Adapted Guided Stereotactic Body Radiotherapy Combined With Chemotherapy and Enhancement of Novel Drug Ivonescimab for Pancreatic Cancer (ASCEND)

Adapted Guided Stereotactic Body Radiotherapy Combined With Chemotherapy and Enhancement of Novel Drug Ivonescimab for Pancreatic Cancer (ASCEND) -A Single-Arm Phase Ib/II Trial

This study aims to evaluate the safety and efficacy of Ivonescimab, a bispecific antibody targeting PD-1 and VEGF, in combination with stereotactic body radiotherapy (SBRT) and chemotherapy for treating locally advanced pancreatic cancer (LAPC). The Phase Ib portion is a dose-escalation study to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and the recommended Phase II dose (RP2D) of Ivonescimab. The Phase II portion will assess the median progression-free survival (mPFS) of patients receiving Ivonescimab with SBRT (25-50Gy/5F) and modified FOLFIRINOX chemotherapy. The study aims to provide critical insights into treatment options for LAPC and inform future therapeutic strategies.

Study Overview

• Status: Recruiting
• Conditions: Pancreatic Cancer
• Intervention / Treatment: Drug: Ivonescimab

Detailed Description

This study is a single-arm, Phase Ib/II clinical trial designed to evaluate the safety and efficacy of Ivonescimab, a bispecific antibody targeting both programmed cell death protein 1 (PD-1) and vascular endothelial growth factor (VEGF), in combination with stereotactic body radiotherapy (SBRT) and chemotherapy for locally advanced pancreatic cancer (LAPC). The trial will recruit 37 patients with LAPC, with Phase Ib focusing on determining the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and the recommended Phase II dose (RP2D) of Ivonescimab.

In the Phase Ib portion, a dose-escalation design using the 3 + 3 methodology will be employed over a 4-week period to establish the RP2D for Ivonescimab. The goal is to identify the optimal dose that can be safely administered to patients without excessive toxicity. Once the RP2D is determined, the trial will proceed to Phase II.

Phase II will evaluate the efficacy of Ivonescimab at the RP2D in combination with SBRT and chemotherapy, with the primary endpoint being the median progression-free survival (mPFS) of patients with LAPC. Initially, participants will receive Ivonescimab combined with SBRT (25-50 Gy in 5 fractions) over two weeks. Following this, they will undergo up to 8-10 cycles of Ivonescimab in combination with modified FOLFIRINOX chemotherapy, which includes oxaliplatin, irinotecan, leucovorin, and fluorouracil.

Patients will continue maintenance treatment with Ivonescimab based on individual tolerance for up to 12 months, or until intolerable toxicity or disease progression occurs. The study aims to assess both the safety and therapeutic efficacy of this novel combination treatment as a first-line approach for LAPC. Results from this Phase Ib/II study will provide critical data for the development of future treatment strategies for LAPC, potentially improving patient outcomes by targeting both the immune response and tumor vasculature.

• Study Type: Interventional
• Enrollment (Estimated): 37
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Jinbo Yue, Doctor; Phone Number: 0531-67626442; Email: jbyue@sdfmu.edu.cn

Study Locations

• China
  • Shandong
    • Jinan, Shandong, China, 0531
      • Recruiting
      • Shandong Cancer Hospital and Institute
      • Contact: Jinbo Yue, Doctor; Phone Number: 0531-67626442; Email: jbyue@sdfmu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Pathologically or cytologically confirmed unresectable LAPC, as defined by the 8th edition of the American Joint Committee on Cancer (AJCC);
2. Age between 18 and 80 years;
3. At least one measurable pancreatic cancer lesion, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1;
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1;
5. Life expectancy of at least 3 months;
6. Adequate hematological, renal, and hepatic function, as defined by the following criteria (within 14 days prior to enrollment): (1) Hemoglobin (Hb) ≥ 90 g/L; Absolute Neutrophil Count (ANC) ≥ 1.0 × 10^9/L; Platelet count (PLT) ≥ 75 × 10^9/L; (2) No significant organ dysfunction, with the following criteria: Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN) or direct bilirubin ≤ ULN if total bilirubin > 1.5 × ULN; Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN; Alkaline phosphatase (ALP) ≤ 2.5 × ULN, or ≤ 2.5 × ULN for the liver fraction if ALP > 2.5 × ULN; Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance (using the MDRD formula) ≥ 40 mL/min if serum creatinine is > 1.5 × ULN; Urine protein < 2+, or if ≥ 2+ on dipstick, 24-hour urine protein must be < 2 g or the urine protein-to-creatinine ratio (UPC) must be < 2; International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN;
7. Ability to provide tissue and blood samples for translational research;
8. Ability to comprehend study details and provide written informed consent.

