AK104IIT018: Cadonilimab in Patients (Pts) With Advanced Non-small Cell Lung Cancer (NSCLC)

Sponsor
Shanghai Chest Hospital (Other)
Overall Status
Recruiting
CT.gov ID
NCT05816499
Collaborator
The Affiliated Hospital of Qingdao University (Other), Anhui Provincial Hospital (Other), Zhejiang University (Other)
44
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1
34.4
8.8
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Study Details

Study Description

Brief Summary

This phase Ib/II trial studies how well cadonilimab combined with anlotinib and docetaxel work in treating patients with non-small cell lung cancer that is stage IV or has come back. Cadonilimab, a PD-1/CTLA-4 bispecific antibody, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Anlotinib can regulate tumor microenvironment. Docetaxel was used in standard of care chemotherapy for non-small cell lung cancer, work to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving cadonilimab, anlotinib and docetaxel together may work better in treating patients with non-small lung cancer compared to standard of care.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:
  1. Dose discovery stage: evaluate the safety of cadonilimab combined with anlotinib and docetaxel in the treatment of locally advanced and metastatic NSCLC after failure of treatment with PD-L1/1 inhibitors and the recommended dose of anlotinib.

  2. Dose expansion stage: evaluate the 6-month PFS rate of patients with locally advanced and metastatic NSCLC after failure of treatment with PD-L1/1 inhibitors by cadonilimab combined with anlotinib and docetaxel, which was evaluated by researchers based on RECIST v1.1.

SECONDARY OBJECTIVES:
  1. evaluate the objective response rate (ORR), progression-free survival (PFS), disease control rate (DCR), duration of response (DoR), time to response (TTR), and total survival (OS) of patients with locally advanced and metastatic NSCLC after failure of treatment with PD-L1/1 inhibitors with cadonilimab, anlotinib, and docetaxel.

  2. evaluate the safety and tolerability of cadonilimab combined with arotinib and docetaxel in the treatment of locally advanced and metastatic NSCLC after failure of treatment with PD-L1/1 inhibitor.

OUTLINE:

This is a prospective, open, single-arm, multi-center, phase I b/II clinical study. All patients were confirmed Locally advanced (stage IIIB/IIIC) that cannot be resected by radical surgery and cannot accept radical synchronous/sequential radiotherapy and chemotherapy or metastatic (stage IV) NSCLC by histology or cytology. Patients must have progressed on at most a PD-1/L1 inhibitor and a platinum-based chemotherapy (combined or sequential, regardless of sequence), and at least two cycles of PD-1/L1 inhibitor (combined or non-combined chemotherapy) with clinical benefits (PFS ≥ 3 months). The study is divided into two parts. The first part is the dose discovery stage. The patients will receive a 21-day observation period of dose limiting toxicity (DLT). 3-6 subjects will be enrolled in each dose, and finally evaluate the safety and determine the recommended dose (RP2D) for phase II clinical study according to the "3+3" principle. We will continue to recruit 44 patients at the dose expansion stage.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
44 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase Ib/II Trial of Cadonilimab (PD-1/CTLA-4 Bispecific Antibody) in Combination With Anlotinib and Docetaxel in Patients (Pts) With Checkpoint Inhibitor (CPI)-Experienced Advanced Non-small Cell Lung Cancer (NSCLC)
Actual Study Start Date :
Feb 16, 2023
Anticipated Primary Completion Date :
Dec 30, 2024
Anticipated Study Completion Date :
Dec 30, 2025

Arms and Interventions

Arm Intervention/Treatment
Experimental: Arm A (cadonilimab,anlotinib,docetaxel )

Patients receive anlotinib 6mg/8mg/10mg qd 2W/3W and cadonilimab IV over 90 minutes on day 1. Patients also receive docetaxel 60-75 mg/m2 IV over 60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Drug: Cadonilimab
Given IV, 10mg/kg Q3W
Other Names:
  • AK104
  • Drug: Anlotinib
    oral,6mg/8mg/10mg qd 2W/3W
    Other Names:
  • AL3818
  • Drug: Docetaxel
    Given IV, 60-75mg/m2 Q3W
    Other Names:
  • Docetaxel Trihydrate
  • Docetaxel Hydrate
  • Taxoltere Metro
  • RP 56976
  • RP-56976
  • RP56976
  • Docetaxel Anhydrous
  • N-Debenzoyl-N-tert-butoxycarbonyl-10-deacetyltaxol
  • N Debenzoyl N tert butoxycarbonyl 10 deacetyltaxol
  • NSC 628503
  • Taxotere
  • Outcome Measures

    Primary Outcome Measures

    1. RP2D of anlotinib [Up to 21 days after the first cycle of study treatment]

      Will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Overall toxicity incidence as well as toxicity profiles will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses. Proportion of acute and late toxicity will be reported, and 95% confidence intervals will be estimated using the Clopper-Pearson method.

