2023-507536-21-00招募中2 期
A Phase 1/2 Open Label, Dose Escalation and Expansion Study of MDNA11, IL-2 Superkine, Administered Alone or in Combination with an Immune Checkpoint Inhibitor in Patients with Advanced Solid Tumors
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 50
- 试验地点
- 13
- 主要终点
- Dose Escalation/Evaluation (Monotherapy and Combination Therapy): Safety and tolerability will be evaluated with respect to incidence and severity of AEs and SAEs, clinically significant abnormal laboratory parameters, vital signs, and ECG parameters per current CTCAE and incidence of dose limiting toxicities (DLTs).
研究概览
简要总结
The aim of this study is to evaluate safety, tolerability, pharmacokinetic properties, pharmacodynamic effects, and preliminary antitumor activity of MDNA11 [both as a monotherapy and in combination with checkpoint inhibitor (pembrolizumab)] in patients with selected advanced solid tumors. Results from this study will be used to determine the recommended dose for expansion (RDE) and dosing schedule and/or maximum tolerable dose (MTD) for MDNA11 and assess early signals of clinical activity in the single agent setting as well as in combination with pembrolizumab.
Primary Objectives (Dose Escalation/Evaluation (Monotherapy and Combination Therapy): ● To evaluate the safety and tolerability of MDNA11 administered in patients with advanced solid tumors (alone or in combination with pembrolizumab) ● To identify the RDE and/or MTD of MDNA11 (alone or in combination with pembrolizumab).
Primary Objectives (Dose Expansion (Monotherapy and Combination Therapy): ● To further evaluate the safety and tolerability of MDNA11 (alone or in combination with pembrolizumab) ● To assess the anti-tumor activity of MDNA11 (alone or in combination with pembrolizumab)
研究设计
- 分配方式
- Not Applicable
- 主要目的
- Phase 1/2, global multi-center, open-label, dose-escalation and expansion study
- 盲法
- None
入排标准
- 年龄范围
- 18 years 至 65+ years（18-64 Years, 65+ Years）
- 接受健康志愿者
- 是
入选标准
- •Aged at least 18 years (inclusive at the time of informed consent).
- •Women of childbearing potential (WOCBP) must have a negative pregnancy test at screening and within 72 hours before the first dose of study drug(s). Women must not be breastfeeding. Note: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
- •Agree to use highly effective contraception methods. WOCBP must agree to use birth control (defined as those, alone or in combination, that result in a low failure rate [i.e., < 1% per year] when used consistently and correctly, such as oral contraceptives, surgical sterilization, an intrauterine device, and/or 2-barrier methods [e.g., condom and cervical barrier such as a diaphragm]). Protections against pregnancy must be continued for at least 6 months after the last dose of study drug. This criterion may be waived for males who have had a vasectomy > 6 months before signing the ICF. Males must agree to refrain from sperm donation during the treatment period and for at least 6 months after the last dose of study drug(s). N.B. WOCBP are defined as those who are not surgically sterile or post-menopausal. Females will be considered postmenopausal if they have been amenorrheic for 12 months without an alternative medical cause. Females < 50 years old who meet the criteria for post-menopausal status without previous surgical sterilization should be considered for further investigation with luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels to confirm serological post-menopausal status.
- •Criteria for Patient known to be Human Immunodeficiency Virus (HIV) Positive: HIV infected participants must be on anti-retroviral therapy (ART) and have a well-controlled HIV infection/disease defined as: • Participants on ART must have a CD4+ T-cell count >350 cells/mm3 at time of screening; • Participants on ART must have achieved and maintained virologic suppression as evidenced by HIV RNA below the limit of detection at screening and for at least 12 weeks prior to screening; • Participants must be on an approved and stable ART regimen, without changes in drug(s) or dose modification, for at least 8 weeks prior to start of treatment. • HIV-infected participants with a history of Kaposi sarcoma and/or Multicentric Castleman Disease are not eligible.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or
- •Must be able and willing to provide written informed consent prior to start of any study procedures and assessments and must be willing to comply with all study procedures.
- •Histologically or cytologically confirmed locally advanced and/or metastatic solid tumor with disease that has progressed after standard therapy, or for which standard therapy has proven to be ineffective, intolerable, is refused by the patient or is considered inappropriate by the Investigator, or if no further standard therapy exists. See Section 4.1 for permitted tumor types in each part of the study.