Exclusion Criteria:

1. History of any malignant tumors within the past 5 years, except for cured localized tumors;
2. Uncontrolled infections (e.g., active tuberculosis or hepatitis), uncontrolled systemic diseases, poorly controlled hypertension or diabetes, or severe comorbidities within the past six months, including myocardial infarction, cerebral embolism, or significant arrhythmias;
3. Previous treatment with drugs targeting other stimulatory or co-inhibitory T-cell receptors;
4. Prior radiotherapy within 2 weeks before enrollment;
5. Known allergy to Ivonescimab or its excipients;
6. Pregnancy or lactation;
7. Current or planned use of strong CYP3A4/5 or CYP1A2 inducers or strong CYP3A4/5 inhibitors;
8. Requirement for oral vitamin K antagonists for anticoagulation. Low-dose warfarin (≤ 2 mg/day) and other low-dose anticoagulants for maintaining central venous access or preventing deep vein thrombosis are permitted. Low-molecular-weight heparin is also permitted;
9. Conditions affecting oral medication administration, such as a history of gastrointestinal perforation or fistula within the past 6 months, history of intestinal obstruction, extensive bowel resection, Crohn's disease, ulcerative colitis, or chronic diarrhea.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Stereotactic Body Radiotherapy Combined with Chemotherapy and Enhancement of Novel Drug Ivonescimab; Phase Ib (Dose Escalation):In this phase, patients will receive Ivonescimab in escalating doses, with the aim of determining the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and the recommended Phase II dose (RP2D). The dose-escalation process will follow a 3+3 design over a 4-week period to establish the RP2D of Ivonescimab.; Phase II (Efficacy Evaluation): After establishing the RP2D, patients will receive Ivonescimab combined with SBRT and modified FOLFIRINOX chemotherapy.

Drug: Ivonescimab; Phase Ib (Dose Escalation):In this phase, patients will receive Ivonescimab in escalating doses, with the aim of determining the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and the recommended Phase II dose (RP2D). The dose-escalation process will follow a 3+3 design over a 4-week period to establish the RP2D of Ivonescimab.; Phase II (Efficacy Evaluation): After establishing the RP2D, patients will receive Ivonescimab combined with SBRT and modified FOLFIRINOX chemotherapy.; Other Names: Chemotherapy; Adapted Guided Stereotactic Body Radiotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD)	MTD is defined as the gradual increase in dose using 10 mg and 20 mg of ivonescimab to approach the maximum tolerated dose	1 years
Dose-Limiting Toxicity (DLT)	DLT is defined as unacceptable toxicities or adverse effects caused by a certain dose level of the drug, which prevent further dose escalation in participants.	1 years
Recommended Phase 2 Dose (RP2D)	The RP2D is the dose level of Ivonescimab recommended for use in Phase 2 clinical trials. This dose is typically chosen based on safety, tolerability, and preliminary efficacy data from Phase 1 trials.	1 years
Progression-Free Survival (PFS)	PFS defined as the time from the first dose of Ivonescimab to either the first radiographic evidence of disease progression or death from any cause, whichever occurs first.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	OS defined as the time from the first dose of Ivonescimab to the time of death from any cause.	3 years
Objective remission rate (ORR)	ORR defined as the proportion of subjects achieving a complete response (CR) or partial response (PR) among the total number of subjects, including an evaluation of both irradiated and non-irradiated lesions.	3 years
Disease control rate (DCR)	DCR defined as the proportion of subjects achieving CR, PR, or stable disease (SD) among the total number of subjects.	3 years
Duration of response (DOR)	DOR defined as the time from the first documented CR or PR to the first occurrence of progressive disease (PD) or death from any cause.	3 years
Local Control Rate (LCR)	LCR defined as the proportion of patients whose tumors have not progressed locally after receiving treatment.	3 years
Adverse Events (AEs)	AEs assessed according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.	3 years

