A Phase 1b/2 Study of Agents Targeting the Mitogen-Activated Protein Kinase Pathway in Patients With Advanced Gastrointestinal Malignancies (HERKULES-3)
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- Erasca, Inc.
- 入组人数
- 102
- 试验地点
- 14
- 主要终点
- Dose Limiting Toxicities (DLT)
研究概览
简要总结
- To evaluate the safety and tolerability of escalating doses of ERAS-007 in combination with other cancer therapies in study participants with advanced GI malignancies.
- To determine the Maximum Tolerated Dose (MTD) and/or Recommended Dose (RD) of ERAS-007 administered in combination with other cancer therapies.
- To evaluate the antitumor activity of ERAS-007 in combination with other cancer therapies.
- To evaluate the PK profiles of ERAS-007 and other cancer therapies when administered in combination.
详细描述
This is a Phase 1b/2, open-label, multicenter clinical study evaluating ERAS-007 in combination with other cancer therapies in study participants with GI malignancies. This study will serve as a platform study, allowing for evaluation of safety/tolerability and efficacy of ERAS-007 in combination with other cancer therapies. The study will initially commence with dose escalation of ERAS-007 administered in combination with encorafenib and cetuximab in study participants with metastatic colorectal cancer (CRC) harboring B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E mutation; and dose escalation of ERAS-007 administered in combination with palbociclib in study participants with metastatic CRC harboring Kirsten rat sarcoma (KRAS) or neuroblastoma rat sarcoma (NRAS) mutations and metastatic pancreatic adenocarcinoma with (PDAC) KRAS mutation. Dose expansion will follow and will test ERAS-007 administered at the RD identified from each dose escalation arm in study participants with metastatic CRC.
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 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years.
- •Willing and able to give written informed consent.
- •Have histologically or cytologically confirmed metastatic CRC harboring applicable mutation(s) (e.g., BRAF V600E; KRAS or NRAS mutations) or metastatic PDAC harboring KRAS mutation based on an analytically validated assay performed on tumor tissue in a certified testing laboratory.
- •Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.
- •Adequate bone marrow and organ function.
- •Have ECOG performance status of 0 or
- •Willing to comply with all protocol-required visits, assessments, and procedures.
- •Able to swallow oral medication.
排除标准
- •Prior therapy with a RAS, MEK, or ERK inhibitor. Depending on which treatment arm the patient is assigned, other therapies could also be prohibitive.
- •Anti-cancer therapy ≤ 21 days or 4 half-lives prior to first dose of study drug, whichever is shorter.
- •Palliative radiation ≤ 7 days prior to first dose of study drug.
- •Symptomatic brain metastasis or leptomeningeal disease.
- •Gastrointestinal conditions that may affect absorption of oral medications
- •Active infection requiring systemic therapy, or a known history of HIV infection, hepatitis B virus, or hepatitis C virus.
- •History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤ 12 months prior to first study drug dose.
- •Active, clinically significant interstitial lung disease or pneumonitis.
- •Impaired cardiovascular function or clinically significant cardiovascular disease.
- •History of thromboembolic or cerebrovascular events ≤ 6 months prior to first dose.
- •Major surgery within 28 days of enrollment, or anticipation of major surgery during study treatment.
- •Known intolerance or contraindication to encorafenib, cetuximab, or palbociclib.
- •Pregnant or breastfeeding women.
- •Any evidence of severe or uncontrolled systemic disease or evidence of any other significant clinical disorder or laboratory finding that renders the patient inappropriate to participate in the study.
研究组 & 干预措施
Dose Escalation (Parts A1a, A2a, or A3a): ERAS-007 in combination with encorafenib and cetuximab
ERAS-007 will be orally administered in combination with encorafenib and cetuximab to study participants with BRAFm CRC in sequential ascending doses until unacceptable toxicity, disease progression, or withdrawal of consent.
干预措施: ERAS-007 (Drug)
Dose Escalation (Parts A1a, A2a, or A3a): ERAS-007 in combination with encorafenib and cetuximab
ERAS-007 will be orally administered in combination with encorafenib and cetuximab to study participants with BRAFm CRC in sequential ascending doses until unacceptable toxicity, disease progression, or withdrawal of consent.
