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A Study to Evaluate the Safety and Efficacy of Oral APL-1202 in Combination With Tislelizumab Compared to Tislelizumab Alone as Neoadjuvant Therapy in Patients With Muscle Invasive Bladder Cancer (ANTICIPATE)

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ClinicalTrials.gov Identifier: NCT04813107
Recruitment Status : Recruiting
First Posted : March 24, 2021
Last Update Posted : February 22, 2022
Sponsor:
Information provided by (Responsible Party):
Jiangsu Yahong Meditech Co., Ltd aka Asieris

Brief Summary:
This trial is designed to evaluate the safety, efficacy, and biomarker response of APL-1202 in combination with tislelizumab as neoadjuvant therapy for patients with MIBC who are cisplatin ineligible or refuse cisplatin-based chemotherapy.

Condition or disease Intervention/treatment Phase
Muscle Invasive Bladder Cancer Drug: APL-1202 in combination with tislelizumab Drug: Tislelizumab alone Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 79 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Open-Label Multicenter Study to Evaluate the Safety and Efficacy of Oral APL-1202 in Combination With Tislelizumab Compared to Tislelizumab Alone as Neoadjuvant Therapy in Patients With Muscle Invasive Bladder Cancer (MIBC)
Actual Study Start Date : December 28, 2021
Estimated Primary Completion Date : November 1, 2023
Estimated Study Completion Date : March 1, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bladder Cancer

Arm Intervention/treatment
Active Comparator: APL-1202 in combination with tislelizumab Drug: APL-1202 in combination with tislelizumab
For those assigned to this group (1), each patient will receive 3 cycles of treatment prior to RC and each cycle is 3 weeks. On day 1 of each cycle, a single dose of 200 mg tislelizumab will be administered intravenously. APL-1202 will be administered orally TID daily for 3 weeks at the RP2D defined from Phase I.

Placebo Comparator: Tislelizumab alone Drug: Tislelizumab alone
For patients assigned to this group (2), each patient will receive 3 cycles of treatments with a single dose of 200 mg tislelizumab administered on day 1 of each cycle, followed by RC.




Primary Outcome Measures :
  1. Adverse events (AE) and serious adverse events (SAE). [ Time Frame: 9 weeks ]
    Adverse events (AE) and serious adverse events (SAE) in Phase Ⅰ(Dose-Escalation)

  2. The RP2D of APL-1202 in combination with tislelizumab. [ Time Frame: 9 weeks ]
    The RP2D of APL-1202 in combination with tislelizumab in Phase Ⅰ(Dose-Escalation)

  3. The rate of pathologic complete response (pCR) in Phase 2. [ Time Frame: 26 months ]
    Pathological complete response (pCR) is defined as no microscopic evidence of residual disease in the bladder based on histological evaluation of the resected bladder specimen collected during cystectomy.


Secondary Outcome Measures :
  1. Radiological response (RR). [ Time Frame: 26 months ]
    CT or MRI scan taken at screening and pre-radical cystectomy visits. Response will be evaluated using standard RECIST 1.1 criteria.

  2. Cmax [ Time Frame: 26 months ]
    PK parameters of APL-1202 expressed as Cmax when administered concurrently with tislelizumab.

  3. Tmax [ Time Frame: 26 months ]
    PK parameters of APL-1202 expressed as Tmax when administered concurrently with tislelizumab.

  4. t1/2 [ Time Frame: 26 months ]
    PK parameters of APL-1202 expressed as t1/2 when administered concurrently with tislelizumab.

  5. AUC [ Time Frame: 26 months ]
    PK parameters of APL-1202 expressed as AUC when administered concurrently with tislelizumab.

  6. Cumulative amount in urinary excretion (Ae) [ Time Frame: 26 months ]
    PK parameters of APL-1202 expressed as Ae when administered concurrently with tislelizumab.

  7. cumulative fraction of dose in urinary excretion (Ae%) [ Time Frame: 26 months ]
    PK parameters of APL-1202 expressed as Ae% when administered concurrently with tislelizumab.

  8. Tumor mutation burdens (TMB) in pre- and post-treatment plasma ctDNA (circulating tumor DNA). [ Time Frame: 26 months ]
    Plasma circulating tumor DNA (ctDNA) were extracted from the patients before and after treatment; somatic mutations were detected by targeted region sequencing. Tumor mutation burdens (TMB) was calculated by mutations per million sequenced bases.

  9. Tumor mutation burdens (TMB) in pre- and post-treatment urine cfDNA (cell free DNA). [ Time Frame: 26 months ]
    Urine cell free DNA (cfDNA) were extracted from the patients before and after treatment; somatic mutations were detected by targeted region sequencing. Tumor mutation burdens (TMB) was calculated by mutations per million sequenced bases.

  10. Tumor mutation burdens (TMB) in pre- and post-treatment tumor tissues. [ Time Frame: 26 months ]
    Tumor tissue FFPE slides were collected from the patients before and after treatment. DNA was extracted from the FFPE slides. Somatic mutations were detected by targeted region sequencing. Tumor mutation burdens (TMB) was calculated by mutations per million sequenced bases.

  11. PD-L1 protein expression levels in pre- and post-treatment tumor tissues. [ Time Frame: 26 months ]
    Tumor tissue FFPE slides were collected from the patients before and after treatment. PD-L1 protein expression levels were evaluated by IHC (immunohistochemistry, VENTANA PD-L1/SP263 Assay).



