A Phase Ia/Ib Study of the Combination of the FGFR Inhibitor Pemigatinib and the EGFR Inhibitor Afatinib in Advanced Refractory Solid Tumors
概览
- 阶段
- 1 期
- 干预措施
- Afatinib
- 疾病 / 适应症
- Advanced Solid Tumor
- 发起方
- Massachusetts General Hospital
- 入组人数
- 70
- 试验地点
- 2
- 主要终点
- Objective response rate (ORR)
- 状态
- 招募中
- 最后更新
- 3个月前
概览
简要总结
This study is researching whether the combination of Afatinib and Pemigatinib is safe and effective in FGFR altered unresectable or metastatic advanced solid tumors.
The study is also trying to discover the highest doses of the study drugs that can be administered without causing any intolerable side effects.
This research study involves the study drugs Afatinib and Pemigatinib.
详细描述
This is an open-label phase Ia/Ib study to evaluate safety, tolerability and preliminary efficacy of the combination of pemigatinib and afatinib in patients with FGFR-altered refractory advanced solid tumors. This study includes 2 parts: phase 1a dose escalation and phase 1b dose expansion. * In the phase 1a dose escalation study patients with FGFR-altered refractory advanced refractory solid tumors will be enrolled. * In the phase Ib dose expansion study, patients with FGFR-altered cholangiocarcinoma will be recruited into 2 cohorts: FGFR inhibitor-naïve cholangiocarcinoma and FGFR-inhibitor-pretreated and resistant cholangiocarcinoma. The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits. This research study involves the study drugs Afatinib and Pemigatinib. Participants will receive study treatment for as long there is benefit and no unacceptable side effects. Participants will be followed for up to 1 year. It is expected that up to 70 people will take part in this research study. This research study is a Phase I clinical trial, which tests the safety of an investigational drug and also tries to define the appropriate dose of the investigational drug to use for further studies. "Investigational" means that the drug is being studied. The U.S. Food and Drug Administration (FDA) has not approved afatinib for this specific disease but it has been approved for other uses. The U.S. Food and Drug Administration (FDA) has approved pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement or fusion. The FDA has not approved the combination of afatinib and pemigatinib as a treatment for any disease.
研究者
Haley Ellis, MD
Principal Investigator
Massachusetts General Hospital
入排标准
入选标准
- •All Patients
- •Unresectable or metastatic, histologically confirmed advanced solid tumor, where standard curative or palliative measures are no longer effective or are not considered appropriate or safe in the opinion of the investigator.
- •FGFR1-3 fusion, rearrangement, activating mutation, or FGFR2 extracellular domain in-frame deletions on tumor profiling in tumor tissue as determined by testing routinely performed at a Clinical Laboratory Improvement Amendments (CLIA) or other similarly certified laboratory. If the FGFR alteration is present on circulating tumor DNA (ctDNA) analysis alone, the patient may be eligible with principal investigator approval. Additional mutations may be considered with principal investigator approval.
- •Eastern Cooperative Oncology Group (ECOG) 0-
- •At least 18 years of age.
- •Ability to swallow tablets.
- •Life expectancy \>/=3 months
- •Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation.
- •Patients with cholangiocarcinoma must have adequate biliary drainage (per investigator's discretion), with no evidence of ongoing infection.
- •Willingness of men and women of reproductive potential to observe conventional and effective birth control for the duration of treatment and for 3 months following the last dose of study treatment.
排除标准
- •Known hypersensitivity to afatinib or pemigatinib or excipients of pemigatinib
- •For patients treated with a prior FGFR inhibitor, those with known activating mutation(s) in the FGFR2 kinase domain on ctDNA or biopsy analysis within 8 weeks of start of study drugs; activating mutations in the FGFR2 kinase domain seen on ctDNA or biopsy analysis prior to the 8-week timepoint may be allowed after discussion with the study PI.
- •Systemic or liver-directed anticancer therapy within 2 weeks; or anticancer monoclonal antibody within 4 weeks prior to planned start of pemigatinib and afatinib.
- •Patient has adverse events from prior therapy that have not resolved to ≤ grade 1; exceptions for non-clinically meaningful adverse events (AEs) can be made with input from the principal investigator.
- •Major surgery within 4 weeks prior to planned start of pemigatinib and afatinib (tumor biopsy, biliary stent or catheter placement, and feeding tube placement are not considered major surgical procedures).
- •Received prior palliative non-CNS radiation within 2 weeks or extended-field radiation administered within 4 weeks of first dose of study drug. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. Fibrotic pulmonary disease from prior radiotherapy is permissible with approval of the study PI.
- •Known pre-existing interstitial lung disease
- •Current hypovitaminosis D requiring supraphysiologic (eg 50,000 IU/weekly) to replenish the deficiency. Vitamin D supplements are allowed.
