临床试验/2024-513312-95-00

2024-513312-95-00招募中2 期

An Open-Label, Dose Escalation and Dose Expansion Trial Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of Orally Administered CA-4948 in Patients With Relapsed or Refractory Primary Central Nervous System Lymphoma

Curis Inc.13 个研究点分布在 5 个国家目标入组 69 人开始时间: 2024年7月1日最近更新: 2025年2月27日

试验速览

阶段: 2 期
状态: 招募中
发起方: Curis Inc.
入组人数: 69
试验地点: 13
主要终点: Part A1 and Part A2: •Incidence of DLTs •Incidence of adverse events (AEs) •Clinically significant changes in vital signs and laboratory parameters • Clinically significant changes from baseline in electrocardiograms (ECGs)

研究概览研究设计入排标准结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

Part A1+ A2 (Dose Escalation Phase) (Enrollment is Closed) To determine the safety and tolerability, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended Phase 2 dose (RP2D) of oral emavusertib as monotherapy and in combination with ibrutinib
Part B (PCNSL Expansion Phase) (Currently Enrolling) To assess the anti-cancer activity of emavusertib in combination with ibrutinib in patients with R/R PCNSL
Part C – PCNSL Contribution of Components (to Inform Contribution of Effect in a BTKi-Naïve Population; Currently Enrolling) To assess the anti-cancer activity of emavusertib as monotherapy, ibrutinib as monotherapy, and emavusertib in combination with ibrutinib in patients with R/R PCNSL