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

Inclusion Criteria:

  1. Willing and able to provide written informed consent.
  2. Age ≥ 18 years.
  3. Histopathologically confirmed transitional cell carcinoma of the bladder. Patients with mixed histologies are required to have a dominant (i.e. > 50%) transitional cell pattern.
  4. Radical cystectomy is planned (according to local guidelines).
  5. Patients who refuse neoadjuvant cisplatin based chemotherapy or in whom neoadjuvant cisplatin based therapy is contraindicated. Contraindications to cisplatin is defined by meeting at least one of the following criteria:

    • Impaired renal function with calculated CrCl 30 to 59 mL/min (by Cockcroft-Gault equation).
    • Eastern Cooperative Oncology Group (ECOG) Performance Status 2.
    • CTCAE v.5 Grade ≥2 audiometric hearing loss.
    • In the clinical judgement of the investigator, potential adverse effects from cisplatin-based neoadjuvant chemotherapy outweighs its benefits.
  6. Clinical stage T2-T4a N0 M0 disease by CT (or MRI) (within 4 weeks of randomization).
  7. Residual disease after transurethral resection of bladder (TURB) (surgical opinion, cystoscopy or radiological presence).
  8. Availability of representative formalin-fixed paraffin-embedded (FFPE) tumor specimens or unstained slides, with an associated pathology report, and determined to be evaluable for tumor PD-L1 expression prior to study enrollment;
  9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
  10. Adequate hematologic and end-organ functions:

    • Hemoglobin > 9.0 g/dL;
    • Absolute neutrophil count (ANC) > 1.5×109 /L;
    • Platelet count > 100×109 /L;
    • Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).
    • Aspartate aminotransferase (AST) /alanine aminotransferase (ALT) ≤ 2.5 x institutional upper limit of normal ULN.
    • CrCl (calculated using Cockcroft-Gault equation) ≥ 30 mL/min (calculated CrCl ≥ 50 mL/min in Phase Ⅰ: Dose-Escalation).
    • INR < 1.5. This applies only to patients who are not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose.
  11. Female patients should be surgically sterilized or post-menopausal or must agree to take effective contraceptive measures during the treatment. Male patients must be surgically sterilized or must agree to take effective contraceptive measures during treatment. Patients must continue to take contraceptive measures for 3 months after the investigational therapy was completed.

Exclusion Criteria:

  1. Previous systemic therapy for bladder cancer.
  2. Malignancies other than urothelial bladder cancer within 5 years prior to cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ of breast treated surgically with curative intent).
  3. Evidence of measurable nodal or metastatic disease.
  4. Evidence of significant uncontrolled concomitant disease that could affect compliance with the protocol or interpretation of results, including significant liver disease (such as cirrhosis, uncontrolled major seizure disorder, or superior vena cava syndrome).
  5. Pregnant female patients. All female patients with a positive pregnancy test within 2 weeks prior to the first dose of study treatment will be excluded from the study.
  6. Significant cardiovascular disease, such as New York Heart Association cardiac disease (more than Class II), myocardial infarction within 3 months prior to enrollment, unstable arrhythmias, or unstable angina.
  7. Severe infections within 4 weeks prior to enrollment in the study including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia.
  8. Major surgical procedure within 4 weeks prior to enrollment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis.
  9. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
  10. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the tislelizumab or APL-1202 formulation.
  11. History of autoimmune disease including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
  12. History of autoimmune-related hypothyroidism, unless on a stable dose of thyroid-replacement hormone.
  13. History of idiopathic pulmonary fibrosis.
  14. Uncontrolled Type 1 diabetes mellitus.
  15. Uncontrolled hypercalcemia (> 1.5 mmol/L ionized calcium or calcium > 12 mg/dL or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab.
  16. Prior allogeneic stem cell or solid organ transplantation.
  17. Positive test for HIV.
  18. Uncontrolled hepatitis infection.
  19. Active tuberculosis.
  20. Optic nerve disorders or with a history of optic nerve disorders.
  21. Cataract or with a history of cataract.
  22. Prior treatment with anti-programmed death-1 (PD-1), or anti-PD-L1 therapeutic antibody or pathway-targeting agents.
  23. Patients taking regular oral steroids, above the allowed limit of 10 mg/day methylprednisolone/prednisone or analogues, for any reason. Patients must not have had steroids for 4 weeks prior to study entry.
  24. Administration of vaccine within 4 weeks prior to enrollment or anticipation that such a vaccine will be required during the study.
  25. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 4 weeks prior to enrollment.
  26. Treatment with systemic immunostimulatory agents within 4 weeks prior to enrollment.

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): NCT04813107


Contacts
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Contact: Mingming Zhang, MD +8613816002336 mmzhang@asieris.cn

Locations
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United States, New York
Mount Sinai Medical Center Recruiting
New York, New York, United States, 10001
Contact: Galsky Matthew, MD,PhD       matthew.galsky@mssm.edu   
Principal Investigator: Galsky Matthew, MD,PhD         
China, Shanghai
Fudan University Shanghai Cancer Center Recruiting
Shanghai, Shanghai, China, 201203
Contact: Dingwei Ye, MD,PhD    +8602164175590      
Principal Investigator: Dingwei Ye, MD,PhD         
Sponsors and Collaborators
Jiangsu Yahong Meditech Co., Ltd aka Asieris
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Responsible Party: Jiangsu Yahong Meditech Co., Ltd aka Asieris
ClinicalTrials.gov Identifier: NCT04813107    
Other Study ID Numbers: YHGT-NP-01
First Posted: March 24, 2021    Key Record Dates
Last Update Posted: February 22, 2022
Last Verified: February 2022
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
Additional relevant MeSH terms:
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Urinary Bladder Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases