A Phase I/II Study of the Immune Checkpoint Inhibitor M7824 and the Immunocytokine M9241 in Combination With Stereotactic Body Radiation Therapy (SBRT) in Adults With Advanced Pancreas Cancer
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 3
- 试验地点
- 1
- 主要终点
- Recommended Phase 2 Dose (RP2D) of NHS-IL12 (M9241) Given With Bintrafusp Alfa (M7824) in Combination With Stereotactic Body Radiation Therapy (SBRT) as Neoadjuvant / Perioperative Treatment in Participants With Pancreas Cancer
研究概览
简要总结
Background:
Fewer than 10 percent of people with pancreas cancer can have surgery. Surgery gives the best outcome. Radiation therapy is usually used to make surgery possible. But it does not work for most people. Adding immunotherapy might help.
Objective:
To find a safe combined dose of Bintrafusp Alfa (M7824), NHS-IL12 (M9241, and radiation and to see if it causes pancreas cancer tumors to shrink.
Eligibility:
People ages 18 and older who have pancreas cancer and cannot have curative surgery
Design:
Participants will be screened under protocol 01-C-0129 with:
Medical history
Physical exam
Heart, urine, and blood tests
Scans. For this, participants will lie in a machine that takes pictures of the body. They may receive a contrast agent by vein.
Possible tumor biopsy
Participants will take the study drugs either alone or with radiation. They will get M7824 by vein every 2 weeks. They will get M9241 injected under the skin every 4 weeks. Participants who get radiation will get it 5 days in a row the first month.
Participants will have visits every 2 weeks. They will repeat screening tests.
If participants tumors shrink, they will have surgery. If their whole tumor is removed, they will stop treatment. They will otherwise continue treatment as long as they can tolerate it and it is helping them.
Participants will have visits 1 week and 1 month after they stop treatment. Then they will be contacted by phone or email for life. If they stop treatment for a reason other than their disease getting worse, they will have scans every 12 weeks.
详细描述
Background:
- At time of diagnosis, fewer than 10% of newly diagnosed pancreatic cancer patients present with resectable disease (patients who can undergo surgery) and patients able to undergo a margin-negative surgical resection (R0) are reported to have the most favorable outcome.
- Locally advanced, non-metastatic pancreas cancer (LAPC) is observed in up to 30% of all pancreas cancer patients at time of diagnosis (including both borderline resectable and non-resectable disease).
- The primary goal of neoadjuvant therapy in LAPC is, among tumor control and extension of survival, the conversion to resectable disease achieving a R0 resection.
- Radiation therapy (RT) is commonly used as neoadjuvant treatment for LAPC.
- However, currently used RT neoadjuvant treatment regimens result in only about 40%-60% of patients with borderline resectable pancreas cancer to undergo surgical resection, in initially unresectable LAPC patient conversion are even lower, with only 7% - 19% able to undergo resection.
- Combining immunotherapy and radiation therapy could synergistically improve anti-cancer activity.
- Bintrafusp alfa (M7824) is a bifunctional fusion protein consisting of an anti-programmed death ligand 1 (PD-L1) antibody functioning as an immune checkpoint inhibitor and the extracellular domain of transforming growth factor beta (TGF-beta) receptor type 2, a TGF-beta trap.
- The NHS-IL12 (M9241) immunocytokine is composed of 2 interleukin-12 (IL-12) heterodimers, each fused to one of the H-chains of the NHS76 antibody, which has affinity for both single- and double-stranded deoxyribonucleic acid (DNA). M9241 targets delivery of IL12, a proinflammatory cytokine that has been shown anti-tumor activity including objective responses in phase I clinical trials, to regions of tumor necrosis where DNA has become exposed, e.g., after radiation therapy.
- We hypothesize that released neo-epitopes upon increased DNA damage induced by radiation therapy together with the local proinflammatory action of M9241 will complement the anti-tumor activity of M7824 in locally advanced pancreas cancer.
Objectives:
- To determine the safety and tolerability and the recommended phase 2 dose (RP2D) of M7824 and M9241 in combination with stereotactic body radiotherapy (SBRT) as neoadjuvant/perioperative treatment in subjects with pancreas cancer.
- To determine a preliminary estimate of efficacy as best overall response (BOR) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 of M7824 and M9241 in combination with SBRT as neoadjuvant/perioperative treatment in subjects with locally advanced pancreas cancer.