干预措施: Encorafenib (Drug)
Dose Escalation (Parts A1a, A2a, or A3a): ERAS-007 in combination with encorafenib and cetuximab
ERAS-007 will be orally administered in combination with encorafenib and cetuximab to study participants with BRAFm CRC in sequential ascending doses until unacceptable toxicity, disease progression, or withdrawal of consent.
干预措施: Cetuximab (Drug)
Dose Escalation (Parts B1a, B2a, B3a or B4a): ERAS-007 in combination with palbociclib
ERAS-007 will be orally administered in combination with palbociclib to study participants with KRASm or NRASm CRC and KRASm PDAC in sequential ascending doses until unacceptable toxicity, disease progression, or withdrawal of consent.
干预措施: ERAS-007 (Drug)
Dose Escalation (Parts B1a, B2a, B3a or B4a): ERAS-007 in combination with palbociclib
ERAS-007 will be orally administered in combination with palbociclib to study participants with KRASm or NRASm CRC and KRASm PDAC in sequential ascending doses until unacceptable toxicity, disease progression, or withdrawal of consent.
干预措施: Palbociclib (Drug)
Dose Expan (Parts A1b, A1c, A2b, A2c, A3b, or A3c): ERAS-007 in combo with encorafenib & cetuximab
ERAS-007 will be orally administered at the recommended dose (as determined from Parts A1a, A2a or A3a) in combination with encorafenib and cetuximab to study participants with BRAFm CRC.
干预措施: ERAS-007 (Drug)
Dose Expan (Parts A1b, A1c, A2b, A2c, A3b, or A3c): ERAS-007 in combo with encorafenib & cetuximab
ERAS-007 will be orally administered at the recommended dose (as determined from Parts A1a, A2a or A3a) in combination with encorafenib and cetuximab to study participants with BRAFm CRC.
干预措施: Encorafenib (Drug)
Dose Expan (Parts A1b, A1c, A2b, A2c, A3b, or A3c): ERAS-007 in combo with encorafenib & cetuximab
ERAS-007 will be orally administered at the recommended dose (as determined from Parts A1a, A2a or A3a) in combination with encorafenib and cetuximab to study participants with BRAFm CRC.
干预措施: Cetuximab (Drug)
Dose Expansion (Parts B1b, B2b, B3b, and B4b): ERAS-007 in combination with palbociclib
ERAS-007 will be orally administered at the recommended dose (as determined from Parts B1a, B2a, B3a or B4a) in combination with palbociclib to study participants with KRASm or NRASm CRC.
干预措施: ERAS-007 (Drug)
Dose Expansion (Parts B1b, B2b, B3b, and B4b): ERAS-007 in combination with palbociclib
ERAS-007 will be orally administered at the recommended dose (as determined from Parts B1a, B2a, B3a or B4a) in combination with palbociclib to study participants with KRASm or NRASm CRC.
干预措施: Palbociclib (Drug)
结局指标
主要结局
Dose Limiting Toxicities (DLT)
时间窗: Study Day 1 up to Day 29
Based on adverse events observed during dose escalation
Maximum Tolerated Dose (MTD)
时间窗: Study Day 1 up to Day 29
Based on adverse events observed during dose escalation
Adverse Events
时间窗: Assessed up to 24 months from time of first dose
Incidence and severity of treatment-emergent AEs and serious AEs
Recommended Dose (RD)
时间窗: Study Day 1 up to Day 29
Based on adverse events observed during dose escalation
次要结局
- Plasma concentration (Cmax)(Study Day 1 up to Day 29)
- Objective Response Rate (ORR)(Assessed up to 24 months from time of first dose)
- Area under the curve(Study Day 1 up to Day 29)
- Half-life(Study Day 1 up to Day 29)
- Duration of Response (DOR)(Assessed up to 24 months from time of first dose)
- Time to achieve Cmax (Tmax)(Study Day 1 up to Day 29)