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

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

INTRODUCTION

  • Org Study ID: KL264-01
  • Secondary ID: N/A
  • NTC ID: NCT04152499
  • Sponsor: 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:

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

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).

  • Overall Status
    Recruiting
  • Start Date
    February 28, 2020
  • Phase
    Phase 1, Phase 2
  • Study Type
    Interventional

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Phase I: Maximum Tolerated Dose (MTD) and Recommended Doses for Expansion (RDEs)

Primary Outcome 1 - Timeframe: Assess up to 12 months

Primary Outcome 2 - Measure: Phase II: Objective Response Rate (ORR)

Primary Outcome 2 - Timeframe: 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

CONDITION

  • Ovarian Epithelial Cancer
  • Gastric Adenocarcinoma
  • Breast Cancer
  • Urothelial Carcinoma
  • Non-Small Cell Lung Cancer
  • Small-Cell Lung Cancer

ELIGIBILITY

Inclusion Criteria:
Phase I:
Patients must be able to provide documented voluntary informed consent.

- Male or female patient aged 18-75 years.
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.
Measurable disease by CT/MRI during dose escalation.

- 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.

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

- International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5×ULN.

- 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).

- 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 (ECOG) Performance Status 0 or 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 . 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.

- Patients must have recovered (i.e., improvement to Grade 1 or better) from all acute toxicities from previous therapy, excluding alopecia and vitiligo.

- Expected survival ≥ 3 months.
Phase II:
Patients must be able to provide documented voluntary informed consent.

- Male or female patient aged 18-75 years.
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
Measurable disease by CT/MRI.

- 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.

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

- International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5×ULN.

- 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).

- 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.

- ECOG Performance Status 0 or 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. 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.

- Patients must have recovered (i.e., improvement to Grade 1 or better) from all acute toxicities from previous therapy, excluding alopecia and vitiligo.

- Expected survival ≥ 3 months.
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.

- 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).

- Require supplemental oxygen for daily activities.

- Documented Grade ≥ 2 peripheral neuropathy.

- History of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, corneal disease that prevents/delays corneal healing, macular degeneration.

- Subjects previously treated with TROP 2 targeted therapies.

- 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.

- 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.

- Have known prior positive test results or medical history for human immunodeficiency virus.

- Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg) or diabetes (HbA1c ≥ 9.0%).

- 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.

- 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 (< 90% oxygen saturation). - Subjects with non-infectious interstitial lung diseases (ILD) or medical history of pneumonia requiring steroid treatments; severe pulmonary dysfunction caused by lung diseases. - 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). - The investigator considers other situations that patients are not appropriate to participate in this trial.
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.

- 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).

- Require supplemental oxygen for daily activities.

- Documented Grade ≥ 2 peripheral neuropathy.

- History of documented severe dry eye syndrome, severe Meibomian gland disease and/or blepharitis, corneal disease that prevents/delays corneal healing, macular degeneration.

- Subjects previously treated with TROP 2 targeted therapies.

- 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.

- 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.

- Have known prior positive test results or medical history for human immunodeficiency virus.

- Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg) or diabetes (HbA1c ≥ 9.0%).

- 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.

- 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 (< 90% oxygen saturation). - Subjects with non-infectious interstitial lung diseases (ILD) or medical history of pneumonia requiring steroid treatments; severe pulmonary dysfunction caused by lung diseases. - 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). - The investigator considers other situations that patients are not appropriate to participate in this trial.

