My Pathway: An Open-Label Phase IIa Study Evaluating Trastuzumab/Pertuzumab, Erlotinib, Vemurafenib/Cobimetinib, Vismodegib, Alectinib, and Atezolizumab in Patients Who Have Advanced Solid Tumors With Mutations or Gene Expression Abnormalities Predictive of Response to One of These Agents
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 673
- 试验地点
- 60
- 主要终点
- Percentage of Atezolizumab-Treated Participants With Tissue Tumor Mutational Burden (tTMB) ≥16 Mutations/Mb With Overall Response, as Assessed by the Independent Review Committee (IRC)
研究概览
简要总结
This multicenter, non-randomized, open-label study will evaluate the efficacy and safety of six treatment regimens in participants with advanced solid tumors for whom therapies that will convey clinical benefit are not available and/or are not suitable options per the treating physician's judgment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
- •Life expectancy greater than or equal to (≥) 12 weeks
- •Histologically documented metastatic cancer (solid tumors, not including hematologic malignancies)
- •Participants who have received standard first-line therapy for metastatic cancer (except for the tumors for which no first-line therapy exists) and in whom a trial of targeted therapy is considered the best available treatment option. Eligible participants should not have available therapies that will convey clinical benefit and/or are not suitable options per the treating physician's judgment
- •No previous treatment with the specific assigned study drug or any other drug sharing the same target
- •Measurable disease by RECIST v1.1
- •Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 (For patients enrolling in the atezolizumab arm, ECOG score must be documented within 7 days prior to first treatment and confirmation of ECOG PS must be entered into the interactive web response system [IWRS] prior to initiation of treatment)
- •Adequate hematologic, renal, and liver function as defined by the protocol
- •If applicable, use of contraception methods or abstinence as defined by the protocol
- •Study-Drug Specific Inclusion Criteria:
- •Trastuzumab plus Pertuzumab
- •Molecular testing results from clinical laboratory improvement amendments (CLIA)-certified laboratories (using tissue and/or blood) demonstrating HER2 overexpression or amplification. Participants must have one of the following tumor types: biliary cancer, salivary cancer, or bladder cancer
- •a) For participants screened using a blood assay: obtain tissue-based testing result confirming study eligibility (within first 4 weeks after enrollment)
- •Left ventricular ejection fraction (LVEF) greater than (>) 50 percent (%) or above the lower limit of the institutional normal range, whichever is lower
- •Availability of an archival or new pre-treatment tissue sample is required if molecular testing was not performed by Foundation Medicine. Any available tumor tissue sample can be submitted. The tissue sample must be submitted within 4 weeks after enrollment
- •Molecular testing results from CLIA-certified laboratories (using tissue and/or blood) demonstrating epidermal growth factor receptor (EGFR)-activating mutations
- •Vemurafenib plus Cobimetinib
- •Molecular testing results from CLIA-certified laboratories (using tissue and/or blood) demonstrating BRAF V600 mutations a) For participants screened using a blood assay: obtain tissue-based testing result confirming study eligibility (within first 4 weeks after enrollment)
- •Molecular testing results from CLIA-certified laboratories (using tissue and/or blood) demonstrating hedgehog pathway relevant mutation (activating mutation of smoothened [SMO] or loss-of-function mutation of protein patched homolog-1 [PTCH-1])
- •a) For participants screened using a blood assay: obtain tissue-based testing result confirming study eligibility (within first 4 weeks after enrollment)
- •All non-hematological adverse events related to any prior chemotherapy, surgery, or radiotherapy must have resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade less than or equal to (≤) 2 prior to starting therapy
- •Molecular testing results from CLIA-certified laboratories (using tissue and/or blood) demonstrating anaplastic lymphoma kinase (ALK) gene rearrangements, ALK mutations, ALK copy number gain or (for melanoma only) increased ALK expression or presence of ALK-alternative transcription initiation transcript (ALKATI) a) For participants screened using a blood assay: obtain tissue-based testing result confirming study eligibility (within first 4 weeks after enrollment)
- •Atezolizumab
- •Molecular testing results from CLIA-certified laboratories (using tissue) demonstrating elevated tissue tumor mutational burden (tTMB ≥10 mutations/ Megabase [Mb])
