An Open-label Phase 1b/2a Study of NT-I7 (Efineptakin Alfa) in Combination With Pembrolizumab in Subjects With Relapsed/Refractory Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 215
- 试验地点
- 8
- 主要终点
- Phase 1b: Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs), Serious AEs (SAEs), Trial Treatment-related TEAEs and Trial Treatment-related SAEs
研究概览
简要总结
The main purposes of Phase 1b of this study are to determine the following in participants with advanced solid tumors:
- Safety and tolerability of NT-I7 in combination with pembrolizumab
- Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D)
The main purpose of Phase 2a of this study is to assess the preliminary anti-tumor activity of NT-I7 in combination with pembrolizumab in participants with checkpoint inhibitor (CPI) treated and naïve relapsed and refractory (R/R) tumors.
The main purpose of the Biomarker Cohort is to assess a potential correlation between tumor infiltrating lymphocytes (TILs) and clinical benefits in participants with CPI-naïve R/R ovarian cancer (OC).
详细描述
This is a multicenter, open-label Phase 1b/2a study of NT-I7 in combination with pembrolizumab. The study consists of a dose escalation phase (Phase 1b) followed by a dose expansion phase (Phase 2a) and a Biomarker Cohort.
The Phase 1b is designed to assess the safety and tolerability, including determination of the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D) of NT-I7.
The main purpose of Phase 2a of this study is to assess the preliminary antitumor activity of NT-I7 in combination with pembrolizumab in participants with relapsed/refractory
- checkpoint inhibitor (CPI)-treated Triple Negative Breast Cancer (TNBC), Non-small Cell Lung Cancer (NSCLC), and Small Cell Lung Cancer (SCLC)
- checkpoint inhibitor (CPI)-naïve Microsatellite Stable Colorectal Cancer (MSS-CRC), and Pancreatic Cancer (PC) The Biomarker Cohort is designed to assess the correlation between tumor infiltrating lymphocytes (TILs) and clinical benefits of NT-I7 in combination with pembrolizumab in participants with CPI naïve R/R Ovarian Cancer (OC).
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
- •(Participants must meet all the following to be eligible)
- •Participants with histologically or cytologically confirmed advanced or metastatic solid tumors.
- •Have measurable disease per RECIST v1.
- •Participants enrolling in the Phase 1b, Arms I, IV, IVa, V, and Va of the Phase 2a, and the Biomarker Cohort OC must have biopsiable disease.
- •Female participants who are either postmenopausal for at least 1 year, are surgically sterile for at least 6 weeks; female participants of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or to use dual methods of contraception for the duration of study treatment and for 120 days after the last dose of study treatment (pembrolizumab and/or NT-I7).
- •Non-sterile male participants who are sexually active with female partners of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or to use highly effective method(s) of contraception for the duration of study treatment and for 120 days after the last dose of study treatment (pembrolizumab and/or NT-I7).
- •Meet the requirements for the intended stages and arms (disease specific inclusion criteria), as follows:
- •Applicable to the Dose escalation phase (Phase 1b) only: (Biopsy Arm)
- •Relapsed/refractory advanced solid tumors.
- •Applicable to the Dose expansion phase (Phase 2a) only:
- •Anti-PD-1/anti-PD-L1 refractory criteria for CPI-treated TNBC, NSCLC, and SCLC
- •Has received at least 2 doses of an approved anti-PD-1/anti-PD-L1 monoclonal antibody (mAb).
- •Has demonstrated disease progression after anti-PD-1/anti-PD-L
- •Specific to Arm I: CPI-treated R/R TNBC (Biopsy Arm)
- •Histopathologic or cytologic documented TNBC.
- •Received one or more prior therapies for TNBC in the advanced or metastatic setting, and prior treatment (for advanced, metastatic or (neo) adjuvant).
- •Specific to Arm II: CPI-treated R/R NSCLC
- •Had prior treatment with CPI. Participants with estimated glomerular filtration rate (EGFR), BRAF, or c-ros oncogene 1(ROS1) mutations or anaplastic lymphoma kinase (ALK) translocations are required to have received prior therapy with the appropriate tyrosine kinase inhibitor (TKI).
- •Specific to Arm III: CPI-treated R/R SCLC
- •Recurrent extensive-stage SCLC; Received prior CPI therapy.
