An Open-label Phase 1b Study of ORIC-101 in Combination With Anticancer Therapy in Patients With Advanced or Metastatic Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 83
- 试验地点
- 11
- 主要终点
- Part I: Recommended Phase 2 Dose (RP2D)
研究概览
简要总结
The purpose of this study is to establish the recommended Phase 2 dose (RP2D), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of ORIC-101 in combination with nab-paclitaxel or other anticancer therapies when administered to patients with advanced or metastatic solid tumors.
详细描述
ORIC-101 is a small molecule GR antagonist being developed for the treatment of patients with solid tumor malignancies. Mechanistically, ORIC-101 inhibits GR transcriptional activity and blocks the pro-survival signals mediated by the activated nuclear receptor.
This is an open-label, uncontrolled, multicenter, dose-finding study to assess the safety and preliminary antitumor activity of ORIC-101 in combination with nab-paclitaxel or other anticancer therapy in patients with advanced or metastatic solid tumors. The study will begin with dose finding in combination initially with nab-paclitaxel in patients with various solid tumors (Part I); additional dose expansion cohorts in specific tumor types with nab-paclitaxel (Part II) or with other anticancer therapies may be evaluated through protocol amendment(s).
The study will first evaluate intermittent administration (5 days on, 2 days off for 21 days) of ORIC-101 followed by continuous administration (daily for 21 days) in combination with nab-paclitaxel using a standard 3+3 dose escalation design.
In Part II, patients will be enrolled across four cohorts of advanced or metastatic disease:
- pancreatic ductal adenocarcinoma (PDAC)
- ovarian cancer
- triple negative breast cancer (TNBC)
- other solid tumors
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
- •PDAC: Advanced or metastatic PDAC previously treated with and progressed on a fluoropyrimidine-based regimen and a taxane-containing chemotherapy regimen (eg, gemcitabine + nab-paclitaxel). Pancreatic neuroendocrine tumors, lymphoma of the pancreas, acinar pancreatic cancer, or ampullary cancer are not eligible.
- •Ovarian Cancer: Advanced or metastatic high grade serous or endometrioid epithelial ovarian, primary peritoneal, fallopian tube cancer or ovarian carcinosarcoma, previously treated with and progressed on a taxane-containing chemotherapy regimen; clear cell, mucinous and borderline histologic subtypes are not eligible; must have received at least one line of therapy with evidence of cancer progression within 6 months after the last dose of platinum-based therapy (ie, having a platinum-free interval of <6 months [platinum resistant]), or progressive disease during or immediately after primary platinum-therapy, (ie, platinum refractory).
- •TNBC: Advanced or metastatic ER-negative, PR-negative, HER2-negative primary breast cancer previously treated and progressed on a taxane-based chemotherapy regimen; no previous or synchronous second breast cancer, unless also confirmed ER-, PR- and HER2-negative; must have received at least one line of therapy in the metastatic setting.
- •Other Solid Tumor: Other advanced or metastatic solid tumor previously treated with and progressed on a taxane-based chemotherapy regimen, with the exception of metastatic colorectal cancer, primary brain tumors, and neuroendocrine tumors that secrete ACTH or CRH; must have received no more than 4 prior lines of cytotoxic or myelosuppressive therapy
- •Other Key Inclusion Criteria:
- •At least 18 years of age
- •ECOG performance status 0 or 1
- •Measurable disease as assessed centrally using RECIST 1.1
- •Treated, stable CNS metastases must be asymptomatic and must not require steroids
- •Agreement and ability to undergo two on-study biopsies, one pre-treatment obtained prior to dosing and during Cycle 2
- •Adequate organ function as defined by the following criteria:
- •ANC ≥1500 cells/mm3 (1.5 × 103 cells/mm3)
- •Platelets ≥100,000 /µL (100 × 109 /L)
- •Hemoglobin ≥9.0 g/dL (90 g/L)
- •Albumin ≥3.0 g/dL
- •AST (SGOT) or ALT (SGPT) ≤2.5 × ULN, ≤5.0 × ULN for patients with liver metastases
- •Bilirubin ≤1.5 × ULN; patients with a known history of Gilbert's syndrome and/or isolated elevations of indirect bilirubin are eligible