研究设计

研究类型: Interventional
分配方式: Randomized
主要目的: Part C
盲法: None

入排标准

年龄范围: 18 years 至 65+ years（65+ Years, 18-64 Years）
接受健康志愿者: 是

入选标准

•Part A2+B+C.
•Males and females >= 18 years of age
•CPK < 2.5× ULN
•Part A2+B+C.
•Life expectancy of ≥ 3 months
•Must have recovered from toxicity after any prior autologous stem cell transplants or CAR-T cell therapy, and must have disease progression prior to initiation of study treatment
•For patients on a cholesterol-lowering agent that has been associated with CPK elevations, such as statins or fibrates, the agent should be discontinued or reduced to the lowest dose possible.
•ECOG Performance Status of ≤ 1
•Diagnosis of histopathologically confirmed B-cell NHL, as per the WHO 2016 classification (Swerdlow et al. 2016). Eligible NHL subtypes include follicular lymphoma, MZL, MCL, DLBCL (including extranodal lymphomas of leg-, testicular-, or NOS [not otherwise specified]-type), and primary or secondary central nervous system (CNS) lymphoma. NOTE: Once a dose has been shown not to exceed the MTD in NHL patients, other hematological malignancies can be considered for enrollment in specific malignancies that have been approved by the CSC and Sponsor. Patients with MCL or MZL should meet clinical criteria for requiring treatment of their disease.
•Relapsed or refractory disease (as defined below) for which patients are ineligible for or have exhausted standard therapeutic options that would be considered standard of care. a. Relapsed NHL is per Revised Response Criteria for Malignant Lymphoma and as documented by excisional/incisional biopsy (preferred) or FNA or CNB as PD after a CR, PR, or stable disease. NOTE: For confirmation of documented relapse during prior treatment, biopsy/FNA of the lymphoma at Screening is recommended but not mandatory. b. Refractory NHL is defined for all eligible NHL by PD (per Revised Response Criteria for Malignant Lymphoma) during prior treatment or failure to achieve an objective response on prior treatment. NOTE: Biopsy (preferred) or FNA at Screening is recommended but not mandatory.
•Measurable disease: Defined as CT scan showing at least 1 clearly demarcated lymph node(s) with a long axis > 1.5 cm and short axis > 1.0 cm or 1 clearly demarcated extranodal lesion(s) with a long axis > 1.0 cm and short axis > 1.0 cm. All lesions must have a maximum diameter of < 10 cm.
•Patients must have failed a total of 1 systemic line of prior anti-PCNSL therapy, which must have contained methotrexate.
•Acceptable marrow and organ function at Screening as described below: a.ANC ≥ 1,000/µL* b.Platelet count ≥ 50,000/µL without transfusion within 1 week prior to start of study treatment* c. SCr ≤ 1.5× ULN or a calculated creatinine clearance ≥ 30 mL/min according to Cockcroft Gault formula (using actual body weight) or by 24-hour urine collection d. AST or ALT ≤ 2× ULN e. Total bilirubin ≤ 1.5× ULN or ≤ 3 × ULN in patients with documented Gilbert’s syndrome *NOTE: For patients with bone marrow involvement of their disease, eligibility will be determined following discussion between Investigator and Sponsor Medical Monitor
•CPK Grade < 2
•Part A2 (10)+ Part B (13)+ Part C (13). Negative serum pregnancy test in WOCP
•Part A2 (09) + Part B (12) + Part C (12) . Ability to swallow and retain oral medications
•Part B+C. 07 Patients must be able to tolerate lumbar punctures or Ommaya taps.
•Any toxicity caused by prior anti-cancer therapies must have recovered to Grade ≤1 with the exception of neurotoxicity and post-transplant cytopenias following a discussion with the Sponsor Medical Monitor.
•Part A2 (11)+ Part B (14)+ Part C (14). WOCP and men who partner with a WOCP must agree to use highly effective contraceptive methods for the duration of the study and for 3 months after the last dose of study treatment.
•Willing and able to provide written informed consent and comply with the requirements of the trial
•Histopathologically confirmed diagnosis of PCNSL (medical record is acceptable). Cerebral biopsies are not required if imaging reveals typical images of PCNSL. a. Patients with parenchymal lesions must have unequivocal evidence of disease progression (e.g., presence of at least 1 measurable target lesion [≥ 10 mm and ≤ 40 mm in the longest diameter on brain MRI or head CT]) on imaging within 28 days prior to Cycle 1 Day
•In cases where the tumor size is smaller but still measurable and located at a critical CNS location, disabling the patient and/or causing symptoms, this patient may be eligible following a discussion with the Sponsor Medical Monitor. b. For patients limited to leptomeningeal involvement, CSF analysis (cytology and/or flow cytometry) with or without additional imaging (MRI) of the spine as clinically indicated is required to document abnormal cells within 28 days prior to Cycle 1 Day
•Patients on a cholesterol lowering statin must be on a stable dose with no changes within 3 weeks prior to study start
•Acceptable organ function at Screening within 28 days prior to Cycle 1 Day 1 as described below: a. ANC ≥ 1000/µL. b. Platelet count ≥ 75,000/µL without transfusion or ≥ 50,000/µL after prior CAR T-cell treatment. c. Estimated creatinine clearance of ≥ 35 mL/min (Appendix M). d. Hemoglobin ≥ 9.0 g/dL and without red blood cell (RBC) transfusion. e. International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (aPTT) ≤ 1.5× ULN. f. AST and ALT ≤ 2 × ULN. g. Total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN in patients with documented Gilbert syndrome.
•ECOG Performance Status of 0, 1, or
•Relapsed or refractory to a systemic frontline chemotherapy (e.g., high-dose methotrexate-based therapies) AND no more than a total of 3 lines of prior anti-PCNSL therapies (patients with 4 prior lines of therapy may be allowed after consultation with the Sponsor Medical Monitor) AND the following: a. For Cohort 1 as of protocol v11.0, must have direct progression on a BTKi (administered as monotherapy or in combination). b. For Cohort 2, must have direct progression on a BTKi (administered as monotherapy or in combination).
•Patients must be able to tolerate gadolinium-enhanced MRI or contrast-enhanced CT if MRI is not possible following a discussion with the Sponsor Medical Monitor.
•For patients on corticosteroids, a stable dose of ≤ 8 mg dexamethasone (or equivalent) per day is acceptable.
•Ability to understand and willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants.