- •History and/or current evidence of clinically significant ectopic mineralization/calcification or non-tumor related alteration of calcium-phosphorus homeostasis.
- •History and/or current evidence of clinically significant corneal or retinal disorder confirmed by ophthalmological examination
研究组 & 干预措施
DOSE ESCALATION PHASE 1A PEMIGATINIB + AFATINIB
In the phase 1a dose escalation study participants with FGFR-altered refractory advanced solid tumors will be enrolled. This research study involves the study drugs Afatinib and Pemigatinib.
干预措施: Afatinib
DOSE ESCALATION PHASE 1A PEMIGATINIB + AFATINIB
In the phase 1a dose escalation study participants with FGFR-altered refractory advanced solid tumors will be enrolled. This research study involves the study drugs Afatinib and Pemigatinib.
干预措施: Pemigatinib
COHORT 1: EXPANSION PHASE 1B COHORT 1 MTD/RP2D PEMIGATINIB + AFATINIB FGFR INHIBITOR-NAIVE
In the phase Ib dose expansion study, patients with FGFR-altered cholangiocarcinoma will be recruited into 2 cohorts: FGFR inhibitor-naïve cholangiocarcinoma and FGFR-inhibitor-pretreated and resistant cholangiocarcinoma. Cohort 1 will enroll patients with FGFR inhibitor-naïve cholangiocarcinoma. This research study involves the study drugs Afatinib and Pemigatinib.
干预措施: Afatinib
COHORT 1: EXPANSION PHASE 1B COHORT 1 MTD/RP2D PEMIGATINIB + AFATINIB FGFR INHIBITOR-NAIVE
In the phase Ib dose expansion study, patients with FGFR-altered cholangiocarcinoma will be recruited into 2 cohorts: FGFR inhibitor-naïve cholangiocarcinoma and FGFR-inhibitor-pretreated and resistant cholangiocarcinoma. Cohort 1 will enroll patients with FGFR inhibitor-naïve cholangiocarcinoma. This research study involves the study drugs Afatinib and Pemigatinib.
干预措施: Pemigatinib
COHORT 2: EXPANSION PHASE 1B COHORT 2 MTD/RP2D PEMIGATINIB + AFATINIB FGFR INHIBITOR-PRETREATED
In the phase Ib dose expansion study, patients with FGFR-altered cholangiocarcinoma will be recruited into 2 cohorts: FGFR inhibitor-naïve cholangiocarcinoma and FGFR-inhibitor-pretreated and resistant cholangiocarcinoma. Cohort 2 will enroll patients with FGFR-inhibitor-pretreated and resistant cholangiocarcinoma. This research study involves the study drugs Afatinib and Pemigatinib.
干预措施: Afatinib
COHORT 2: EXPANSION PHASE 1B COHORT 2 MTD/RP2D PEMIGATINIB + AFATINIB FGFR INHIBITOR-PRETREATED
In the phase Ib dose expansion study, patients with FGFR-altered cholangiocarcinoma will be recruited into 2 cohorts: FGFR inhibitor-naïve cholangiocarcinoma and FGFR-inhibitor-pretreated and resistant cholangiocarcinoma. Cohort 2 will enroll patients with FGFR-inhibitor-pretreated and resistant cholangiocarcinoma. This research study involves the study drugs Afatinib and Pemigatinib.
干预措施: Pemigatinib
结局指标
主要结局
Objective response rate (ORR)
时间窗: Baseline, Every 9 weeks during treatment and Off Study up to 1 year
Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) in patients with FGFR2-fusion, rearrangement or in-frame deletion positive intrahepatic cholangiocarcinoma. Defined as the proportion of patients achieving Complete response (CR) and partial response(PR) per RECIST v1.1
Maximum tolerated dose (MTD)
时间窗: Through Cycle 1 (21 Days)
All patients in the dose-escalation part who have received ≥ 75% (21 days) of study drug and completed Cycle 1 through Cycle 1 Day 21 or experienced a dose limiting toxicity (DLT)
次要结局
- Disease Control Rate(Baseline, Every 9 weeks during treatment and Off Study up to 1 year)
- Duration of Response(Baseline, Every 9 weeks during treatment and Off Study up to 1 year)
- Time to response(Baseline, Every 9 weeks during treatment and Off Study up to 1 year)
- Maximum Plasma Concentration [Cmax]) and C trough of pemigatinib and afatinib(Cycle 1 day 1 and Cycle 1 day 8)
- Overall Survival(Baseline, Every 9 weeks during treatment and Off Study up to 1 year)
- Progression-free Survival(Baseline, Every 9 weeks during treatment and Off Study up to 1 year)
- Best Overall Response(Baseline, Every 9 weeks during treatment and Off Study up to 1 year)
- Treatment Related Adverse Events(Each visit until 30 days after study discontinuation.)
- Molecular correlates of response(Through study completion, an average of 6 months.)