A Study of AK104 Monotherapy or AK104 Plus Axitinib in Advanced/Metastatic Renal Cell Carcinoma

Phase II Trial of Cadonilimab (AK104) Monotherapy or AK104 Plus Axitinib in Advanced/Metastatic Renal Cell Carcinoma (RCC)

This is a Phase II, open-label trial to evaluate the efficacy and safety of AK104 monotherapy or AK104 in combination with axitinib as a first-line treatment for advanced/metastatic renal cell carcinoma (RCC). There are two parts in this trial. In part 1 of this study, subjects with unresectable advanced clear cell or non-clear cell renal cell carcinoma (ccRCC or nccRCC) who had not received systemic therapy for advanced disease will be enrolled to randomly received three different dosage of AK104 monotherapy. In part 2 of this study, subjects with unresectable advanced clear cell renal cell carcinoma (ccRCC) who had not received systemic therapy for advanced disease will be enrolled to receive AK104 plus Axitinib. All subjects will receive treatment until disease progression, development of unacceptable toxicity, death, a decision by the physician or patient to withdraw from the trial. The primary endpoint is ORR per RECIST v1.1 as assessed by investigators.

Study Overview

• Status: Recruiting
• Conditions: Renal Cell Carcinoma; First-line Treatment
• Intervention / Treatment: Drug: AK104; Drug: axitinib

• Study Type: Interventional
• Enrollment (Estimated): 70
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Weifeng Song, MD; Phone Number: +86(0760)89873999; Email: clinicaltrials@akesobio.com

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Recruiting
      • Fudan University Shanghai Cancer Center
      • Contact: Dingwei Ye, MD; Phone Number: +86-13701663571; Email: FUSCC2012@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Provide written informed consent/assent for the trial.
2. Be≥18 and ≤ 75 years of age on day of signing informed consent, no matter male or female.
3. Have Karnofsky performance status (KPS) ≥ 70% as assessed within 10 days prior to first dosing of AK104.
4. Have estimated life expectancy of at least 3 months.
5. Have histologically or cytologically confirmed diagnosis of RCC with advanced/metastatic disease (i.e., Stage IV RCC per American Joint Committee on Cancer) with clear cell or non-clear cell component (part 1) or solely clear cell component (part 2).
6. Have received no prior systemic therapy for advanced RCC . Note: Prior neoadjuvant/adjuvant therapies are acceptable if disease progression occurred > 12 months after last dosage of neoadjuvant/adjuvant treatment.
7. Have measurable disease per RECIST 1.1 as assessed by the investigator /site radiologist. (brain metastases were excluded).
8. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.

9. Adequate organ function as determined by:

   1. Hematology: i. absolute neutrophil count (ANC) ≥ 1.5 × 109/L (1,500/mm3); ii. platelets ≥ 100 × 109/L (100,000/mm3); iii. hemoglobin ≥ 90 g/L.
   2. Renal: i. calculated creatinine clearance * (CrCl) ≥ 50 mL/min; * CrCl will be calculated using the Cockcroft-Gault formula CrCL (mL/min) = {(140-age) × body weight (kg) × F }/(SCr (mg/dL) × 72) Where F = 1 for males and F = 0.85 for females; SCr = serum creatinine. ii. urine protein < 2 + or 24-hour urine protein must be < 2.0 g.
   3. Hepatic: i. serum total bilirubin (TBil) ≤ 1.5 × ULN; ii. AST and ALT ≤ 2.5 × ULN, ≤ 3.0 × ULN with liver metastasis; iii. serum albumin (ALB) ≥ 28 g/L.
   4. Coagulation function: i. international normalized ratio (INR) and activated partial thromboplastin time (APTT) ≤ 1.5 × ULN.
   5. Cardiac Function: i. Left ventricular ejection fraction (LVEF) ≥ 50%.

