A Phase II Study of Ivonescimab as Monotherapy or in Combination With Platinum/Pemetrexed Chemotherapy in Patients With Advanced Non-small Cell Lung Cancer (NSCLC) Harboring Actionable Genomic Alterations (AGAs)
概览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 46
- 试验地点
- 3
- 主要终点
- Objective Response Rate (ORR) of Ivonescimab Monotherapy
概览
简要总结
The goal of this clinical trial is to assess the efficacy of ivonescimab monotherapy in patients with advanced non-small cell lung cancer harboring actionable genomic alterations who have received prior targeted therapies and chemotherapy. This clinical trial also aims to assess the efficacy of ivonescimab plus carboplatin/pemetrexed chemotherapy in patients with advanced non-small cell lung cancer harboring actionable genomic alterations other than epidermal growth factor receptor mutations who have received prior targeted therapies but no chemotherapy. The main questions it aims to answer are:
- Will ivonescimab alone or together with carboplatin/pemetrexed chemotherapy shrink tumors in the clinical trial's patients?
- Will ivonescimab alone or together with carboplatin/pemetrexed chemotherapy effectively influence if the patients' cancer grows, how long the treatment takes to start working, how long the treatment keeps working after it first starts to help, how long the treatment keeps the cancer from getting worse, and overall survival of patients?
- How many patients receiving ivonescimab alone or together with carboplatin/pemetrexed chemotherapy will experience treatment-emergent, treatment-related, immune-related, and especially interesting side effects? Patients receiving ivonescimab alone will receive an intravenous infusion of ivonescimab every 3 weeks for up to 24 months. Patients receiving ivonescimab together with carboplatin/pemetrexed chemotherapy will receive separate intravenous infusions of ivonescimab, pemetrexed, and carboplatin every 3 weeks for 4 cycles (each cycle is 21 days). These patients will continue to receive infusions of ivonescimab and pemetrexed every 3 weeks for up to 24 total months.
详细描述
This is a phase II, open-label, two-cohort study designed to determine the efficacy of ivonescimab as monotherapy or in combination with carboplatin/pemetrexed chemotherapy in patients with advanced non-small cell lung cancer harboring actionable genomic alterations who have received prior standard-of-care therapies.
Ivonescimab monotherapy will be evaluated in patients with advanced non-small cell lung cancer with actionable genomic alterations after prior standard-of-care targeted therapies and platinum/pemetrexed chemotherapy. Ivonescimab plus carboplatin/pemetrexed combination regimen will be evaluated in patients with advanced non-small cell lung cancer with non-epidermal growth factor receptor actionable genomic alterations after prior standard-of-care targeted therapies (and no prior chemotherapy).
The U.S. Food and Drug Administration has not approved ivonescimab as a treatment for any disease. The U.S. Food and Drug Administration has approved carboplatin and pemetrexed as a treatment option for non-small cell lung cancer harboring actionable genomic alterations.
Ivonescimab, also known as AK112 and SMT112 during development, is a specially engineered antibody that can attach to both PD-1 and VEGF-A. PD-1 is a protein found on immune cells that "turn off" the immune response. VEGF-A is a protein that helps tumors grow new blood vessels. By binding to both proteins, ivonescimab can reactivate immune cells so they can attack the tumor, block blood vessel growth that feeds the tumor, and reduce the tumor's ability to suppress the immune system, making it easier for immune cells to reach and fight the cancer. Carboplatin is a type of chemotherapy drug that contains a special form of platinum. The drug damages DNA inside cancer cells by creating links or bonds between different parts of the DNA that makes it harder for the cancer cells to grow and divide, eventually leading to cell death. Carboplatin works at any stage of the cell's life cycle, not just when the cell is dividing. Carboplatin is currently sold as Paraplatin. Pemetrexed is a type of chemotherapy drug that works by blocking specific substances, called folates, that cancer cells need to grow and multiply. Folates help cells make DNA and other important cell structures. By preventing folates from working, pemetrexed helps slow down or stop the growth of cancer cells. Pemetrexed is currently sold as Alimta.