排除标准

•Patients with active CNS involvement other than PCNSL at study entry are ineligible. Patients with prior CNS disease (leptomeningeal disease or brain metastasis) that has been adequately treated (eg, radiation or intravenous or intrathecal chemotherapy) are permitted, but must have completed such treatment and have no evidence of active CNS disease for at least 4 weeks prior to the first dose of study treatment. Intrathecal chemoprophylaxis to prevent the emergence or recurrence of lymphoma in the CNS is permitted on study during dose expansion only and may be administered per institutional guidelines.
•Prior history of hypersensitivity or anaphylaxis to emavusertib, ibrutinib, or any of their excipients.
•Prior history of Stevens Johnson syndrome or toxic epidermal necrolysis
•Major surgery, other than diagnostic surgery, < 28 days from the start of study treatment; minor surgery < 14 days from the start of study treatment NOTE: Insertion of a vascular access device is not considered minor surgery.
•Patient who is intolerant of contrast-enhanced MRI due to allergic reactions to contrast agents
•Major surgery < 28 days prior to Cycle 1 Day 1; minor surgery < 7 days prior to Cycle 1 Day
•Note: Insertion of a vascular access device is not considered surgery
•Viral Infections. a. Known to be HIV positive or have an acquired immunodeficiency syndrome (AIDS) related illness. If HIV is undetectable or maintained on treatment, enrollment may be allowed after discussion with the Sponsor Medical Monitor. b. HBV DNA positive or HCV infection < 6 months prior to Cycle 1 Day 1, unless viral load is undetectable, or HCV with cirrhosis. Note: Testing required only in patients with history of HCV < 6 months or history of HBV prior to Cycle 1 Day
•c. Active systemic infection, including HIV, cytomegalovirus infection, or SARS CoV-2 infection, or has had, within 28 days prior to Cycle 1 Day 1, an infection (other than nail trichophytosis) that requires hospitalization or an intravenous antibiotic.
•B-cell NHL of the following subtypes: a. Burkitt lymphoma b. Lymphoblastic lymphoma or leukemia c. Post-transplantation lymphoproliferative disorder d. Known primary mediastinal, ocular, or epidural DLBCL
•Patients with history of hemophagocytic lymphohistiocytosis (HLH)
•Uncontrolled or severe cardiovascular disease, including myocardial infarction, unstable angina, or atrial fibrillation within 6 months prior to the start of study treatment; New York Heart Association Class II or greater congestive heart failure; serious arrhythmias requiring medication for treatment; clinically significant pericardial disease; cardiac amyloidosis; or QT interval corrected (QTc) with Fridericia’s correction (QTcF) that is unmeasurable or ≥ 480 msec on Screening ECG. NOTE: For QTcF ≥ 480 msec on the Screening ECG, the ECG may be repeated twice at least 24 hours apart; the mean QTcF from the 3 Screening ECGs must be < 480 msec in order to meet eligibility for trial participation.
•Gastrointestinal disease or disorder that could interfere with the swallowing, oral absorption, or tolerance of study treatment. This includes uncontrolled diarrhea (> 1 watery stool/day), major abdominal surgery, significant bowel obstruction, and/or gastrointestinal diseases that could alter the assessment of PK or safety, including but not limited to irritable bowel syndrome, ulcerative colitis, Crohn’s disease, and hemorrhagic coloproctitis.
•Received prior investigational drugs (including treatment in clinical research, unapproved combination products, and new dosage forms) within 28 days or 5 half-lives, whichever is shorter, prior to Cycle 1 Day 1; allogeneic hematopoietic stem cell transplant (HSCT) within 60 days prior to Cycle 1 Day 1; or had clinically significant graft-versus-host disease (GVHD) requiring ongoing up titration of immunosuppressive medications prior to Screening (with the exception of a BTKi for Part B only). Note: The use of a stable or tapering dose of immunosuppressive therapy post-HSCT and/or topical steroids for ongoing skin GVHD is permitted with Sponsor Medical Monitor approval.
•History of other invasive malignancy, unless adequately treated with curative intent and with no known active disease present within 2 years prior to the start of study treatment, provided it is deemed to be at low risk for recurrence by the treating physician NOTE: These latter conditions include but are not limited to non-melanoma skin cancer, carcinoma in situ [including superficial bladder cancer and cervical intraepithelial neoplasia], and organ-confined prostate cancer.
•Concomitant use of drugs with a known risk of causing prolonged QTc and/or Torsades de Pointes or a history of risk factors for Torsades de Pointes (eg, familial long QT syndrome, heart failure, left ventricular hypertrophy). See crediblemeds.org for a list of drugs that may prolong QT by risk category.
•Known to be human immunodeficiency virus (HIV) positive or have an acquired immunodeficiency syndrome-related illness
•Part A2 (17) + Part B and C (21) . Pregnant or lactating
•Systemic fungal, bacterial, viral, or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
•Evidence of systemic lymphoma. This must be demonstrated by a positron emission tomography (PET) scan (or CT scan with contrast if applicable) of the chest, abdomen, and pelvis at Screening (testicular ultrasound may be considered to exclude a testicular lymphoma disseminated to the brain).
•Previous BTKi treatment (Part C only).
•Radiotherapy delivered to non-target lesions involving > 25% of bone marrow within 1 week prior to starting study treatment or delivered to target lesions that will be followed on the study NOTE: Prior sites of radiation will be recorded.