- •Agree to collection of medical history data including all available relevant peripheral blood and tumor biomarker, and/or relevant blood viral markers [e.g., serum LDH, serum tumor markers (e.g., CA 125, CA 15-3, CA 19-9, CEA), PD-L1 expression level and status, MSI, MMR, TMB, BRAF mutation, hormonal receptor, HER2 status, if available].
- •Tissue requirement. See Section 4.1 for tissue requirement in each part of the study.
- •Demonstrated adequate organ function, as defined below, within 14 days prior to start of treatment: a. Absolute neutrophil count (ANC): Monotherapy cohorts: ≥ 1000/μL (after at least 7 days without growth factor support or transfusion); Combination cohorts: ≥ 1500/μL (after at least 7 days without growth factor support or transfusion) b. Platelet count ≥ 90x 103 /μL c. Absolute lymphocyte count ≥ 1000/μL d. Hemoglobin ≥ 9.0 g/dL; criteria must be met without packed red blood cell (pRBC) transfusion. Patients can be on a stable dose of erythropoiesis-stimulating agent. e. Aspartate aminotransferase (AST) ≤ 3 × ULN (≤ 5x ULN for patients with liver metastases) f. Alanine aminotransferase (ALT) ≤ 3 × ULN (≤ 5x ULN for patients with liver metastases) g. Total bilirubin ≤ 1.5 ×ULN OR direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 × ULN h. Lactate Dehydrogenase (LDH) ≤ 3 ULN i. C-Reactive Protein < 10 x ULN j. Albumin ≥ 35 g/L Note: Patients with albumin between 30-35 g/L may be considered for enrolment on a case-by-case discussion with the Sponsor if other favorable characteristics for immunotherapy response are met. k. International normalized ratio (INR) OR prothrombin time (PT) ≤ 1.5 × ULN unless patient is receiving anticoagulant therapy as long as PT OR INR is within the therapeutic range of intended use of the anticoagulant l. Estimated GFR (eGFR, estimated glomerular filtration rate) ≥30 mL/min/1.73 m2 by local lab or use of the CKD-EPI equation (https://www.kidney.org/professionals/kdoqi/gfr_calculator).
- •Measurable disease as per Response Evaluation Criteria in Solid Tumors, (RECIST 1.1) and documented by CT and/or MRI. Lesions situated in a previously irradiated area are considered measurable provided clear progression has been demonstrated in such lesions and can be measured accurately.
- •Anticipated life expectancy ≥ 12 weeks at the time of informed consent by investigator assessment.
排除标准
- •Last administration of prior antitumor therapy: • Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks (could consider shorter interval for kinase inhibitors or other short half-life drugs) prior to start of treatment. • Has received prior radiotherapy within 2 weeks prior to start of treatment or has had a history of radiation pneumonitis. A 1-week washout is required for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease. • Has received radiation therapy to the lung that is > 30Gy within 6 months prior to start of treatment. • Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to start of treatment. • Concomitant participation in an observational study must be discussed on a case-by-case basis with the MM for approval. Note: Patients who have entered the follow-up phase of an investigational study may participate provided it has been 4 weeks after the last dose/use of the previous investigational agent/device.
- •Prior Interleukin-2 (IL-2) or Interleukin-15 (IL-15) based cytokine therapy without Sponsor agreement.
- •Initiation of warfarin or therapeutic dose of anti-coagulation therapies within 21 days prior to start of treatment.
- •Has known active CNS metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging at baseline, clinically stable and without requirement of steroid treatment for at least 14 days prior to start of treatment, subject to discussion with MM.
- •Has had an allogeneic tissue/solid organ transplant.
- •Inability to comply with study protocol and follow up procedures as judged by the Investigator.
- •Presence of CTCAE toxicity > Grade 1 related to prior systemic anti-cancer therapy, radiotherapy and/or surgery. Patients with Grade > 1 toxicity related to prior systemic anti-cancer therapy, radiotherapy and/or surgery may be allowed on a case-by-case basis in discussion with study MM, if it is determined unlikely to put the patient at an increased risk of treatment-related toxicity and/or impact the integrity of study outcome. • If the patient had major surgery, the patient must have recovered adequately from the procedure and/or any complications from the surgery prior to start of treatment. • Patients must have recovered from all radiation-related toxicities and not requiring corticosteroids.
- •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 irAE.
- •Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. • Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of bladder, that have undergone potentially curative therapy are not excluded. • Patients with known additional malignancy within the past 3 years may be allowed on a case-by-case basis in discussion with study MM, if it is determined unlikely to put the patient at an increased risk of treatment-related toxicity and/or impact the integrity of study outcome.
