IL Believe: A Phase 1/2, Open-label, Dose Escalation and Dose Expansion Study to Investigate the Safety and Tolerability of TransCon IL-2 β/γ Alone or in Combination With Pembrolizumab, TransCon TLR7/8 Agonist, or Other Anticancer Therapies, in Adult Participants With Locally Advanced or Metastatic Solid Tumor Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 320
- 试验地点
- 69
- 主要终点
- Safety and Tolerability
研究概览
简要总结
TransCon IL-2 β/γ is an investigational drug being developed for treatment of locally advanced or metastatic solid tumors. This is a first-in-human, open-label, Phase 1/2, dose escalation and dose expansion study of TransCon IL-2 β/γ as monotherapy or in combination therapy in adult participants with advanced or metastatic solid tumors. Given the unique PK profile enabled by the TransCon technology, TransCon IL-2 β/γ presents the opportunity to enhance the therapeutic index of current IL-2 therapy.
详细描述
IL-2 is a key cytokine that directs the immune system through pleiotropic effects mediated by promoting expansion of both cytotoxic effector cells and Tregs. TransCon IL-2 β/γ is designed as a long-acting delivery prodrug of IL-2 β/γ, a potent cytokine signaling molecule, with the potential to improve the safety and efficacy of IL-2.
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
- •At least 18 years of age, or country defined local legal age
- •Demonstrated adequate organ function at screening
- •Life expectancy >12 weeks as determined by the Investigator
- •Female and male participants of childbearing potential who are sexually active must agree to use highly effective methods of contraception
- •Participants must have histologically confirmed locally advanced, recurrent, or metastatic solid tumor malignancies that cannot be treated with curative intent (surgery or radiotherapy), with the exception of the neoadjuvant cohorts
- •Part 1 and Part 2: Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
- •Part 3 and Part 4: Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- •Participants who have undergone treatment with anti-PD-1, anti-PD-L1, or anti-cytotoxic T-lymphocyte-associated protein (CTLA-4) antibody must have a washout of at least 4 weeks from the last dose and evidence of disease progression per investigator assessment before Cycle 1 Day 1 (C1D1) with the exception of the neoadjuvant cohorts
- •Participants who have previously received an immunotherapy prior to C1D1 must have any immune-related toxicities resolved to ≤Grade 1 or baseline (prior to the immunotherapy) to be eligible, with the exception of participants on well controlled physiologic endocrine replacement
- •Part 3: Neoadjuvant cohorts: participants must have completely resectable disease
排除标准
- •Symptomatic central nervous system metastases and/or carcinomatous meningitis
- •Active autoimmune diseases, regardless of need for immunosuppressive treatment, with the exception of participants well controlled on physiologic endocrine replacement
- •Any uncontrolled bacterial, fungal, viral, or other infection
- •Significant cardiac disease
- •A marked clinically significant baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >480 ms) [CTCAE Grade 1]) using Fridericia's QT correction formula
- •Positive for human immunodeficiency virus (HIV) or has known active hepatitis B or C infection
- •Known hypersensitivity to any study treatment(s) used in the specific study part/cohort
- •Participants who have been previously treated with IL-2 or IL-2 variants (all participants)
- •Systemic immunosuppressive treatment with the exception for patients on corticosteroid taper (for example, for chronic obstructive pulmonary disease exacerbation).
- •Vaccination with live, attenuated vaccines within 4 weeks of C1D1
- •Treatment with any other anti-cancer systemic treatment (approved or investigational) or radiation therapy within 4 weeks of C1D1
- •Part 3: Other active malignancies within the last 2 years
- •Women who are breastfeeding or have a positive serum pregnancy test during screening
研究组 & 干预措施
Part 3 Monotherapy Dose Expansion: TransCon IL-2 β/γ followed by surgery
(Optional Arm): TransCon IL-2 β/γ using the RP2D followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination
干预措施: Surgery (Procedure)
Part 3 Combination Dose Expansion:TransCon IL-2 β/γ with TransCon TLR7/8 Agonist followed by surgery
TransCon IL-2 β/γ with TransCon TLR7/8 Agonist using the RP2D followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination
干预措施: Surgery (Procedure)
Part 2 Combination Dose Escalation: TransCon IL-2 β/γ with Pembrolizumab
TransCon IL-2 β/γ with Pembrolizumab in escalating doses to evaluate safety/tolerability and determine the MTD and RP2D
干预措施: Pembrolizumab (Drug)
Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with Pembrolizumab followed by surgery
TransCon IL-2 β/γ using the RP2D with Pembrolizumab followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination
干预措施: Pembrolizumab (Drug)
Part 3 Combination Dose Expansion:TransCon IL-2 β/γ + Pembrolizumab + SOC Chemo followed by surgery
TransCon IL-2 β/γ using the RP2D with Pembrolizumab and SOC Chemotherapy followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination
干预措施: Surgery (Procedure)
Part 3 Combination Dose Expansion: TransCon IL-2 β/γ + trastuzumab emtansine (T-DM1)
TransCon IL-2 β/γ + trastuzumab emtansine (T-DM1)
干预措施: Trastuzumab emtansine (T-DM1) (Drug)
Part 4 Combination Dose Optimization
TransCon IL-2 β/γ + Pembrolizumab TransCon IL-2 β/γ using the RP2D in titrating doses and/or different dose frequencies with Pembrolizumab
干预措施: TransCon IL-2 β/γ (Drug)
Part 3 Combination Dose Expansion:TransCon IL-2 β/γ + Pembrolizumab + SOC Chemo followed by surgery
TransCon IL-2 β/γ using the RP2D with Pembrolizumab and SOC Chemotherapy followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination
干预措施: Pembrolizumab (Drug)
Part 3 Combination Dose Expansion
TransCon IL-2 β/γ + Pembrolizumab TransCon IL-2 β/γ using the RP2D with Pembrolizumab
干预措施: TransCon IL-2 β/γ (Drug)
Part 3 Combination Dose Expansion: TransCon IL-2 β/γ monotherapy
TransCon IL-2 β/γ monotherapy
干预措施: TransCon IL-2 β/γ (Drug)
Part 3 Combination Dose Expansion: TransCon IL-2 β/γ + trastuzumab
TransCon IL-2 β/γ + trastuzumab
干预措施: TransCon IL-2 β/γ (Drug)
Part 1 Monotherapy Dose Escalation: TransCon IL-2 β/γ
TransCon IL-2 β/γ in escalating doses to evaluate safety/tolerability and to determine the MTD and RP2D
干预措施: TransCon IL-2 β/γ (Drug)
Part 2 Combination Dose Escalation: TransCon IL-2 β/γ with Pembrolizumab
TransCon IL-2 β/γ with Pembrolizumab in escalating doses to evaluate safety/tolerability and determine the MTD and RP2D
干预措施: TransCon IL-2 β/γ (Drug)
Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with SOC Chemo
TransCon IL-2 β/γ using the RP2D with SOC Chemotherapy to evaluate safety/tolerability and anti-tumor activity of the combination
干预措施: TransCon IL-2 β/γ (Drug)
Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with SOC Chemo
TransCon IL-2 β/γ using the RP2D with SOC Chemotherapy to evaluate safety/tolerability and anti-tumor activity of the combination
干预措施: Chemotherapy drug (Drug)
Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with TransCon TLR7/8 Agonist
TransCon IL-2 β/γ with TransCon TLR7/8 Agonist using the RP2D to evaluate safety/tolerability and anti-tumor activity of the combination
干预措施: TransCon IL-2 β/γ (Drug)
Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with TransCon TLR7/8 Agonist
TransCon IL-2 β/γ with TransCon TLR7/8 Agonist using the RP2D to evaluate safety/tolerability and anti-tumor activity of the combination
干预措施: TransCon TLR7/8 Agonist (Drug)
Part 3 Monotherapy Dose Expansion: TransCon IL-2 β/γ followed by surgery
(Optional Arm): TransCon IL-2 β/γ using the RP2D followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination
干预措施: TransCon IL-2 β/γ (Drug)
Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with Pembrolizumab followed by surgery
TransCon IL-2 β/γ using the RP2D with Pembrolizumab followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination
干预措施: TransCon IL-2 β/γ (Drug)
Part 3 Combination Dose Expansion: TransCon IL-2 β/γ with Pembrolizumab followed by surgery
TransCon IL-2 β/γ using the RP2D with Pembrolizumab followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination
干预措施: Surgery (Procedure)
Part 3 Combination Dose Expansion:TransCon IL-2 β/γ with TransCon TLR7/8 Agonist followed by surgery
TransCon IL-2 β/γ with TransCon TLR7/8 Agonist using the RP2D followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination
干预措施: TransCon IL-2 β/γ (Drug)
Part 3 Combination Dose Expansion:TransCon IL-2 β/γ with TransCon TLR7/8 Agonist followed by surgery
TransCon IL-2 β/γ with TransCon TLR7/8 Agonist using the RP2D followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination
干预措施: TransCon TLR7/8 Agonist (Drug)
Part 3 Combination Dose Expansion:TransCon IL-2 β/γ + Pembrolizumab + SOC Chemo followed by surgery
TransCon IL-2 β/γ using the RP2D with Pembrolizumab and SOC Chemotherapy followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination
干预措施: TransCon IL-2 β/γ (Drug)
Part 3 Combination Dose Expansion:TransCon IL-2 β/γ + Pembrolizumab + SOC Chemo followed by surgery
TransCon IL-2 β/γ using the RP2D with Pembrolizumab and SOC Chemotherapy followed by surgery to evaluate safety/tolerability and anti-tumor activity of the combination
干预措施: Chemotherapy drug (Drug)
Part 3 Combination Dose Expansion: TransCon IL-2 β/γ + trastuzumab emtansine (T-DM1)
TransCon IL-2 β/γ + trastuzumab emtansine (T-DM1)
干预措施: TransCon IL-2 β/γ (Drug)
Part 3 Combination Dose Expansion
TransCon IL-2 β/γ + Pembrolizumab TransCon IL-2 β/γ using the RP2D with Pembrolizumab
干预措施: Pembrolizumab (Drug)
Part 3 Combination Dose Expansion: TransCon IL-2 β/γ + trastuzumab
TransCon IL-2 β/γ + trastuzumab
干预措施: Trastuzumab (Drug)
Part 4 Combination Dose Optimization
TransCon IL-2 β/γ + Pembrolizumab TransCon IL-2 β/γ using the RP2D in titrating doses and/or different dose frequencies with Pembrolizumab
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Safety and Tolerability
时间窗: Through study completion, expected average of 2 years
Treatment emergent and treatment related adverse events (assessed by NCI CTCAE v5.0), serious adverse events (SAEs), adverse events leading to treatment discontinuation, deaths.
Maximum Tolerated Dose (MTD)
时间窗: Each cycle is 21 days
Determine the maximum tolerated dose by assessing the Incidence of Dose Limiting Toxicities (DLTs), treatment emergent and treatment related adverse events (assessed by NCI CTCAE v5.0), serious adverse events (SAEs), adverse events leading to treatment discontinuation and deaths.
Recommended Phase 2 Dose (RP2D)
时间窗: 12 months
To determine a recommended phase 2 dose of TransCon IL-2 β/γ and combination regimen for further development by evaluating number of patients with treatment-related adverse events as assessed by CTCAE.
次要结局
- Overall Response Rate(Average of 2 years)
- Pathologic Complete Response(15 weeks)
- Major Pathologic Response(15 weeks)
- Duration of Response(Average of 2 years)
- Time to Response(Expected up to 1 year from first dose)
- Progression Free Survival (PFS)(Average of 2 years)
- Event free survival (EFS) by RECIST 1.1(2 years)
- Overall Survival (OS)(Average of 2 years)
- PK Characterization (Cmax)(Average of 2 years)
- PK Characterization (Tmax)(Average of 2 years)
- PK Characterization (AUClast)(Average of 2 years)
- PK Characterization (AUC0-t)(Average of 2 years)
- PK Characterization (t1/2)(Average of 2 years)