Patients will receive study treatment for up to 24 months as long as their disease does not progress, treatment does not cause worsening symptoms, they do not have unacceptable side effects, until they demonstrate an inability or unwillingness to receive the medication regimen and/or follow the document requirements, or they withdraw from the study. Patients will be followed for up to 2 years after the last patient is enrolled. It is expected that about 46 people will take part in this research study.
Summit Therapeutics, Inc. is supporting this research study by providing the study drug, ivonescimab, and funding for the clinical trial activities.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically or cytologically confirmed advanced or metastatic non-squamous NSCLC not amenable to curative resection or radiation.
- •AGA requirements as follows:
- •Ivonescimab monotherapy: Tumor harboring classical EGFR sensitizing mutation (i.e., L858R, exon 19 deletion), or ALK, ROS1, RET, or NTRK1-3 fusion, per local testing. Note: The number of patients with EGFR mutation-positive NSCLC enrolled will be capped at maximum of 10 (in order to ensure the assessment of non-EGFR disease subsets). Ivonescimab plus carboplatin/pemetrexed: Tumor harboring ALK, ROS1, RET, or NTRK1-3 fusion, per local testing.
- •Prior therapy requirements as follows:
- •a. Prior genotype-specific standard-of-care targeted therapy must have included at least one genotype-appropriate TKI(s) specified below: i. EGFR sensitizing mutation: a third-generation EGFR TKI such as osimertinib or lazertinib ii. ALK fusion: a third- or fourth-generation ALK TKI such as lorlatinib or neladalkib (NVL-655) iii. ROS1 fusion: crizotinib, entrectinib, repotrectinib, or taletrectinib iv. RET fusion: selpercatinib or pralsetinib v. NTRK1-3 fusion: entrectinib, larotrectinib, or repotrectinib Ivonescimab monotherapy: Must have received platinum/pemetrexed chemotherapy. No limitations on the number of prior lines of systemic therapy including the number of lines of chemotherapy or TKI(s). Ivonescimab plus carboplatin/pemetrexed: May not have received any prior chemotherapy. No limitations on the number of prior TKI(s).
- •At least 1 measurable lesion as assessed by investigator per the RECIST v1.1 criteria for both cohorts.
- •Participants must be willing to undergo the mandatory pre-treatment and post-progression tissue biopsies. If archival pre-treatment tissue is available from within 6 months of study enrollment, with no new intervening systemic therapy since the biopsy, a repeat pre-treatment biopsy may be omitted upon discussion with the principal investigator. On-treatment tissue biopsy (obtained within 7 days prior to Cycle 2 Day 1) will be mandatory for patients in Cohort 1 and optional for patients in Cohort
- •In select cases, if medically deemed unsafe/not feasible, exception may be granted upon discussion with the principal investigator.
- •Clinically asymptomatic treated or untreated brain metastases are allowed if they have not required increasing doses of steroids within 2 weeks prior to study entry for CNS symptoms.
- •Age ≥18 years old.
排除标准
- •Participants previously treated with immune checkpoint inhibitors or other T cell immune-modulating antibodies, including anti-CTLA-4, anti-PD-1 and/or anti-PD-L1 agents.
- •Major surgical procedures or serious trauma within 4 weeks prior to first ivonescimab dose or plans for major surgical procedures within 4 weeks after the first ivonescimab dose (as determined by the investigator). Minor local procedures (excluding central venous catheterization and port implantation) within 3 days prior to first ivonescimab dose.
- •History of bleeding tendencies or coagulopathy and/or clinically significant bleeding symptoms or risk within 4 weeks prior to first ivonescimab dose, including but not limited to:
- •Hemoptysis (defined as coughing up ≥ 0.5 teaspoon of fresh blood or small blood clots). Note: transient hemoptysis associated with diagnostic bronchoscopy is allowed.
- •Nasal bleeding/epistaxis (bloody nasal discharge is allowed)
- •Current use of prophylactic or full-dose anticoagulants or anti-platelet agents for therapeutic purposes that is not stable prior to first ivonescimab dose is not allowed; stability of anti-coagulation dosing will be defined by remaining on the same dose for at least one month prior to study enrollment.