Collaborators and Investigators

• Sponsor: Shandong Cancer Hospital and Institute
• Investigators: Principal Investigator: Jinbo Yue, Doctor, Shandong Cancer Hospital and Institute

Publications and helpful links

General Publications

• Frentzas S, Austria Mislang AR, Lemech C, Nagrial A, Underhill C, Wang W, Wang ZM, Li B, Xia Y, Coward JIG. Phase 1a dose escalation study of ivonescimab (AK112/SMT112), an anti-PD-1/VEGF-A bispecific antibody, in patients with advanced solid tumors. J Immunother Cancer. 2024 Apr 19;12(4):e008037. doi: 10.1136/jitc-2023-008037.
• Cheng WC, Wang G, Mei Q. Ivonescimab Plus Chemotherapy in Patients With EGFR Variant Non-Small Cell Lung Cancer. JAMA. 2025 Jan 14;333(2):172. doi: 10.1001/jama.2024.23088. No abstract available.
• Liu Z, Shan D, Han X. Ivonescimab Plus Chemotherapy in Patients With EGFR Variant Non-Small Cell Lung Cancer. JAMA. 2025 Jan 14;333(2):172-173. doi: 10.1001/jama.2024.23091. No abstract available.
• Wang L, Luo Y, Ren S, Zhang Z, Xiong A, Su C, Zhou J, Yu X, Hu Y, Zhang X, Dong X, Meng S, Wu F, Hou X, Dai Y, Song W, Li B, Wang ZM, Xia Y, Zhou C. A Phase 1b Study of Ivonescimab, a Programmed Cell Death Protein-1 and Vascular Endothelial Growth Factor Bispecific Antibody, as First- or Second-Line Therapy for Advanced or Metastatic Immunotherapy-Naive NSCLC. J Thorac Oncol. 2024 Mar;19(3):465-475. doi: 10.1016/j.jtho.2023.10.014. Epub 2023 Oct 23.
• Dhillon S. Ivonescimab: First Approval. Drugs. 2024 Sep;84(9):1135-1142. doi: 10.1007/s40265-024-02073-w. Epub 2024 Jul 29.
• HARMONi-A Study Investigators; Fang W, Zhao Y, Luo Y, Yang R, Huang Y, He Z, Zhao H, Li M, Li K, Song Q, Du X, Sun Y, Li W, Xu F, Wang Z, Yang K, Fan Y, Liu B, Zhao H, Hu Y, Jia L, Xu S, Yi T, Lv D, Lan H, Li M, Liang W, Wang Y, Yang H, Jia Y, Chen Y, Lu J, Feng J, Liu C, Zhou M, Zhou J, Liu X, Zhou N, He M, Dong X, Chen H, Chen Y, Su H, Li X, Zhang Z, Yang L, Cheng Y, Chen L, Hou X, Zhang Y, Guo J, Wang Z, Lu H, Wu D, Feng W, Li W, Huang J, Wang Y, Song X, Peng J, Liu L, Guo Y, Li W, Lu D, Hu M, Wang ZM, Li B, Xia M, Zhang L. Ivonescimab Plus Chemotherapy in Non-Small Cell Lung Cancer With EGFR Variant: A Randomized Clinical Trial. JAMA. 2024 Aug 20;332(7):561-570. doi: 10.1001/jama.2024.10613.

Study record dates

Study Major Dates

• Study Start (Actual): February 8, 2025
• Primary Completion (Estimated): February 18, 2028
• Study Completion (Estimated): February 18, 2028

Study Registration Dates

• First Submitted: February 19, 2025
• First Submitted That Met QC Criteria: February 19, 2025
• First Posted (Actual): February 25, 2025

Study Record Updates

• Last Update Posted (Actual): April 28, 2026
• Last Update Submitted That Met QC Criteria: April 27, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Pancreatic Cancer; Chemotherapy; Ivonescimab; Adapted Guided Stereotactic Body Radiotherapy
• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Therapeutics; Drug Therapy
• Other Study ID Numbers: SDZLEC2024-414-02

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
• product manufactured in and exported from the U.S.: No