- •Condition requiring systemic treatment with either corticosteroids > 10 mg daily prednisone equivalent or any other form of immunosuppressive therapy within 7 days prior to start of treatment. a. Known history of severe asthma and/or chronic obstructive airways disease exacerbation requiring systemic steroid therapy in the year prior to start of treatment. b. Known history of severe eczema and other skin/pruritic conditions requiring systemic steroid therapy in the year prior to start of treatment. c. Patients requiring systemic treatment with either corticosteroids > 10 mg daily prednisone equivalent or any other form of immunosuppressive therapy within 7 days prior to start of treatment may be approved on a case-by-case basis in discussion with study MM, if it is determined unlikely to put the patient at an increased risk of treatment-related toxicity and/or impact the integrity of study outcome, e.g., for management of allergic reaction to CT contrast.
- •Clinically significant active, known, or suspected autoimmune disease (including but not limited to ulcerative colitis, Crohn's disease, non-infectious immune-driven myocarditis), or diseases that can be exacerbated with immunotherapy. • Vitiligo, type I diabetes mellitus, residual hypothyroidism or thyroiditis due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur or worsen in the absence of an external trigger or with use of immunotherapy are allowed.
- •Severe pulmonary, cardiac, or other systemic disease, specifically: a. New York Heart Association ≥ class 2 congestive heart failure within 6 months prior to start of treatment (may be considered, if unless currently asymptomatic and well controlled with medication upon review with MM); b. Uncontrolled or clinically significant cardiovascular disease, i.e., new, uncontrolled, or unstable significant arrhythmia (e.g., sustained ventricular tachycardia), thromboembolic events, treatment resistant hemodynamic instability, severe treatment-resistant uncontrolled hypertension, significant symptomatic restrictive cardiomyopathy and/or constrictive pericarditis. Patients with paroxysmal, persistent or permanent atrial arrythmias are permitted if the rhythm and/or rate (both as appropriate) are adequately controlled; c. Coronary/peripheral artery bypass grafting, myocardial infarction, stroke, unstable angina, or symptomatic pulmonary embolism (PE) within 4 months prior to start of treatment. Clinically stable patients with deep vein thrombosis (DVT) or PE on appropriate therapeutic anticoagulation may be considered on a case-by-case basis; d. Documented LVEF < 40% determined by any appropriate cardiac imaging modality, e.g., echo, CMR, nuclear imaging (SPECT, MUGA). Patients with suboptimal imaging may have LVEF quantified by another modality; e. QT interval corrected for heart rate using Fridericia formula (QTcF) prolongation > 470 msec at screening, except for right or left bundle branch block on discussion with the MM. Patients with congenital long QT to be discussed with the MM; f. Uncontrolled or clinically significant pulmonary disease (such as ≥ Grade 2 dyspnea according to CTCAE 5.0 i.e., shortness of breath with minimal exertion; limiting instrumental ADL or hypoxia [PaO2 < 60 mmHg (8 KPa)] at rest and/or SpO2 or SaO2 < 90% or requirement for supplemental oxygen); N.B. Patients with known or suspected chronic respiratory disease (e.g., asthma, COPD, pulmonary fibrosis), Grade 1 dyspnea (i.e., shortness of breath with moderate exertion), moderate or greater pleural effusion(s), and/or abnormal peripheral/arterial oxygen saturation (SpO2 or SaO2 <95%) must be discussed on a case-by-case basis with the Sponsor to determine eligibility; g. Patients with adrenal insufficiency or autonomic failure may be discussed on an individual case-by-case basis with the sponsor to determine eligibility taking into account appropriate testing [e.g., early morning cortisol ¬± dynamic testing with cosyntropin (ACTH) stimulation] and the risk of developing clinically significant hypotension on study.
- •Has received any live attenuated vaccine within 21 days of first dose of study drug(s).
- •Has had or is scheduled to have major surgery < 21 days prior to start of treatment. Note: patients undergoing surgery judged of low risk within the 21-day window may be permitted upon discussion with the MM.
- •Body Mass Index (BMI) ≤
- •Females who are pregnant or lactating or planning to become pregnant during the study.
- •Active infection requiring systemic therapy.
- •Any medical, surgical, or psychiatric condition that is judged to significantly interfere with the patient’s ability to safely adhere to the protocol and study requirements or expose the patient to additional risk.
- •History of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease.
- •Any other underlying medical conditions that, in the Investigator’s opinion, will make the administration of study drug(s) unsafe or obscure the interpretation of toxicity determination or adverse events.