•Part A2 + Part B +C : - Part A2 (04) Any prior systemic anti-cancer treatment such as chemotherapy, immunomodulatory drug therapy, etc., received within 14 days prior to the start of study treatment (with the exception of ibrutinib for Parts A2 , which may be continued as part of this study without interruption). - Part B and C (10). Any prior systemic anti-cancer treatment such as chemotherapy, immunomodulatory drug therapy, etc., received within 21 days or 5 half-lives, whichever is shorter, prior to Cycle 1 Day 1 (with the exception of ibrutinib or other BTKi for Part B only, which may be continued until the day before Cycle 1 Day 1).
•Current or planned glucocorticoid therapy, with the following exceptions: a. Doses ≤ 10 mg/day prednisolone or equivalent is allowed, provided that the steroid dose has been stable or tapering for at least 14 days prior to the first dose of study treatment. b.Inhaled, intranasal, intra-articular, and topical steroids are permitted.
•Receiving the following medications within 7 days or 5 half-lives, whichever is shorter, prior to Cycle 1 Day 1: a. Medications which, in the opinion of the Investigator, have a high risk of causing prolonged QTc and/or Torsades de Pointes (Appendix L). b. Peg-filgrastim or equivalent. c. St John’s Wort.
•Use of any investigational agent within 21 days or 5 half-lives, whichever is shorter, prior to start of study treatment
•Presence of an acute or chronic toxicity resulting from prior anti-cancer therapy, with the exception of alopecia, that has not resolved to Grade ≤ 1, as determined by NCI CTCAE v4.03, within 7 days prior to the start of study treatment unless approved by the Medical Monitor
•Known allergy or hypersensitivity to any component of the formulation of emavusertib (or ibrutinib for entry into Parts A2) used in this study
•Hepatitis B virus (HBV) DNA positive or hepatitis C virus (HCV) infection < 6 months prior to start of study treatment unless viral load is undetectable, or HCV with cirrhosis (NOTE: testing required only in patients with history of HBV or history of HCV < 6 months prior to start of study treatment)
•Received external beam radiation therapy to the CNS within 28 days prior to Cycle 1 Day
•Patients with only intraocular PCNSL without brain lesion or CSF involvement, T-cell lymphoma, systemic presence of lymphoma, or non-CNS lymphoma metastatic to the CNS.
•Prior history of malignancies other than lymphoma (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast) or prior history of systemic lymphoma, unless the patient has been free of the disease for ≥ 3 years.
•Active malignancy other than PCNSL requiring systemic therapy
•History of Grade ≥ 3 rhabdomyolysis without complete recovery
•Requirement for urgent therapy due to uncontrolled tumor mass/edema effects.
•Any other severe, acute, or chronic medical, psychiatric, or social condition, or laboratory abnormality that may increase the risk of trial participation or study treatment administration, may interfere with the informed consent process and/or with compliance with the requirements of the trial, or may interfere with the interpretation of the trial results and, in the Investigator’s opinion, would make the patient inappropriate for entry into this trial.
•History of stroke or intracranial hemorrhage within 6 months prior to Cycle 1 Day
•Patients with post-biopsy hemorrhagic sequela defined as a small hyperdense lesion < 3 mm on T2 sequence will not be excluded.
•Patients who require anticoagulation with warfarin or equivalent vitamin K antagonists, including dual antiplatelet agents, within 5 half-lives of the anti-coagulant or 7 days, whichever is longer, prior to Cycle 1 Day
•Low molecular weight heparin is allowed. Patients who require the use of antiplatelet agents should be discussed with the Sponsor Medical Monitor (e.g., use of factor Xa inhibitors).
•Vaccinated with live-attenuated vaccines within 4 weeks prior to Cycle 1 Day 1
•In patients with a history of HBV, hepatitis B core antibody testing is required and if positive, then hepatitis B DNA testing will be performed and if positive the patient will be excluded.
•Concomitant illness that would preclude safe participation in the study, including: a. Uncontrolled or severe cardiovascular disease, including myocardial infarction or unstable angina within 6 months prior to Cycle 1 Day 1, New York Heart Association Class II or greater congestive heart failure or left ventricular ejection fraction ≤ 50% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan, serious arrhythmias uncontrolled on treatment, clinically significant pericardial disease, cardiac amyloidosis, or QTcF that is unmeasurable or > 450 msec on Screening ECG. Note: For QTcF > 450 msec on the Screening ECG, the ECG may be repeated twice ≥ 24 hours apart; the mean QTcF from the 3 Screening ECGs must be ≤ 450 msec to meet eligibility for study participation. Patients with bundle branch block and/or ventricular paced rhythms should be reviewed by the Sponsor Medical Monitor for potential inclusion. b. Gastrointestinal disease or disorder that could interfere with swallowing, oral absorption, or tolerance of study treatment. This includes major abdominal surgery and/or significant bowel resection and/or gastrointestinal diseases that could alter the assessment of PK or safety. c. Known bleeding diathesis (e.g., von Willebrand disease) or hemophilia. d. Uncontrolled hypertension or electrolytic imbalance. e. Any other severe, acute, or chronic medical, psychiatric or social condition, or laboratory abnormality that may increase the risk of study participation or study treatment administration, may interfere with the informed consent process and/or with compliance with the requirements of the study, or may interfere with the interpretation of the study results and, in the Investigator's opinion, would make the patient inappropriate for entry into this study.

