure within 4 weeks of first infusion of study drug.
  11. Diagnosed active liver disease, including viral or other hepatitis, current or history of alcoholism, or cirrhosis.
  12. Have known prior positive test results or medical history for human immunodeficiency virus.
  13. Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg) or diabetes (HbA1c ≥ 9.0%).
  14. 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.
  15. Pregnancy or lactation.
  16. Left ventricular ejection fraction < 45% determined by echocardiogram or multiple gated acquisition scan.
  17. Resting QTc > 480 msec at baseline.
  18. Ascites requiring paracentesis ≥1 per week.
  19. Symptomatic pleural effusion (< 90% oxygen saturation).
  20. Subjects with non-infectious interstitial lung diseases (ILD) or medical history of pneumonia requiring steroid treatments; severe pulmonary dysfunction caused by lung diseases.
  21. New diagnosed thromboembolic events that requires therapeutic intervention over the last 6 months (patients with stable control of lower limb deep venous thrombosis are allowed).
  22. The investigator considers other situations that patients are not appropriate to participate in this trial.

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. Subjects with second primary cancers (except for cured in situ non-melanoma skin cancer and in situ cervical cancer with no relapse in the last 3 years).
  5. Require supplemental oxygen for daily activities.
  6. Documented Grade ≥ 2 peripheral neuropathy.
  7. History of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, corneal disease that prevents/delays corneal healing, macular degeneration.
  8. Subjects previously treated with TROP 2 targeted therapies.
  9. Any standard cancer therapy (e.g chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or biologic therapy treatment, or therapy with traditional Chinese medicines approved for anti-tumor treatment, etc.) within 4 weeks or 5 half-lives, whichever is shorter, of first infusion of study drug.
  10. Any experimental therapy within 4 weeks or 5 half-lives, whichever is shorter, of first infusion of study drug.
  11. Any major surgical procedure within 4 weeks of first infusion of study drug.
  12. Diagnosed active liver disease, including viral or other hepatitis, current or history of alcoholism, or cirrhosis.
  13. Have known prior positive test results or medical history for human immunodeficiency virus.
  14. Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg) or diabetes (HbA1c ≥ 9.0%).
  15. 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.
  16. Pregnancy or lactation.
  17. Left ventricular ejection fraction < 45% determined by echocardiogram or multiple gated acquisition scan.
  18. Resting QTc > 480 msec at baseline.
  19. Ascites requiring paracentesis ≥1 per week.
  20. Symptomatic pleural effusion (< 90% oxygen saturation).
  21. Subjects with non-infectious interstitial lung diseases (ILD) or medical history of pneumonia requiring steroid treatments; severe pulmonary dysfunction caused by lung diseases.
  22. New diagnosed thromboembolic events that requires therapeutic intervention over the last 6 months (patients with stable control of lower limb deep venous thrombosis are allowed).
  23. The investigator considers other situations that patients are not appropriate to participate in this trial.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04152499


Contacts
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Contact: Study Manager 650-237-9339 jenny.li@kluspharma.com

Locations
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Sponsors and Collaborators
Klus Pharma Inc.
Investigators
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Study Chair: Jordi Rodon Ahnert, MD, PhD M.D. Anderson Cancer Center
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Responsible Party: Klus Pharma Inc.
ClinicalTrials.gov Identifier: NCT04152499    
Other Study ID Numbers: KL264-01
First Posted: November 5, 2019    Key Record Dates
Last Update Posted: June 25, 2021
Last Verified: June 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Klus Pharma Inc.:
TROP2, ADC
Additional relevant MeSH terms:
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Lung Neoplasms
Small Cell Lung Carcinoma
Carcinoma, Ovarian Epithelial
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Ovarian Neoplasms
Endocrine Gland Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders