A First-in-human, Open-label Dose Escalation Followed by Dose Expansion Phase I/IIa Trial to Evaluate the Safety, Preliminary Efficacy and Pharmacokinetics of Intratumoral CyPep-1 Monotherapy and in Combination With Pembrolizumab in Patients With Advanced Solid Cancers.
概览
- 阶段
- 1 期
- 干预措施
- CyPep-1
- 疾病 / 适应症
- Advanced Solid Tumor Malignancy
- 发起方
- Cytovation AS
- 入组人数
- 60
- 试验地点
- 8
- 主要终点
- Type and Number of Adverse Events (AEs)
- 状态
- 已完成
- 最后更新
- 3个月前
概览
简要总结
This Phase I/IIa trial is designed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of CyPep-1 when administered directly into malignant tumors in monotherapy and in combination with anti programmed cell death protein 1(anti-PD-1) antibody pembrolizumab. Additionally, the trial will monitor anti-tumor effects on both injected lesions and distant non-injected deposits.
详细描述
Treatment with immune modulating agents may result in long lasting anti-tumor responses in patients with cancer. However, only a subset of patients obtains durable remission. Treatment strategies that aim at recruiting tumor antagonizing cellular components of the immune system holds great promise. CyPep-1 is a chemically synthesized peptide with oncolytic properties. It selectively targets cancer cells based on their altered molecular composition, and removes the surrounding cell membrane. This releases tumor neoantigens to the microenvironment and potentially induces an anti-tumour immune response. Preclinical studies showing that CyPep-1 can synergize with anti-PD-1 antibody treatment in terms of decreased tumor volumes and prolonged survival highlight the possible clinical utility of CyPep-1 in the combination setting with Immune checkpoint inhibitors (ICIs). This is a phase I/IIa, open label trial, with a dose escalation phase to evaluate the safety and tolerability of CyPep-1 as monotherapy and in combination with pembrolizumab, to identify the recommended phase 2 dose, followed by a dose expansion phase in subjects with advanced solid tumors. The trial consists of two phases and multiple arms. Secondary objectives are preliminary anti-tumor efficacy and to assess the pharmacokinetics (PK) of CyPep-1 as monotherapy and in combination with pembrolizumab. As part of the exploratory analysis, it is planned to determine local and systemic immunological effects after CyPep-1 administration, alone and in combination with pembrolizumab.
研究者
入排标准
入选标准
- •For Phase I and Phase IIa Arms A and C:
- •Histologically or cytologically confirmed locally advanced (unresectable) or metastatic tumors (solid tumor or lymphoma) with an accessible tumor lesion for intratumoral injection of CyPep-1 malignancy (including lymphomas) that is either:
- •Refractory to standard-of-care treatment
- •Have a disease for which there is no standard therapy considered appropriate. Metastatic deposits (including cutaneous/subcutaneous lesions and metastatic deposits in lymph nodes) of tumors for which IT injections may be performed are eligible. Pure cutaneous infiltrations (e.g., breast cancer cutaneous carcinomatosis) are ineligible.
- •1 to 3 non-ulcerated transcutaneously accessible lesion(s) for injection and measurable as defined by Immune Response Evaluation Criteria in Solid Tumors (iRECIST). All other tumor lesion(s) may be selected for efficacy follow-up but will not be subjected to treatment with CyPep-
- •Presence of tumor lesion(s) (that have not been previously irradiated) suitable for biopsy at screening and at Week
- •Confirmation of the presence of at least 1 liver metastasis by imaging.
- •Subjects must have measurable disease which is equal to one or more metastatic liver lesions that can be accurately and serially measured that are greater than 1 cm dimension and for which the longest diameter is greater or equal to 1 cm as measured by computed tomography (CT) scan or magnetic resonance imaging (MRI). The metastatic liver lesion must not be in an area that received prior localized therapies.
- •Metastatic liver lesion for injection with \>50% radiological visible necrosis must be avoided and the lesion must be located where any tumor swelling will not lead to gall bladder tract obstruction or lead to bleeding risk.
- •Histologically or cytologically confirmed diagnosis of advanced (unresectable Stage III) or metastatic (Stage IV: M1a) melanoma considered incurable by Standard of Care. For metastatic melanoma, only distal cutaneous, subcutaneous, or lymph node metastases are allowed.
排除标准
- •For Phase I and Phase IIa Arms A, C, and D: subjects who meet any of the following criteria at screening will be excluded from trial entry:
- •There is no limit to the number of prior treatment regimens, but prior treatment(s) should not include compounds delivered by IT injection to the to-be injected lesion(s), including investigational agents. Subjects with prior IT therapies are allowed in Arm D.
- •Participation in another clinical trial within 4 weeks prior to first dose of CyPep-
- •Anti-cancer therapy within 4 weeks prior to the first dose of CyPep-1 (within 2 weeks for palliative radiotherapy, within 1 week for endocrine therapy).
- •Major surgical procedure within 14 days prior to the first dose of CyPep-
- •Live vaccine within 30 days prior to first dose of CyPep-
- •Expected to require any other form of systemic or localized antineoplastic therapy while in this trial. Localized palliative radiotherapy for pain relief is allowed on tumor lesions that are not selected for evaluation of treatment response.
- •Clinical evidence of an active second malignancy that is progressing or requires active treatment, except for curatively treated early stage (carcinoma in situ or stage 1) carcinomas or non-melanoma skin cancer.
- •Active autoimmune disease requiring immunosuppressive therapy.
- •Any condition requiring continuous systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive agents within 2 weeks prior to first dose of CyPep-
研究组 & 干预措施
Phase I Cohort 1
Dose escalation at 0.5 mg (milligrams)/mL, n=3
干预措施: CyPep-1
Phase I Cohort 2
Dose escalation at 2 mg/mL, n=5
干预措施: CyPep-1
Phase I Cohort 3
Dose escalation at 5 mg/mL, n=6
干预措施: CyPep-1
Phase IIa: Arm A
CyPep-1 5.0mg/mL Monotherapy
干预措施: CyPep-1
Phase IIa Arm B
The safety and tolerability of CyPep-1 in combination with pembrolizumab was evaluated in a cohort of 15 patients in total, using a staggered approach. Initially, 3 patients received CyPep-1 at Recommended Phase 2 Dose (RP2D) in combination with pembrolizumab once every 6 weeks (Q6W)
干预措施: CyPep-1
Phase IIa Arm B
The safety and tolerability of CyPep-1 in combination with pembrolizumab was evaluated in a cohort of 15 patients in total, using a staggered approach. Initially, 3 patients received CyPep-1 at Recommended Phase 2 Dose (RP2D) in combination with pembrolizumab once every 6 weeks (Q6W)
干预措施: Pembrolizumab 25 MG/ML [KEYTRUDA®]
Phase IIa Arm C Cohort 4
The safety and tolerability of at least 2 dose levels of CyPep-1, the RP2D and the dose immediately below that, were evaluated when CyPep-1 was administered IT using ultrasound guidance to one metastatic lesion in the liver (Cohort 4: 2 mg/mL, n=6)
干预措施: CyPep-1
Phase IIa Arm C Cohort 5
The safety and tolerability of at least 2 dose levels of CyPep-1, the RP2D and the dose immediately below that, were evaluated when CyPep-1 was administered intratumoral (IT) using ultrasound guidance to one metastatic lesion in the liver. The RP2D (Cohort 5: 5 mg/mL, n=6).
干预措施: CyPep-1
Phase IIa Arm D
The safety and tolerability of CyPep-1 at RP2D was planned to be further evaluated with focus on assessing efficacy signals of CyPep-1 monotherapy in 30 patients with cutaneous melanoma.
干预措施: CyPep-1
结局指标
主要结局
Type and Number of Adverse Events (AEs)
时间窗: From Informed Consent Form (ICF) signing until Follow Up (FU) or until End of Treatment (EoT) visit. After FU visit, only ongoing AEs or Serious Adverse Events (SAEs) related to CyPep-1 were collected. Duration: up to a maximum of 28 months.
According to National Cancer Institute (NCI) - Common Terminology Criteria for Adverse Events (CTCAE) criteria v5.0, and additional safety parameters.
次要结局
- Objective Response Rate (ORR)(up to approximately 28 months)