- •The use of full-dose anticoagulants is permitted as long as the international normalized ratio (INR) or activated partial thromboplastin time (aPTT) is within therapeutic limits according to the medical standard of the enrolling institution.
- •Poorly controlled hypertension with repeated systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg after oral antihypertensive therapy.
- •Active autoimmune or lung disease requiring systemic therapy (eg, with disease modifying drugs, prednisone \>10 mg daily or equivalent, immunosuppressant therapy) within 2 years prior to first ivonescimab dose; however, the following will be allowed:
- •Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is permitted.
研究组 & 干预措施
Ivonescimab Monotherapy
Patients with advanced/metastatic non-small cell lung cancer harboring actionable genomic alterations with disease progression after prior targeted therapies and chemotherapy will receive ivonescimab monotherapy. Ivonescimab will be administered at the pre-determined dose every 3 weeks on day 1 of each cycle (each cycle is 21 days) until disease progression, unacceptable toxicity, withdrawal of consent, or for up to 24 months, whichever occurs first.
干预措施: Ivonescimab (Drug)
Ivonescimab plus Carboplatin/Pemetrexed
Patients with advanced/metastatic non-small cell lung cancer harboring actionable genomic alterations other than epidermal growth factor receptor mutations with disease progression after prior targeted therapies but no prior chemotherapy will receive ivonescimab, carboplatin, and pemetrexed. Ivonescimab will be administered at the pre-determined dose with the pre-determined doses of carboplatin and pemetrexed on day 1 of the first 4 treatment cycles (each cycle is 21 days) or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever occurs first. Patients who have stable disease or response after the first 4 treatment cycles will continue to receive pre-determined doses of ivonescimab and pemetrexed every 3 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or for up to 24 months, whichever occurs first.
干预措施: Ivonescimab (Drug)
Ivonescimab plus Carboplatin/Pemetrexed
Patients with advanced/metastatic non-small cell lung cancer harboring actionable genomic alterations other than epidermal growth factor receptor mutations with disease progression after prior targeted therapies but no prior chemotherapy will receive ivonescimab, carboplatin, and pemetrexed. Ivonescimab will be administered at the pre-determined dose with the pre-determined doses of carboplatin and pemetrexed on day 1 of the first 4 treatment cycles (each cycle is 21 days) or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever occurs first. Patients who have stable disease or response after the first 4 treatment cycles will continue to receive pre-determined doses of ivonescimab and pemetrexed every 3 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or for up to 24 months, whichever occurs first.
干预措施: carboplatin (Drug)
Ivonescimab plus Carboplatin/Pemetrexed
Patients with advanced/metastatic non-small cell lung cancer harboring actionable genomic alterations other than epidermal growth factor receptor mutations with disease progression after prior targeted therapies but no prior chemotherapy will receive ivonescimab, carboplatin, and pemetrexed. Ivonescimab will be administered at the pre-determined dose with the pre-determined doses of carboplatin and pemetrexed on day 1 of the first 4 treatment cycles (each cycle is 21 days) or until disease progression, unacceptable toxicity, or withdrawal of consent, whichever occurs first. Patients who have stable disease or response after the first 4 treatment cycles will continue to receive pre-determined doses of ivonescimab and pemetrexed every 3 weeks until disease progression, unacceptable toxicity, withdrawal of consent, or for up to 24 months, whichever occurs first.
干预措施: pemetrexed (Drug)
结局指标
主要结局
Objective Response Rate (ORR) of Ivonescimab Monotherapy
时间窗: Day 1 of cycle 1 (each cycle is 21 days) to disease progression, loss of follow-up, withdrawal of consent, study termination, or for up to 2 years from the day the last patient is enrolled, whichever occurs first.
The objective response rate (ORR) is defined as the number of patients with confirmed best overall response or complete response or partial response (PR) divided by the number of treated patients in the cohort. ORR will be measured per investigator. BOR will be assessed per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria.
Objective Response Rate (ORR) of Ivonescimab plus Carboplatin/Pemetrexed
时间窗: Day 1 of cycle 1 (each cycle is 21 days) to disease progression, loss of follow-up, withdrawal of consent, study termination, or for up to 2 years from the day the last patient is enrolled, whichever occurs first.
