Afatinib + Pemigatinib for Solid Tumors
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Massachusetts General Hospital
Must not be taking: Strong p-gp inhibitors, Potent CYP3A4 inducers
Disqualifiers: HIV, Active CNS metastases, Uncontrolled infection, others
No Placebo Group
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?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.
Will I have to stop taking my current medications?
The trial protocol does not specify if you must stop taking your current medications. However, you cannot take certain medications like strong p-gp inhibitors or potent CYP3A4 inhibitors or inducers within 14 days before starting the study treatment. It's best to discuss your current medications with the trial team.
What data supports the effectiveness of the drug combination Afatinib and Pemigatinib for solid tumors?
Pemigatinib has shown effectiveness in treating tumors with FGFR2 alterations, such as cholangiocarcinomas, by inhibiting the growth of cancer cells. Afatinib has demonstrated antitumor activity when combined with other drugs in patients with advanced solid tumors, suggesting potential benefits when used with Pemigatinib.
12345Is the combination of Afatinib and Pemigatinib safe for humans?
Pemigatinib has shown an acceptable safety profile in patients with advanced solid tumors, with some experiencing serious side effects. Afatinib, used for lung cancer, generally has manageable side effects like diarrhea and skin rash, which can be controlled by adjusting the dose.
13567What makes the drug combination of Afatinib and Pemigatinib unique for treating solid tumors?
The combination of Afatinib and Pemigatinib is unique because it targets two different pathways involved in cancer growth: Afatinib inhibits the ErbB family of proteins, which are involved in cell growth and division, while Pemigatinib selectively inhibits fibroblast growth factor receptors (FGFR) 1-3, which are often altered in certain tumors. This dual approach may offer a more comprehensive treatment for solid tumors with specific genetic alterations.
12567Eligibility Criteria
This trial is for individuals with advanced solid tumors that can't be removed by surgery or have spread (metastatic), and whose tumors have specific genetic alterations called FGFR. The exact eligibility criteria are not provided, but typically participants must meet certain health standards to ensure safety.Inclusion Criteria
Patients able to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation
Patients with measurable or non-measurable disease as determined by RECIST 1.1
My organs are functioning well.
+8 more
Exclusion Criteria
Patients living outside the US
Lactating or breastfeeding individuals during the study or within 30 days of the last dose of study intervention
I am allergic to afatinib, pemigatinib, or their ingredients.
+31 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Dose Escalation
Phase 1a dose escalation to determine the maximum tolerated dose of Pemigatinib and Afatinib in patients with FGFR-altered refractory advanced solid tumors
3 weeks
Cycle 1 Day 1 to Cycle 1 Day 21
Dose Expansion
Phase 1b dose expansion to evaluate safety and efficacy in FGFR inhibitor-naïve and FGFR-inhibitor-pretreated cholangiocarcinoma cohorts
6 months
Every 9 weeks during treatment
Follow-up
Participants are monitored for safety and effectiveness after treatment
Up to 1 year
Every 9 weeks during treatment and off study
Participant Groups
The study is testing the combination of two drugs, Afatinib and Pemigatinib, to see if they're safe and effective against advanced solid tumors with FGFR alterations. It also aims to find the highest doses patients can take without severe side effects.
3Treatment groups
Experimental Treatment
Group I: DOSE ESCALATION PHASE 1A PEMIGATINIB + AFATINIBExperimental Treatment2 Interventions
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.
Group II: COHORT 2: EXPANSION PHASE 1B COHORT 2 MTD/RP2D PEMIGATINIB + AFATINIB FGFR INHIBITOR-PRETREATEDExperimental Treatment2 Interventions
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.
Group III: COHORT 1: EXPANSION PHASE 1B COHORT 1 MTD/RP2D PEMIGATINIB + AFATINIB FGFR INHIBITOR-NAIVEExperimental Treatment2 Interventions
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.
Afatinib is already approved in United States, European Union, Canada, Japan for the following indications:
🇺🇸 Approved in United States as Gilotrif for:
- Non-small cell lung cancer
🇪🇺 Approved in European Union as Giotrif for:
- Non-small cell lung cancer
🇨🇦 Approved in Canada as Gilotrif for:
- Non-small cell lung cancer
🇯🇵 Approved in Japan as Giotrif for:
- Non-small cell lung cancer
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Massachusetts General HospitalBoston, MA
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Who Is Running the Clinical Trial?