- •Specific to Arm IV and IVa: CPI-naïve R/R MSS-CRC (Biopsy Arm)
- •MSS-CRC (categorized as MSS by immunohistochemistry(IHC) or polymerase chain reaction (PCR).
- •Previously treated with standard therapies, which must include fluoropyrimidine, oxaliplatin, and irinotecan; participants treated with CPI are not eligible.
- •Specific to Arm V and Va: CPI-naïve R/R Pancreatic Cancer (Biopsy Arm)
- •Have documented radiographic progression to or documented in tolerance of first line systemic chemotherapy which included either gemcitabine or Fluorouracil (5-FU)-based regimen (including capecitabine); participants treated previously with CPI are not eligible.
- •Specific to Biomarker Cohort: CPI-naïve R/R Ovarian Cancer
- •Up to 5 prior lines of treatment, including platinum-based treatment(s); participants treated previously with CPIs are not eligible.
- •Willing to provide pre- and on-treatment tumor biopsies.
排除标准
- •Pregnant, lactating or breastfeeding.
- •Receiving chemotherapy or any anti-cancer therapy (approved or investigational) with half-life <1 week within 30 days or 5 half-lives.
- •Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate if stable.
- •Participants who have received treatment with systemic immunosuppressive medications.
- •Has a history of non-infectious pneumonitis that required steroids or current pneumonitis.
- •Has had an allogenic tissue/solid organ transplant or bone marrow transplant.
- •Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137) and was discontinued from that treatment due to a Grade 3 or higher Immune related adverse event (irAE).
研究组 & 干预措施
Phase 2a: CPI Treated Small Cell Lung Cancer
Participants with checkpoint inhibitor (CPI) treated relapsed or refractory small cell lung cancer (SCLC). Participants will receive the recommended phase 2 dose (RP2D) identified during Phase 1b.
Pembrolizumab will be administered on Day 1 of every 21 day cycle.
干预措施: NT-I7 (Drug)
Phase 2a: CPI Treated Small Cell Lung Cancer
Participants with checkpoint inhibitor (CPI) treated relapsed or refractory small cell lung cancer (SCLC). Participants will receive the recommended phase 2 dose (RP2D) identified during Phase 1b.
Pembrolizumab will be administered on Day 1 of every 21 day cycle.
干预措施: pembrolizumab (KEYTRUDA®) (Drug)
Phase 1b: NT-I7 Dose Escalation
NT-I7 will be administered on Day 1 of alternate 21 day cycles (Cycle 1, 3, 5 etc.). Dosage will increase until the maximum tolerated dose (MTD) and/or the recommended phase 2 (RP2D) dose is reached.
Pembrolizumab will be administered on Day 1 of every 21 day cycle.
干预措施: NT-I7 (Drug)
Phase 1b: NT-I7 Dose Escalation
NT-I7 will be administered on Day 1 of alternate 21 day cycles (Cycle 1, 3, 5 etc.). Dosage will increase until the maximum tolerated dose (MTD) and/or the recommended phase 2 (RP2D) dose is reached.
Pembrolizumab will be administered on Day 1 of every 21 day cycle.
干预措施: pembrolizumab (KEYTRUDA®) (Drug)
Phase 2a: CPI Treated Triple Negative Breast Cancer
Participants with checkpoint inhibitor (CPI) treated relapsed or refractory triple negative breast cancer (TNBC). Participants will receive the recommended phase 2 dose (RP2D) identified during Phase 1b.
Pembrolizumab will be administered on Day 1 of every 21 day cycle.
干预措施: NT-I7 (Drug)
Phase 2a: CPI Treated Triple Negative Breast Cancer
Participants with checkpoint inhibitor (CPI) treated relapsed or refractory triple negative breast cancer (TNBC). Participants will receive the recommended phase 2 dose (RP2D) identified during Phase 1b.
Pembrolizumab will be administered on Day 1 of every 21 day cycle.
干预措施: pembrolizumab (KEYTRUDA®) (Drug)
Phase 2a: CPI Treated Non-small Cell Lung Cancer
Participants with checkpoint inhibitor (CPI) treated relapsed or refractory non-small cell lung cancer (NSCLC). Participants will receive the recommended phase 2 dose (RP2D) identified during Phase 1b.
