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

• ClinicalTrials.gov Identifier: NCT04152499
• Recruitment Status: Recruiting
• First Posted: November 5, 2019
• Last Update Posted: August 18, 2020
• Sponsor: Klus Pharma Inc.
• Information provided by (Responsible Party): Klus Pharma Inc.

Study Description

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:

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)

Condition or disease	Intervention/treatment	Phase
Ovarian Epithelial Cancer; Gastric Adenocarcinoma; Pancreas Adenocarcinoma; Triple Negative Breast Cancer; Bladder 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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 78 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

Arms and Interventions

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: • Cohort 1; Histologically documented, incurable, locally advanced or metastatic Gastric Adenocarcinoma refractory to standard therapies.	Drug: SKB264; SKB264 is an Antibody Drug Conjugate (ADC) targeting TROP2 expressing cancer cells.
Experimental: Phase II: • Cohort 2; Histologically documented, incurable, locally advanced or metastatic Pancreatic Adenocarcinoma refractory to standard therapies.	Drug: SKB264; SKB264 is an Antibody Drug Conjugate (ADC) targeting TROP2 expressing cancer cells.
Experimental: Phase II: • Cohort 3; Histologically documented, incurable, locally advanced or metastatic Bladder Cancer refractory to standard therapies.	Drug: SKB264; SKB264 is an Antibody Drug Conjugate (ADC) targeting TROP2 expressing cancer cells.

Outcome Measures

Primary Outcome Measures :

1. Phase I: Maximum Tolerated Dose (MTD) [ Time Frame: A minimum of 28 days after first infusion of study drug ]
   Number of patients with dose limiting toxicities
2. Phase II: 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 ]
   As determined by the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1, which will be complete response (CR) + partial response (PR)

Secondary Outcome Measures :

1. Phase I: Dose Limiting Toxicities (DLTs) [ Time Frame: A minimum of 28 days after first infusion of study drug ]
   DLT Reporting at D28
2. 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 ]
   Treatment-related adverse event reporting
3. 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 ]
   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 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 ]
   DOR in patients who responded during time frame per protocol
5. 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 ]
   Kaplan Meier Curve for survival without progression in patients who responded to treatment
6. 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 ]
   Kaplan Meier Curve for survival in all enrolled patients
7. 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 ]
   ADA data from Bioanalytical Lab.
8. Phase I and II: Maximum observed serum or plasma concentration (Cmax) [ Time Frame: Through study completion, an average of 24 months ]
   One of the PK (pharmacokinetics) parameters for SKB264
9. 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 ]
   One of the PK (pharmacokinetics) parameters for SKB264
10. Phase I and II: Clearance (CL) [ Time Frame: Through study completion, an average of 24 months ]
    One of the PK (pharmacokinetics) parameters for SKB264
11. Phase I and II: Terminal phase elimination half life (t½) [ Time Frame: Through study completion, an average of 24 months ]
    One of the PK (pharmacokinetics) parameters for SKB264
12. Phase I and II: Volume of distribution at terminal phase (Vz) [ Time Frame: Through study completion, an average of 24 months ]
    One of the PK (pharmacokinetics) parameters for SKB264
13. Phase I and II: Volume of distribution at steady state (Vss) [ Time Frame: Through study completion, an average of 24 months ]
    One of the PK (pharmacokinetics) parameters for SKB264
14. Phase I and II: Levels of TROP2 (trophoblast antigen 2) expression in tumor tissue [ Time Frame: Through study completion, an average of 24 months ]
    To investigate any potential correlations of TROP2 (trophoblast antigen 2) levels with responses and toxicity

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (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 ≥ 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

Contacts and Locations

Contacts

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

Locations

United States, California

University of California Los Angeles; Recruiting

Los Angeles, California, United States, 90404

Contact: Zev Wainberg

United States, District of Columbia

Georgetown University; Recruiting

Washington, District of Columbia, United States, 20057

Contact: Paula Pohlmann

United States, Florida

Florida Cancer Specialists and Research Institute; Recruiting

Sarasota, Florida, United States, 34232

Contact: Judy Wang

United States, Massachusetts

Beth Israel Deaconess Medical Center; Recruiting

Boston, Massachusetts, United States, 02215

Contact: Andrea Bullock

United States, Michigan

START MidWest; Recruiting

Grand Rapids, Michigan, United States, 49546

Contact: Manish Sharma

United States, Oklahoma

The University of Oklahoma Health Sciences Center; Recruiting

Oklahoma City, Oklahoma, United States, 73104

Contact: Susanna Ulahannan

United States, Oregon

Providence Cancer Institute, Franz Clinic; Recruiting

Portland, Oregon, United States, 97213

Contact: Rachel Sanborn

United States, Texas

Mary Crowley Cancer Research; Recruiting

Dallas, Texas, United States, 75230

Contact: Minal Barve

MD Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Contact: Jordie Rodon

United States, Virginia

Virginia Cancer Specialists; Recruiting

Fairfax, Virginia, United States, 22031

Contact: Alexander Spira

China

Shanghai East Hospital; Recruiting

Shanghai, China

Contact: Jin Li, MD

Principal Investigator: Jin Li, MD

Sponsors and Collaborators

Klus Pharma Inc.

Investigators

• Study Chair: Jordi Rodon Ahnert, MD, PhD; M.D. Anderson Cancer Center

More Information

• Responsible Party: Klus Pharma Inc.
• ClinicalTrials.gov Identifier: NCT04152499
• Other Study ID Numbers: KL264-01
• First Posted: November 5, 2019
• Last Update Posted: August 18, 2020
• Last Verified: August 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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:

Adenocarcinoma; Triple Negative Breast Neoplasms; Carcinoma, Ovarian Epithelial; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Breast Neoplasms; Breast Diseases; Skin Diseases; Ovarian Neoplasms; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Endocrine System Diseases; Gonadal Disorders