- •Known hepatitis B or C virus infection.
- •Known hypersensitivity to any component of study drug(s).
结局指标
主要结局
Dose Escalation/Evaluation (Monotherapy and Combination Therapy): Safety and tolerability will be evaluated with respect to incidence and severity of AEs and SAEs, clinically significant abnormal laboratory parameters, vital signs, and ECG parameters per current CTCAE and incidence of dose limiting toxicities (DLTs).
Dose Escalation/Evaluation (Monotherapy and Combination Therapy): Safety and tolerability will be evaluated with respect to incidence and severity of AEs and SAEs, clinically significant abnormal laboratory parameters, vital signs, and ECG parameters per current CTCAE and incidence of dose limiting toxicities (DLTs).
Dose Escalation/Evaluation (Monotherapy and Combination Therapy): RDE will be evaluated using safety, tolerability, immunological response, PK/PD results and preliminary anti-tumor efficacy data (see secondary objectives).
Dose Escalation/Evaluation (Monotherapy and Combination Therapy): RDE will be evaluated using safety, tolerability, immunological response, PK/PD results and preliminary anti-tumor efficacy data (see secondary objectives).
Dose Expansion (Monotherapy and Combination Therapy): Safety will be evaluated based on incidence, nature and severity of AEs and SAEs, abnormal laboratory parameters, vital signs, and ECG results per CTCAE (currently, v5.0) and incidence of DLTs.
Dose Expansion (Monotherapy and Combination Therapy): Safety will be evaluated based on incidence, nature and severity of AEs and SAEs, abnormal laboratory parameters, vital signs, and ECG results per CTCAE (currently, v5.0) and incidence of DLTs.
Dose Expansion (Monotherapy and Combination Therapy): Assessment by iRECIST and RECIST 1.1: o ORR o CBR o DCR o DOR o TTR o PFS o BOR.
Dose Expansion (Monotherapy and Combination Therapy): Assessment by iRECIST and RECIST 1.1: o ORR o CBR o DCR o DOR o TTR o PFS o BOR.
Dose Expansion (Monotherapy and Combination Therapy): OS.
Dose Expansion (Monotherapy and Combination Therapy): OS.
次要结局
- Dose Escalation/Evaluation (Monotherapy and Combination Therapy): Assessment by iRECIST and RECIST 1.1: o Objective Response Rate (ORR) o Clinical Benefit Rate (CBR) o Disease Control Rate (DCR) o Duration of Response (DOR) o Time to Response (TTR) o Progression Free Survival (PFS) o Best Overall Response (BOR).
- Dose Escalation/Evaluation (Monotherapy and Combination Therapy): Overall Survival (OS).
- Dose Escalation/Evaluation (Monotherapy and Combination Therapy): PK profile may include but are not limited to maximum concentration (Cmax), time to reach Cmax (Tmax), area under the curve (AUC), clearance (CL), half-life (t1/2), etc.
- Dose Escalation/Evaluation (Monotherapy and Combination Therapy): Incidence and persistence of anti-drug antibodies (ADA) to MDNA11.
- Dose Escalation/Evaluation (Monotherapy and Combination Therapy): Measurement of translational parameters.
- Dose Escalation/Evaluation (Monotherapy and Combination Therapy): Measurement of cytokines.
- Dose Expansion (Monotherapy and Combination Therapy): Measurement of translational parameters.
- Dose Expansion (Monotherapy and Combination Therapy): Measurement of biomarkers, including but not limited to immune cell lineages and markers of functional status such as determined by quantitative multiparameter immunofluorescence analysis.
- Dose Expansion (Monotherapy and Combination Therapy): PK profile may include but are not limited to Cmax, Tmax, AUC, CL, t1/2, etc.
- Dose Expansion (Monotherapy and Combination Therapy): Incidence and persistence of ADA to MDNA11.
- Exploratory (applicable to all study parts except where indicated): Measurement of translational parameters.
- Exploratory (applicable to all study parts except where indicated): Effect of baseline prognostic factors [e.g., lymphocyte count, lymphocyte to neutrophil ratio (LNR), C-Reactive Protein (CRP) levels, Lactate Dehydrogenase (LDH), etc.] on efficacy endpoints.
- Exploratory (applicable to all study parts except where indicated): Exposure-pharmacodynamic relationship based on MDNA11 serum PK parameters and select markers in the peripheral blood and/or tumor biopsy samples.
研究者
Nina Merchant
Scientific
Medicenna Therapeutics Inc.
研究点 (13)
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