- •QTcF ≤480 msec
- •Ability to swallow ORIC-101 intact without chewing or crushing the capsules or tablets
- •Adequate gastrointestinal absorption. If the patient has undergone gastric bypass surgery and/or surgery of gastrointestinal or hepatobiliary tract, the patient must demonstrate adequate absorption as evidenced by albumin ≥3.0 g/dL, controlled pancreatic insufficiency (if present), and lack of evidence of malabsorption
- •Expansion Cohorts Part II
排除标准
- •Any other current or active malignancy
- •Prior or current treatment with ORIC-101 or any other GR antagonist (eg, mifepristone, relacorilant)
- •Concurrent treatment with any other anticancer therapy including chemotherapy, hormonal therapy, immunotherapy, radiotherapy, chemoembolization, targeted therapy, or an investigational agent within 28 days prior to Cycle 1 Day 1
- •Major surgery or radiotherapy within 21 days prior to Cycle 1 Day 1 or incomplete recovery from adverse effects resulting from such procedures; palliative radiotherapy within 1 week of Cycle 1 Day 1
- •Systemic, inhaled, or prescription strength topical corticosteroids within 21 days prior to Cycle 1 Day 1; short courses (≤5 days) for non-cancer-related reasons are allowed if clinically required
- •Grade 2 (moderate) or higher peripheral neuropathy per CTCAE v5.0; patients with mild peripheral neuropathy may be eligible at the discretion of the investigator in consultation with ORIC
- •All other toxicities from prior therapy (except alopecia) that have not resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 ≤ Grade 1
- •Females: history of unexplained vaginal bleeding in the 8 weeks prior to Cycle 1 Day 1 (given potential for ORIC-101 to exacerbate such bleeding)
- •Females: use of hormone replacement therapy; hormone replacement therapy must be discontinued to allow for confirmation of postmenopausal status
- •History of Cushing's syndrome or adrenal insufficiency
- •Current (within 10 days prior to Cycle 1 Day 1) or expected on-study treatment with specified strong CYP3A4 inhibitors or inducers
- •Known human immunodeficiency virus (HIV) infection, unless patient is healthy and has a low risk of AIDS-related outcomes
- •Presence of Hepatitis B surface antigen (HBsAg) at screening
- •Positive Hepatitis C (HCVAb) antibody test result at screening or within 3 months prior to Cycle 1 Day
- •NOTE: Patients with positive HCVAb due to prior resolved disease can be enrolled if a confirmatory negative Hepatitis C RNA test is obtained
- •Positive Hepatitis C RNA test result at screening or within 3 months prior to Cycle 1 Day
- •NOTE: Test is optional and patients with negative HCVAb test are not required to also undergo Hepatitis C RNA testing
研究组 & 干预措施
Dose Expansion (Part II)
RP2D dose
干预措施: ORIC-101 (Drug)
Dose Escalation (Part I)
ORIC-101 dosed orally, once per day, for 5 or 7 days/week in combination with nab-paclitaxel (75 or 100 mg/m2 on Days 1, 8, and 15) of each 28-day cycle.
干预措施: Nab-paclitaxel (Drug)
Dose Escalation (Part I)
ORIC-101 dosed orally, once per day, for 5 or 7 days/week in combination with nab-paclitaxel (75 or 100 mg/m2 on Days 1, 8, and 15) of each 28-day cycle.
干预措施: ORIC-101 (Drug)
Dose Expansion (Part II)
RP2D dose
干预措施: Nab-paclitaxel (Drug)
结局指标
主要结局
Part I: Recommended Phase 2 Dose (RP2D)
时间窗: 12 months
RP2D as determined by 3+3 dose escalation design
Part II: Objective Response Rate (ORR)
时间窗: 18 months
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and assessed by Blinded Independent Central Review (BICR)
次要结局
- Part II: Overall Survival (OS)(36 months)
- Part I: Time of maximum observed concentration (Tmax)(28 Days)
- Part I: Area under the curve (AUC(0-t))(28 Days)
- Parts I and II: Number of Participants with Adverse Events(36 months)
- Parts I and II: Number of Participants with Abnormal Laboratory Values(36 months)
- Parts I and II: Number of Participants with Abnormal 12-lead ECG(36 months)
- Parts I and II: Number of Participants with Abnormal Vital Signs(36 months)
- Part I: Number of Participants with Antitumor Activity(36 months)
- Part II: Duration of Response (DOR)(36 months)
- Part II: Progression-Free Survival (PFS)(36 months)
- Part II: Investigator-assessed ORR(36 months)
- Part I: Maximum plasma concentration (Cmax)(28 Days)