Pembrolizumab will be administered on Day 1 of every 21 day cycle.
干预措施: NT-I7 (Drug)
Phase 2a: CPI Treated Non-small Cell Lung Cancer
Participants with checkpoint inhibitor (CPI) treated relapsed or refractory non-small cell lung cancer (NSCLC). Participants will receive the recommended phase 2 dose (RP2D) identified during Phase 1b.
Pembrolizumab will be administered on Day 1 of every 21 day cycle.
干预措施: pembrolizumab (KEYTRUDA®) (Drug)
Phase 2a: CPI Naïve Microsatellite Stable Colorectal Cancer
Participants with checkpoint inhibitor (CPI) naïve relapsed or refractory microsatellite stable colorectal cancer (MSS-CRC). Participants will receive the recommended phase 2 dose (RP2D) identified during Phase 1b.
Pembrolizumab will be administered on Day 1 of every 21 day cycle.
干预措施: NT-I7 (Drug)
Phase 2a: CPI Naïve Microsatellite Stable Colorectal Cancer
Participants with checkpoint inhibitor (CPI) naïve relapsed or refractory microsatellite stable colorectal cancer (MSS-CRC). Participants will receive the recommended phase 2 dose (RP2D) identified during Phase 1b.
Pembrolizumab will be administered on Day 1 of every 21 day cycle.
干预措施: pembrolizumab (KEYTRUDA®) (Drug)
Phase 2a: CPI Naïve Pancreatic Cancer
Participants with checkpoint inhibitor (CPI) naïve relapsed or refractory pancreatic cancer (PC). Participants will receive the recommended phase 2 dose (RP2D) identified during Phase 1b.
Pembrolizumab will be administered on Day 1 of every 21 day cycle.
干预措施: NT-I7 (Drug)
Phase 2a: CPI Naïve Pancreatic Cancer
Participants with checkpoint inhibitor (CPI) naïve relapsed or refractory pancreatic cancer (PC). Participants will receive the recommended phase 2 dose (RP2D) identified during Phase 1b.
Pembrolizumab will be administered on Day 1 of every 21 day cycle.
干预措施: pembrolizumab (KEYTRUDA®) (Drug)
Phase 2a: CPI Naïve Microsatellite Stable Colorectal Cancer, Expansion Cohort
Participants with checkpoint inhibitor (CPI) naïve relapsed or refractory microsatellite stable colorectal cancer (MSS-CRC). Participants will receive 1200 µg/kg of NT-I7 and and a fixed dose of 200 mg of pemprolizumab.
Pembrolizumab will be administered on Day 1 of every 21 day cycle.
干预措施: NT-I7 (Drug)
Phase 2a: CPI Naïve Microsatellite Stable Colorectal Cancer, Expansion Cohort
Participants with checkpoint inhibitor (CPI) naïve relapsed or refractory microsatellite stable colorectal cancer (MSS-CRC). Participants will receive 1200 µg/kg of NT-I7 and and a fixed dose of 200 mg of pemprolizumab.
Pembrolizumab will be administered on Day 1 of every 21 day cycle.
干预措施: pembrolizumab (KEYTRUDA®) (Drug)
Phase 2a: CPI Naïve Pancreatic Cancer, Expansion Cohort
Participants with checkpoint inhibitor (CPI) naïve relapsed or refractory pancreatic cancer (PC).Participants will receive 1200 µg/kg of NT-I7 and a fixed dose of 200 mg of pemprolizumab.
Pembrolizumab will be administered on Day 1 of every 21 day cycle.
干预措施: NT-I7 (Drug)
Phase 2a: CPI Naïve Pancreatic Cancer, Expansion Cohort
Participants with checkpoint inhibitor (CPI) naïve relapsed or refractory pancreatic cancer (PC).Participants will receive 1200 µg/kg of NT-I7 and a fixed dose of 200 mg of pemprolizumab.
Pembrolizumab will be administered on Day 1 of every 21 day cycle.
干预措施: pembrolizumab (KEYTRUDA®) (Drug)
Biomarker Cohort: CPI Naïve Ovarian Cancer
Participants with checkpoint inhibitor (CPI) naïve relapsed or refractory ovarian cancer (OC). Participants will receive a starting dose of 960 µg/kg of NT-I7 and a fixed dose of 200 mg of pemprolizumab.