    2. 6-month progression-free survival (PFS) rate [up to 6 months]

      Will be determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Will be reported and its 95% confidence intervals will be estimated using the Clopper-Pearson method. PFS rates of two patient groups stratified by binary biomarker (PD-L1 and KRAS status), respectively will be estimated with the Kaplan-Meier method and compared using the log-rank test, respectively. Cox proportional hazards models will be further used in the multivariable analyses to assess adjusted effect of PD-L1 and KRAS status on the patients' PFS after adjusting for other factors. Interaction terms between these factors will also be tested for statistical significance. The proportional hazards assumption will be evaluated graphically and analytically with regression diagnostics. Violations of the proportional hazards assumptions will be addressed by use of time-dependent covariates or extended Cox regression models.

    Secondary Outcome Measures

    1. Overall response rate [Through study completion, an average of 1 year]

      Will be determined per RECIST 1.1 and immune-modified Response Evaluation Criteria in Solid Tumors.

    2. Overall survival (OS) [up to 10 years]

      OS and rates of two patient groups stratified by binary biomarker (PD-L1 and KRAS status), respectively will be estimated with the Kaplan-Meier method and compared using the log-rank test, respectively. Cox proportional hazards models will be further used in the multivariable analyses to assess adjusted effect of PD-L1 and KRAS status on the patients' OS after adjusting for other factors. Interaction terms between these factors will also be tested for statistical significance. The proportional hazards assumption will be evaluated graphically and analytically with regression diagnostics. Violations of the proportional hazards assumptions will be addressed by use of time-dependent covariates or extended Cox regression models.

    3. Investigator assessed-progression-free survival (IA-PFS) [From date of sub-study registration to date of first documentation of progression assessed by central review or symptomatic deterioration, or death due to any cause, assessed up to 3 years]

      Will be estimated using the method of Kaplan-Meier. Median and landmark time-point estimates will be based on the Kaplan-Meier estimates. The average hazard ratio (HR) will be estimated using a Cox proportional hazards model. An assessment of the proportional hazards assumption will be performed and an assessment of the time-dependent HR will be done.

    4. Incidence of adverse events [Up to 30 days after the last dose of study treatment]

      Will be evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Overall toxicity incidence as well as toxicity profiles will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses. Proportion of acute and late toxicity will be reported, and 95% confidence intervals will be estimated using the Clopper-Pearson method.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Age≥18 years old

    2. Locally advanced (stage IIIB/IIIC) that cannot be resected by radical surgery and cannot accept radical synchronous/sequential radiotherapy and chemotherapy and metastatic (stage IV) NSCLC confirmed by histology or cytology

    3. Patients must have progressed on at most a PD-1/L1 inhibitor and a platinum-based chemotherapy (combined or sequential, regardless of sequence), and at least two cycles of PD-1/L1 inhibitor (combined or non-combined chemotherapy) with clinical benefits (PFS ≥ 3 months)

    4. Patients must not have EGFR sensitizing mutations, EGFR T790M mutation, ALK gene fusion, and ROS 1 gene rearrangement, and BRAF V600E mutation.

    5. Has measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions

    6. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1

    7. Life expectancy > 12 weeks as determined by the investigator

    8. Patients must have at least one measurable lesion (as defined by RECIST v1.1), which is suitable for repeated and accurate measurement

    9. Absolute neutrophil count (ANC) ≥ 1500/uL (collected within 10 days prior to the start of study treatment)

    10. Platelets ≥ 100 000/uL (collected within 10 days prior to the start of study treatment)

    11. Hemoglobin ≥ 9.0 g/dL (collected within 10 days prior to the start of study treatment)

    12. Creatinine clearance [CrCl]) ≥ 50 mL/min(Creatinine clearance (CrCl) should be calculated per institutional standard)