- •For patients where molecular testing was not performed using Foundation Medicine, submission of an archival or new pretreatment tissue sample is mandatory. For patients where molecular testing was performed using Foundation Medicine, submission of an archival or new pretreatment tissue sample is required, if available. The tissue sample must be submitted within 4 weeks after enrollment
排除标准
- •Participants with hematologic malignancies
- •Concurrent administration of any other anti-cancer therapy (except male participants with prostate cancer receiving androgen blockade): Bisphosphonates and denosumab are allowed; Most recent anti-cancer therapy ≤28 days and have not recovered from the side effects, excluding alopecia; Radiation therapy within ≤14 days
- •Active or untreated brain metastases
- •History of carcinomatous meningitis
- •Uncontrolled concurrent malignancy (early stage is allowed if not requiring active therapy or intervention)
- •Pregnant or breastfeeding women, or intending to become pregnant during the study
- •Any significant cardiovascular events within 6 months prior to study entry
- •Pulmonary embolism within 30 days prior to study entry
- •History or presence of clinically significant ventricular or atrial dysrhythmia >Grade 2 per NCI CTCAE v4.0
- •Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results
- •Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol
- •Study-Drug Specific Exclusion Criteria:
- •Trastuzumab plus Pertuzumab
- •Previous treatment with any HER2-targeted therapy
- •Non-small cell lung cancer (NSCLC) or pancreatic cancer identified by exon 19 deletions or exon 21 L858R substitution mutations
- •EGFR amplifications in the absence of EGFR-activating mutations
- •Cancers with exon 20 mutations
- •Previous treatment with erlotinib or any other EGFR inhibitor
- •Inability to swallow pills
- •Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude absorption of erlotinib
- •Vemurafenib plus Cobimetinib
- •Malignant melanoma, papillary thyroid cancer, colorectal cancer, or hematologic malignancy including multiple myeloma
- •LVEF below institutional lower level of normal (LLN) or below 50%, whichever is lower
- •History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration
- •Presence of any of the following conditions, which are risk factors for RVO: Uncontrolled glaucoma with intraocular pressure >21 millimetres of mercury (mm Hg); Serum cholesterol ≥Grade 2; Hypertriglyceridemia ≥Grade 2; Hyperglycemia (fasting) ≥Grade 2; Grade ≥2 uncontrolled hypertension (participants with a history of hypertension controlled with anti-hypertensive medication to Grade </=1 are eligible)
- •Prior or concurrent malignancy with known RAS mutation
- •Previous treatment with vemurafenib or any other BRAF inhibitor (prior sorafenib is allowed)
- •Previous treatment with cobimetinib or any other mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor
- •Prior treatment with a RAF inhibitor
- •Inability to swallow pills
- •Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude absorption of vemurafenib
- •History of congenital long QT syndrome or mean (average of triplicate measurements) corrected QT (QTc) measured using Fridericia's method ≥450 millisecond (ms) at baseline or uncorrectable abnormalities in serum electrolytes (sodium, potassium, calcium, magnesium, phosphorus)
- •Basal cell carcinoma of the skin, medulloblastoma, small-cell lung cancer, or hematologic malignancies
- •Previous treatment with vismodegib or any other hedgehog pathway inhibitor
- •Inability to swallow pills
- •Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude absorption of vismodegib
- •ALK-positive NSCLC, neuroblastoma, and childhood tumors
- •Previous treatment with alectinib or any other ALK inhibitor
- •Participants with symptomatic bradycardia
- •Administration of strong/potent cytochrome P3A4 (CYP3A4) inhibitors or inducers within 14 days prior to the first dose of study treatment and while on treatment with alectinib
- •Inability to swallow pills
- •Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude absorption of alectinib
- •Atezolizumab
- •History of leptomeningeal disease
- •Uncontrolled tumor pain
- •Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to enrollment
- •Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Patients with indwelling catheters are allowed
- •Uncontrolled or symptomatic hypercalcemia
- •Previous treatment with atezolizumab or another programmed death-1 (PD-1)/PD-L1 inhibitor
- •History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
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研究组 & 干预措施
Trastuzumab Plus Pertuzumab
Participants will receive trastuzumab 8 milligrams per kilogram (mg/kg) intravenous (IV) infusion as loading dose, followed by 6 mg/kg IV infusion every 3 weeks; and pertuzumab 840 mg IV infusion as loading dose, followed by 420 mg IV infusion every 3 weeks.