Eligibility:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Cohort 1 Phase 1A/Arm 1A
De-escalating doses of NHS-IL12 (M9241) in combination with bintrafusp alfa (M7824)
干预措施: M7824 (Drug)
Cohort 1 Phase 1A/Arm 1A
De-escalating doses of NHS-IL12 (M9241) in combination with bintrafusp alfa (M7824)
干预措施: M9241 (Drug)
Cohort 2 Phase 1B/Arm 1B
De-escalating doses of NHS-IL12 (M9241) in combination with bintrafusp alfa (M7824) and stereotactic body radiotherapy (SBRT)
干预措施: M7824 (Drug)
Cohort 2 Phase 1B/Arm 1B
De-escalating doses of NHS-IL12 (M9241) in combination with bintrafusp alfa (M7824) and stereotactic body radiotherapy (SBRT)
干预措施: M9241 (Drug)
Cohort 2 Phase 1B/Arm 1B
De-escalating doses of NHS-IL12 (M9241) in combination with bintrafusp alfa (M7824) and stereotactic body radiotherapy (SBRT)
干预措施: SBRT (Radiation)
Phase II Cohort 3/Arm 2
Recommended phase 2 dose (RP2D) of bintrafusp alfa (M7824) and NHS-IL12 (M9241) in combination with stereotactic body radiotherapy (SBRT)
干预措施: M7824 (Drug)
Phase II Cohort 3/Arm 2
Recommended phase 2 dose (RP2D) of bintrafusp alfa (M7824) and NHS-IL12 (M9241) in combination with stereotactic body radiotherapy (SBRT)
干预措施: M9241 (Drug)
Phase II Cohort 3/Arm 2
Recommended phase 2 dose (RP2D) of bintrafusp alfa (M7824) and NHS-IL12 (M9241) in combination with stereotactic body radiotherapy (SBRT)
干预措施: SBRT (Radiation)
结局指标
主要结局
Recommended Phase 2 Dose (RP2D) of NHS-IL12 (M9241) Given With Bintrafusp Alfa (M7824) in Combination With Stereotactic Body Radiation Therapy (SBRT) as Neoadjuvant / Perioperative Treatment in Participants With Pancreas Cancer
时间窗: First 28 days of treatment
The recommended phase 2 dose (RP2D) is the dose level of M9241 in combination with M7824 at which ≤1 of 6 individuals experienced a dose limiting toxicity (DLT) during the first cycle (28 days) of combinational treatment with M9241 and M7824. A DLT is any Grade ≥ 3 adverse events occurring during the first 28 days of treatment except adverse events unrelated, or unlikely related to study agents and probably or definitely related to other causes.
Number of Participants With ≥Grade 3 Toxicities Possibly, Probably, or Definitely Related to Treatment of Bintrafusp Alfa (M7824) and NHS-IL12 (M9241) in Combination With Stereotactic Body Radiation Therapy (SBRT)
时间窗: Date treatment consent signed to date off study, approximately 4 months and 13 days.
Adverse events were assessed using the Common Terminology Criteria for Adverse Events (CTCAE)v5.0. Grade 3 is severe, Grade 4 is life-threatening, and Grade 5 is death related to adverse events.
Best Overall Response (BOR) According to the Response Evaluation Criteria in Solid Tumors (RECIST) of Bintrafusp Alfa (M7824) & NHS-IL12 (M9241) in Combination With Stereotactic Body Radiation Therapy in Participants With Locally Advanced Pancreas Cancer
时间窗: time measurement criteria are met for complete response or partial response until the first date that recurrent or progressive disease is objectively documented
Best overall response is measured from the time measurement criteria are met for complete response or partial response until the first date that recurrent or progressive disease is objectively documented using the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in target lesions. In the case of a PR or CR a confirmatory computed tomography or magnetic resonance imaging scan should be done no sooner than 4 weeks. Progressive Disease (PD) is at least a 20% increase in target lesions and/or the appearance of new lesions.
次要结局
- Overall Survival (OS) in Participants After Completion of Radiation Therapy (RT) in Combination With NHS-IL12 (M9241) and Bintrafusp Alfa (M7824)(date of on-study to the date of death from any cause or last follow)
- Progression-free Survival (PFS) for All Participants(Time interval from start to treatment to disease progression, an average of 4 months.)
- Progression-free Survival (PFS) for Participants Who Did Not Undergo Surgical Resection(time interval from start of treatment to documented evidence of disease progression)
- Fraction of Participants With Locally Advanced, Non-metastatic Pancreas Cancer (LAPC) Who Are Able to Undergo Surgical Resection After Bintrafusp Alfa (M7824) and NHS-IL12 (M9241) in Combination With Stereotactic Body Radiation Therapy (SBRT) Treatment(At time of surgical resection)
- Time-to-recurrence of the Disease For Participants Who Underwent Surgical Resection After Bintrafusp Alfa (M7824) and NHS-IL12 (M9241) in Combination With Stereotactic Body Radiation Therapy (SBRT) Treatment(At disease recurrence after surgical resection)
- Complete Pathological Response Rate(s) For Participants Who Underwent Surgical Resection After Bintrafusp Alfa (M7824) and NHS-IL12 (M9241) in Combination With Stereotactic Body Radiation Therapy (SBRT) Treatment(At time of surgical resection)
研究者
Udo Rudloff, MD
Principal Investigator
National Cancer Institute (NCI)