Gender: All

Minimum Age: 18 Years

Maximum Age: 75 Years

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: Jordi Rodon Ahnert, MD, PhD

Role: Study Chair

Affiliation: M.D. Anderson Cancer Center

Overall Contact

Name: Jordi Rodon Ahnert, MD, PhD

Phone: 2678887498

Email: jean.mastrangelo@kluspharma.com

LOCATION

Facility Status Contact
Facility: University of California Los Angeles
Los Angeles, California 90404
United States
Status: Recruiting Contact: Contact
Zev Wainberg

Facility: Florida Cancer Specialists and Research Institute
Sarasota, Florida 34232
United States
Status: Recruiting Contact: Contact
Manish Sharma

Facility: START MidWest
Grand Rapids, Michigan 49546
United States
Status: Recruiting Contact: Contact
Rachel Sanborn

Facility: The University of Oklahoma Health Sciences Center
Oklahoma City, Oklahoma 73104
United States
Status: Recruiting Contact: Contact
Minal Barve

Facility: Providence Cancer Institute, Franz Clinic
Portland, Oregon 97213
United States
Status: Recruiting Contact: Contact
Jordie Rodon

Facility: Mary Crowley Cancer Research
Dallas, Texas 75230
United States
Status: Recruiting Contact: Contact
Alexander Spira

Facility: MD Anderson Cancer Center
Houston, Texas 77030
United States
Status: Recruiting Contact: Contact
Yunong Gao

Facility: Virginia Cancer Specialists
Fairfax, Virginia 22031
United States
Status: Recruiting Contact: Contact
Weihong Zhao

Facility: Beijing Cancer Hospital
Beijing,
China
Status: Recruiting Contact: Contact
Ying Cheng

Facility: Chinese PLA General Hospital (301 Hospital)
Beijing,
China
Status: Recruiting Contact: Contact
Quchang Ouyang

Facility: Jilin Cancer Hospital
Changchun,
China
Status: Recruiting Contact: Contact
Kui Jiang

Facility: Hunan Cancer Hospital
Changsha,
China
Status: Recruiting Contact: Contact
Ying Wang

Facility: The Second Hospital of Dalian Medical University
Dalian,
China
Status: Recruiting Contact: Contact
Ge Lou

Facility: Sun Yat-Sen Memorial Hospital , Sun Yat-sen University
Guangzhou,
China
Status: Recruiting Contact: Contact
Keqiang Zhang

Facility: Harbin Medical University Cancer Hospital
Harbin,
China
Status: Recruiting Contact: Contact
Yongmei Yin

Facility: Hunan Cancer Hospital
Hunan,
China
Status: Recruiting Contact: Contact
Lihua Song

Facility: Jiangsu Province Hospital
Nanjing,
China
Status: Recruiting Contact: Contact
Jin Li, MD

Facility: Shandong Cancer Hospital
Shandong,
China
Status: Recruiting Contact: Principal Investigator
Jin Li, MD

Facility: Shanghai East Hospital
Shanghai,
China
Status: Recruiting Contact: Contact
Tianshu Liu

Facility: Zhongshan Hospital, Fudan University
Shanghai,
China
Status: Recruiting Contact: Contact
Danbo Wang

Facility: Liaoning Cancer Hospital
Shenyang,
China
Status: Recruiting Contact: Contact
Yunpeng Liu

Facility: The First Hospital of China Medical University
Shenyang,
China
Status: Recruiting Contact: Contact
Cuizhi Geng

Facility: The Fourth Hospital of Hebei Medical University
Shijiazhuang,
China
Status: Recruiting Contact: Contact
Zhongsheng Tong

Facility: Tianjin Cancer Hospital
Tianjin,
China
Status: Recruiting Contact: Contact
Guohua Yu

Facility: Weifang People's Hospital
Weifang,
China
Status: Recruiting Contact: Contact
Xinhong Wu

Facility: Hubei Cancer Hospital
Wuhan,
China
Status: Recruiting Contact: Contact
Ruifang An

Facility: The First Affiliated Hospital of Xi'an Jiaotong University
Xi'an,
China
Status: Recruiting Contact: Contact
Xiang Wang

Facility: Xuzhou Central Hospital
Xuzhou,
China
Status: Recruiting Contact: Contact
Min Yan

Facility: Henan Cancer Hospital
Zhengzhou,
China
Status: Recruiting Contact: N/A