结局指标

主要结局

Part A1 and Part A2: •Incidence of DLTs •Incidence of adverse events (AEs) •Clinically significant changes in vital signs and laboratory parameters • Clinically significant changes from baseline in electrocardiograms (ECGs)

Part B: ORR: the percentage of patients achieving CR, unconfirmed complete response (CRu), or PR (as determined by an independent review committee [IRC] assessment for Cohort 2 only) using the International Primary CNS Lymphoma Collaborative Group (IPCG) Response Criteria guidelines for PCNSL (Abrey et al, 2005)

Part C: ORR: the percentage of patients achieving CR, CRu, or PR using the IPCG Response Criteria guidelines for PCNSL (Abrey et al, 2005)

次要结局

Part A1 and Part A2: • Maximum observed plasma concentration (Cmax) • Minimum observed plasma concentration (Cmin) • Time after dosing that a drug is present at the maximum concentration in serum (Tmax) • Area under the concentration-time curve (AUC) • Terminal elimination half-life (T1/2)
Part A1 and Part A2: • ORR: complete response (CR) + partial response (PR) • Waldenström macroglobulinemia/ lymphoplasmacytic lymphoma (WM/LPL) ORR: CR + PR + very good partial response (VGPR)
Part A1 and Part A2: • DOR: time from CR or PR to first documentation of relapse, disease progression, or death from any cause • WM/LPL DOR: time from CR, PR, or VGPR to first documentation of relapse, disease progression, or death from any cause
Part A1 and Part A2: • DCR: PR + CR + stable disease • WM/LPL DCR: CR + PR + VGPR + stable disease
Part A1 and Part A2: • PFS: time from date of first dose of study treatment until first documentation of relapse, disease progression, or death from any cause
Part A1 and Part A2: OS: time from date of first dose of study treatment until death from any cause
Part B+C: DOR:the time from the date CR, CRu, or PR is achieved to the date of first documented disease progression (as determined by an IRC assessment for Cohort 2 only) or death due to any cause, whichever occurs first/PFS:the time from the date of the first dose of study treatment to the date of the first documented disease progression (as determined by an IRC assessment for Cohort 2 only) or death due to any cause, whichever occurs first/OS:the time from date of 1st dose until death
Part B+C: Incidence of treatment-emergent adverse events (TEAEs) and treatment-related AEs, physical examinations, vital signs, ECGs, and laboratory values
Part B+C: PK parameters including but not limited to AUC, Cmax, Tmax, and T1/2 for emavusertib and ibrutinib

研究者

发起方

Curis Inc.

申办方类型

Pharmaceutical company

责任方

Principal Investigator

主要研究者

Catherine Wang

Scientific

Curis Inc.

研究点 (13)

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