    13. Total bilirubin ≤ 1.5 x ULN (collected within 10 days prior to the start of study treatment)

    14. Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 x ULN (≤ 5 x ULN for participants with liver metastases) (collected within 10 days prior to the start of study treatment

    15. Serum albumin(ALB)≥28 g/L

    16. International standardized ratio (INR) and activated partial thrombin time (APTT) ≤ 1.5 × ULN

    17. Left ventricular ejection fraction (LVEF) ≥ 50%

    18. A male participant must agree to use a contraception during the treatment period plus an additional 120 days after the last dose of study treatment and refrain from donating sperm during this period

    19. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

    20. Not a woman of childbearing potential (WOCBP) OR

    21. A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days plus 30 days (a menstruation cycle) after the last dose of study treatment

    Exclusion Criteria:
    1. Previously received treatment for tumor immune mechanism other than any anti-PD-1/L1 inhibitor for advanced NSCLC stage, such as CTLA-4(CD152)、TIGIT、OX-40、CD137、ICOS、CD40、CD47、CD73、GITR、TOX、LAG-3、TIM3、SIRPα、BTLA(CD2 72)、VISTA(B7-H5)、LIGHT(CD258)、B7-H3(CD276)、 B7-H4(VTCN1)、HVEM、CD80/CD86、MHC Ⅱ、GAL9、IDO、PVR(CD155)、Nectin-2(CD112).

    2. Patients have prior exposure to docetaxel, anlotinib, lenvatinib, apatinib, cabozantinib.

    3. The last systemic anti-tumor treatment (chemotherapy, immunotherapy, biological agents, anti-angiogenic drugs, etc.) was received within 3 weeks before the first administration.

    4. The following treatments were received within 2 weeks before the first administration: TKI treatment, hormone anti-tumor treatment, palliative local treatment for non-target lesions Non-specific immunomodulatory therapy (such as interleukin, interferon, thymosin, tumor necrosis factor, etc., excluding IL-11 for thrombocytopenia).

    5. Patients with explosive progress.

    6. Patients with other active malignant tumors except for NSCLC within 3 years before enrollment. Patients with other malignant tumors that have been cured by local treatment, such as basal or cutaneous squamous cell carcinoma, superficial bladder cancer cancer, cervical or breast cancer in situ, are not excluded.

    7. Patients with active autoimmune diseases that require systemic treatment in the past two years (such as the use of disease improvement drugs, corticosteroids, immunosuppressants) (excluding irAE caused by the use of PD-1/L1 inhibitors). Replacement therapy (such as thyroid hormone, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered as a systemic treatment.

    8. Patients can not swallow pills, with malabsorption syndrome, or any condition that affects gastrointestinal absorption;

    9. Patients with active or previous history of inflammatory bowel disease (such as Crohn's disease, ulcerative colitis or chronic diarrhea).

    10. Patients have a history of immune deficiency, with HIV antibody test positive or use systemic corticosteroids or other immunosuppressants for a long time.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 lejie Cao Hefei Anhui China 230000
    2 Jing Wang Qingdao Shandong China 266000
    3 Zhuang Yu Qingdao Shandong China 266000
    4 Shanghai Chest Hospital Shanghai Shanghai China 200000
    5 Jianya Zhou Hangzhou Zhejiang China 310000

    Sponsors and Collaborators

    • Shanghai Chest Hospital
    • The Affiliated Hospital of Qingdao University
    • Anhui Provincial Hospital
    • Zhejiang University

    Investigators

    • Study Chair: Baohui Han, M.D, ShanghaiChest Hospital
    • Principal Investigator: Jianya Zhou, M.D, Zhejiang University
    • Principal Investigator: Zhuang Yu, M.D, The Affiliated Hospital of Qingdao University
    • Principal Investigator: Jing Wang, M.D, The Affiliated Hospital of Qingdao University
    • Principal Investigator: lejie Cao, M.D, Anhui Provincial Hospital

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    Responsible Party:
    Baohui Han, chief physician, Shanghai Chest Hospital
    ClinicalTrials.gov Identifier:
    NCT05816499
    Other Study ID Numbers:
    • AK104-IIT-018
    First Posted:
    Apr 18, 2023
    Last Update Posted:
    Apr 18, 2023
    Last Verified:
    Apr 1, 2023
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Baohui Han, chief physician, Shanghai Chest Hospital
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Apr 18, 2023