干预措施: Trastuzumab (Drug)
Trastuzumab Plus Pertuzumab
Participants will receive trastuzumab 8 milligrams per kilogram (mg/kg) intravenous (IV) infusion as loading dose, followed by 6 mg/kg IV infusion every 3 weeks; and pertuzumab 840 mg IV infusion as loading dose, followed by 420 mg IV infusion every 3 weeks.
干预措施: Pertuzumab (Drug)
Atezolizumab
Participants will receive atezolizumab 1200 mg IV infusion every 3 weeks.
干预措施: Atezolizumab (Drug)
Vemurafenib
Participants will receive vemurafenib 960 mg orally twice daily (BID) in each 28-day cycle.
干预措施: Vemurafenib (Drug)
Vemurafenib Plus Cobimetinib
Participants will receive vemurafenib 960 mg orally twice daily (BID) in each 28-day cycle; and cobimetinib 60 mg orally once daily for 21 days on and 7 days off in each 28-day cycle.
干预措施: Vemurafenib (Drug)
Vemurafenib Plus Cobimetinib
Participants will receive vemurafenib 960 mg orally twice daily (BID) in each 28-day cycle; and cobimetinib 60 mg orally once daily for 21 days on and 7 days off in each 28-day cycle.
干预措施: Cobimetinib (Drug)
Vismodegib
Participants will receive vismodegib 150 mg orally once daily in each 28-day cycle.
干预措施: Vismodegib (Drug)
Alectinib
Participants will receive alectinib 600 mg orally BID in each 28-day cycle.
干预措施: Alectinib (Drug)
Erlotinib
Participants will receive erlotinib 150 mg orally once daily in each 28-day cycle.
干预措施: Erlotinib (Drug)
结局指标
主要结局
Percentage of Atezolizumab-Treated Participants With Tissue Tumor Mutational Burden (tTMB) ≥16 Mutations/Mb With Overall Response, as Assessed by the Independent Review Committee (IRC)
时间窗: From the date of first study treatment until disease progression or death from any cause, whichever occurs first (68.9 months)
The Objective Response Rate (ORR) is defined as the proportion of patients whose best response on or before the first occurrence of disease progression is a complete response (CR) or partial response (PR). Tumor responses were assessed by Independent Review Committee (IRC) using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Percentage of Participants in All Tumor-Pathway Cohorts With Overall Response, as Assessed by the Investigator
时间窗: From the date of first study treatment until disease progression or death from any cause, whichever occurs first (72.1 months)
The Objective Response Rate (ORR) is defined as the percentage of patients whose best response on or before the first occurrence of disease progression is a complete response (CR) or partial response (PR). Tumor responses were assessed by investigators using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for all arms.
次要结局
- Progression-Free Survival (PFS)(From the date of first study treatment until disease progression as assessed by the investigator, or death from any cause, whichever occurs first (72.1 months))
- Percentage of Participants With Disease Control(From the date of first study treatment until disease progression or death from any cause, whichever occurs first (72.1 months))
- Duration of Response (DoR)(From the date of first documented response (complete response [CR] or partial response [PR]) to the time of disease progression or death from any cause, whichever occurs first (70.8 months))
- Overall Survival (OS)(87.5 months)
- Number of Participants With Adverse Events(From first study treatment administration to 30 days (45 days for vismodegib, 90 days for atezolizumab) after the last dose (up to approximately 6.3 years))