Pembrolizumab will be administered on Day 1 of every 21 day cycle.
干预措施: NT-I7 (Drug)
Biomarker Cohort: CPI Naïve Ovarian Cancer
Participants with checkpoint inhibitor (CPI) naïve relapsed or refractory ovarian cancer (OC). Participants will receive a starting dose of 960 µg/kg of NT-I7 and a fixed dose of 200 mg of pemprolizumab.
Pembrolizumab will be administered on Day 1 of every 21 day cycle.
干预措施: pembrolizumab (KEYTRUDA®) (Drug)
结局指标
主要结局
Phase 1b: Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs), Serious AEs (SAEs), Trial Treatment-related TEAEs and Trial Treatment-related SAEs
时间窗: Up to 2 years and 3 months
A TEAE was any AE that starts on/after the first day of trial treatment or that worsens on/after the first day of trial treatment and up to 30 days (90 days for serious adverse events) after the date of last dose of trial drugs, or initiation of new anticancer therapy, whichever is earlier. A SAE was defined as any AE that resulted in any of the following outcomes: 1. Death; 2. A life-threatening AE; 3. An AE that resulted in inpatient hospitalization or prolongation of existing hospitalization for ≥24 hours; 4. A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; 5. A congenital anomaly/birth defect; 6. Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
Phase 1b: Number of Participants Who Experienced a Dose Limiting Toxicity (DLT)
时间窗: Up to 21 days
A DLT was defined as any AE occurring within the first 21 days that was considered to be related to the trial treatments (NT-I7 and/or pembrolizumab) per the investigator, and that met at least one of the non-hematologic or hematologic criteria: * Grade 4 non-hematologic toxicity * Grade ≥ 3 diarrhea, nausea and vomiting * Grade ≥ 3 rash for ≥ 5 days * Grade 4 neutropenia for ≥ 5 days * Febrile neutropenia Grade 3 or Grade 4 * Other Grade 4 hematologic toxicity for ≥7 days, except thrombocytopenia * Any non-hematologic AE ≥ Grade 3 in severity * Any Grade 3 or Grade 4 non-hematologic laboratory value if medical intervention was required, led to hospitalization, persisted for \> 1 week, resulted in potential drug-induced liver injury * Other Grade ≥ 3 clinical laboratory abnormalities not reversible to ≤ Grade 1 within 72 hours * Prolonged delay in initiating Cycle 2 * Any treatment-related toxicity that caused treatment discontinuation in Cycle 1 * Grade 5 toxicity.
Phase 2a (Arms I to Va): Objective Response Rate (ORR)
时间窗: Up to 2 years
ORR was defined as the percentage of participants who had at least one confirmed partial response (PR) or complete response (CR), per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST v1.1) and immune RECIST (iRECIST) as determined by the investigator. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have had reduction in short axis to \<10 mm (\<1 cm). PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Biomarker Cohort: Percentage of Area Occupied by Tumor-Infiltrating Lymphocytes (TILs)
时间窗: Pre-treatment and post-treatment (maximum duration of treatment of approximately 2 years)
CD8 positivity TILs in tumor biopsy samples were identified using a validated immunohistochemistry (IHC) assay and certified by a pathologist. The percentage of area occupied by TILs was evaluated in the stroma area, tumor area and tumor - relevant tissue area both pre- and post-treatment.
次要结局
- Biomarker Cohort: ORR(Up to 2 years)
- Phase 1b/2a: Duration of Objective Response (DOR)(Up to 2 years)
- Phase 1b/2a: Disease Control Rate (DCR)(Up to 2 years)
- Phase 1b/2a: Progression Free Survival (PFS)(Up to 2 years)
- Phase 1b/2a: Overall Survival (OS)(Up to 2 years)
- Phase 1b/2a: Number of Participants Who Experienced an Increase in Anti-Drug Antibodies (ADAs) to NT-I7(Up to 2 years)
- Biomarker Cohort: Number of Participants Who Experienced TEAEs, SAEs, Trial Treatment-related TEAEs and Trial Treatment-related SAEs(Up to 2 years and 3 months)