The objective response rate (ORR) is defined as the number of patients with confirmed best overall response or complete response or partial response (PR) divided by the number of treated patients in the cohort. ORR will be measured per investigator. BOR will be assessed per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria.
次要结局
- Disease Control Rate (DCR) of Ivonescimab Monotherapy(Day 1 of cycle 1 (each cycle is 21 days) to disease progression, loss of follow-up, withdrawal of consent, study termination, or for up to 2 years from the day the last patient is enrolled, whichever occurs first.)
- Disease Control Rate (DCR) of Ivonescimab plus Carboplatin/Pemetrexed(Day 1 of cycle 1 (each cycle is 21 days) to disease progression, loss of follow-up, withdrawal of consent, study termination, or for up to 2 years from the day the last patient is enrolled, whichever occurs first.)
- Time to Response (TTR) of Ivonescimab Monotherapy(Day 1 of cycle 1 (each cycle is 21 days) to the first documentation of complete or partial response for up to 2 years from the day the last patient is enrolled.)
- Time to Response (TRR) of Ivonescimab plus Carboplatin/Pemetrexed(Day 1 of cycle 1 (each cycle is 21 days) to the first documentation of complete or partial response for up to 2 years from the day the last patient is enrolled.)
- Duration of Response (DOR) of Ivonescimab Monotherapy(First day complete or partial response is recorded to the first day progressive disease is recorded or, if no progressive disease occurs, the date of last radiological assessment up to 2 years from the day the last patient is enrolled.)
- Duration of Response (DOR) of Ivonescimab plus Carboplatin/Pemetrexed(First day complete or partial response is recorded to the first day progressive disease is recorded or, if no progressive disease occurs, the date of last radiological assessment up to 2 years from the day the last patient is enrolled.)
- Progression-Free Survival (PFS) of Ivonescimab Monotherapy(Day 1 of cycle 1 (each cycle is 21 days) to the first day of documented disease progression, death, or if no disease progression or death occurs, the day of the last radiological assessment, up to 2 years from the day the last patient was enrolled.)
- Progression-Free Survival (PFS) of Ivonescimab plus Carboplatin/Pemetrexed(Day 1 of cycle 1 (each cycle is 21 days) to the first day of documented disease progression, death, or if no disease progression or death occurs, the day of the last radiological assessment, up to 2 years from the day the last patient was enrolled.)
- Overall Survival (OS) of Ivonescimab Monotherapy(Day 1 of cycle 1 (each cycle is 21 days) to death, day of last consent for patients who are lost to follow-up or withdraw, or the study cutoff date for patients will receiving treatment, up to 2 years from the day the last patient was enrolled.)
- Overall Survival (OS) of Ivonescimab plus Carboplatin/Pemetrexed(Day 1 of cycle 1 (each cycle is 21 days) to death, day of last consent for patients who are lost to follow-up or withdraw, or the study cutoff date for patients will receiving treatment, up to 2 years from the day the last patient was enrolled.)
- Number of Patients who Experience Adverse Events and Serious Adverse Events on Ivonescimab Monotherapy(Day 1 of cycle 1 (each cycle is 21 days) to the day 90 follow-up visit.)
- Number of Patients who Experience Adverse Events and Serious Adverse Events on Ivonescimab plus Carboplatin/Pemetrexed(Day 1 of cycle 1 (each cycle is 21 days) to the day 90 follow-up visit.)
- Number of Patients who Experience Immune-Related and Especially Interesting Adverse Events on Ivonescimab Monotherapy(Day 1 of cycle 1 (each cycle is 21 days) to the 90 day follow-up visit.)
- Number of Patients who Experience Immune-Related and Especially Interesting Adverse Events on Ivonescimab plus Carboplatin/Pemetrexed(Day 1 of cycle 1 (each cycle is 21 days) to the 90 day follow-up visit.)
研究者
Jessica Jiyeong Lin, M.D.
Principal Investigator
Massachusetts General Hospital