Exclusion Criteria:

1. Has a known additional malignancy that has progressed or has required active treatment in the last 3 years. Note: Subjects with basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or carcinoma in situ are not excluded.
2. Has had prior treatment with any anti-PD-1, or PD-L1, or PD-L2 agent or an antibody targeting any other immune-regulatory receptors or mechanisms. Examples of such antibodies include (but are not limited to) antibodies against IDO, IL-2R, GITR，CTLA-4，CD40, CD137.
3. Has received prior therapy with VEGF/VEGFR or mTOR targeting agents.
4. Has received radiotherapy within 14 days prior to start of study treatment and has not recovered adequately from any toxicity and/or complications from prior radiotherapy.
5. Has newly diagnosed brain metastases or known symptomatic brain metastases requiring steroids. Subjects with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to receiving first dose of trial treatment, have discontinued corticosteroid treatment for these metastases for at least 3 days and are neurologically stable.
6. Had major surgery 4 weeks or major radiation therapy 2 weeks prior to receiving first dose of trial treatment. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided it has been completed at least 48 hours prior to receiving first dose of trial treatment.
7. Has active autoimmune disease that might deteriorate when receiving an immunostimulatory agents. Subjects with diabetes type I, vitiligo, psoriasis, hypo-or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
8. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to receiving first dose of trial treatment.
9. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
10. Has an active tuberculosis and syphilitic infection.
11. Has a known history of Human Immunodeficiency Virus (HIV) infection (HIV antibodies).
12. Has known active Hepatitis B (e.g., Hepatitis B surface antigen [HBsAg] reactive and HBV-DNA>200 IU/ml) or Hepatitis C virus (e.g., HCV RNA [qualitative] is detected).
13. Has poorly controlled hypertension defined as systolic blood pressure (SBP) ≥ 140 mm Hg and/or diastolic blood pressure (DBP) ≥ 90 mmHg.
14. Has active bleeding disorder or other history of significant bleeding episodes within 30 days of screening.
15. Has been pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment (30 days for axitinib, whichever occurs last).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AK104 monotherapy cohort (Part 1); Subjects in this cohort will randomly receive three different dosage of AK104 monotherapy administered intravenously.	Drug: AK104; anti-PD-1/CTLA-4 bi-specific antibody drug; RP2D intravenously (IV)
Experimental: combination treatment cohort (Part 2); Subjects in this cohort will receive AK104 (RP2D, administered intravenously) plus Axitinib 5 mg bid, administered orally.	Drug: AK104; anti-PD-1/CTLA-4 bi-specific antibody drug; RP2D intravenously (IV); Drug: axitinib; an oral, small molecule, TKI selective for VEGFRs 1, 2 and 3; 5mg bid orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR per RECIST v1.1 as assessed by investigators	ORR is the proportion of subjects with complete response(CR) or partial response(PR) , based on RECIST v1.1	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival (OS)	Overall survival is defined as the time from the start of treatment until death due to any cause.	Up to 2 years
Deep response rate	(% patients with >75% tumor reduction at 6 months ) per RECIST v1.1	Up to 2 years
Duration of response (DOR)	Duration of response (DOR) assessed according to RECIST v1.1	Up to 2 years
Disease control rate (DCR)	Disease control rate (DCR) assessed according to RECIST v1.1	Up to 2 years
Progression-free survival (PFS)	PFS is defined as the time from the the start of treatment till the first documentation of disease progression (per RECIST v1.1 criteria) assessed by the investigator or death due to any cause (whichever occurs first).	Up to 2 years
Peak Plasma Concentration (Cmax)	The maximum (or peak) plasma concentration of AK104 in subjects treated with AK104 plus axitinib.	Up to 2 years
Area under the plasma concentration versus time curve (AUC)	AUC = Area under the plasma concentration of AK104-time curve. The area under the plasma concentration time curve (AUC) is a measure of overall exposure to the drug	Up to 2 years
Immunogenicity assessment	Number and percentage of subjects with detectable anti-drug antibodies (ADAs) treated with AK104 plus axitinib	Up to 2 years

Collaborators and Investigators

• Sponsor: Akeso
• Investigators: Principal Investigator: Dingwei Ye, MD, Shanghai Cancer Center of Fudan University

Study record dates

Study Major Dates

• Study Start (Actual): July 6, 2023
• Primary Completion (Estimated): July 31, 2024
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: January 24, 2022
• First Submitted That Met QC Criteria: February 16, 2022
• First Posted (Actual): February 25, 2022

Study Record Updates

• Last Update Posted (Actual): September 21, 2023
• Last Update Submitted That Met QC Criteria: September 17, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Axitinib; AK104
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Carcinoma, Renal Cell; Carcinoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Axitinib
• Other Study ID Numbers: AK104-213

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No