Massachusetts General HospitalLead Sponsor
Boehringer IngelheimIndustry Sponsor
Incyte CorporationIndustry Sponsor
References
A drug safety evaluation of pemigatinib for advanced cholangiocarcinoma. [2023]Pemigatinib is a selective small-molecule inhibitor of the fibroblast growth factor receptor (FGFR) 1-3. FGFR is associated with increased cell division, proliferation, and survival. Inhibition of this receptor is an effective treatment against tumors driven by activated fusions in FGFR2.
INCB054828 (pemigatinib), a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays activity against genetically defined tumor models. [2020]Alterations in fibroblast growth factor receptor (FGFR) genes have been identified as potential driver oncogenes. Pharmacological targeting of FGFRs may therefore provide therapeutic benefit to selected cancer patients, and proof-of-concept has been established in early clinical trials of FGFR inhibitors. Here, we present the molecular structure and preclinical characterization of INCB054828 (pemigatinib), a novel, selective inhibitor of FGFR 1, 2, and 3, currently in phase 2 clinical trials. INCB054828 pharmacokinetics and pharmacodynamics were investigated using cell lines and tumor models, and the antitumor effect of oral INCB054828 was investigated using xenograft tumor models with genetic alterations in FGFR1, 2, or 3. Enzymatic assays with recombinant human FGFR kinases showed potent inhibition of FGFR1, 2, and 3 by INCB054828 (half maximal inhibitory concentration [IC50] 0.4, 0.5, and 1.0 nM, respectively) with weaker activity against FGFR4 (IC50 30 nM). INCB054828 selectively inhibited growth of tumor cell lines with activation of FGFR signaling compared with cell lines lacking FGFR aberrations. The preclinical pharmacokinetic profile suggests target inhibition is achievable by INCB054828 in vivo with low oral doses. INCB054828 suppressed the growth of xenografted tumor models with FGFR1, 2, or 3 alterations as monotherapy, and the combination of INCB054828 with cisplatin provided significant benefit over either single agent, with an acceptable tolerability. The preclinical data presented for INCB054828, together with preliminary clinical observations, support continued investigation in patients with FGFR alterations, such as fusions and activating mutations.
A phase I, dose-escalation trial of continuous- and pulsed-dose afatinib combined with pemetrexed in patients with advanced solid tumors. [2021]Afatinib, an irreversible ErbB family blocker, demonstrated synergistic inhibition of epidermal growth factor receptor-mutant cell growth with pemetrexed. This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of afatinib plus pemetrexed in patients with advanced solid tumors.
Pemigatinib Is Active in Some FGFR2-Altered Cholangiocarcinomas. [2021]Pemigatinib was effective in patients with cholangiocarcinomas with FGFR2 fusions or rearrangements.
FIGHT-101, a first-in-human study of potent and selective FGFR 1-3 inhibitor pemigatinib in pan-cancer patients with FGF/FGFR alterations and advanced malignancies. [2022]The phase I/II FIGHT-101 study (NCT02393248) evaluated safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of pemigatinib, a potent and selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor, as monotherapy or in combination therapy, for refractory advanced malignancies, with and without fibroblast growth factor (FGF) and receptor (FGFR) gene alterations.
Pharmacokinetics, pharmacodynamics and efficacy of pemigatinib (a selective inhibitor of fibroblast growth factor receptor 1-3) monotherapy in Chinese patients with advanced solid tumors: a phase i clinical trial. [2023]Pemigatinib is a selective fibroblast growth factor receptor (FGFR)1-3 inhibitor and has demonstrated acceptable tolerability and clinical activity in advanced solid tumors in Western population. This phase I trial evaluated pharmacokinetics/pharmacodynamics (PK/PD) characteristics, preliminary safety and efficacy of pemigatinib in Chinese patients with advanced, solid tumors. Patients with unresectable advanced or metastatic solid tumors bearing FGF/FGFR1-3 alterations received oral pemigatinib at 13.5 mg once daily (QD) on a 2-weeks-on/1-week-off schedule. The primary endpoint was PK/PD characteristics; secondary endpoints were safety and efficacy. Twelve patients were enrolled (median age: 61 years, 58.3% males). PK data demonstrated pemigatinib (13.5 mg QD) was rapidly absorbed with a geometric mean elimination half-life of 11.3 h. The geometric mean values of maximum serum concentration and area under the plasma concentration-time curve from 0 to 24 h at steady state were 215.1 nmol/L and 2636.9 h·nmol/L, respectively. The mean clearance adjusted by bioavailability at steady state was low (11.8 L/h), and the apparent oral volume of distribution was moderate (170.5 L). The PD marker, serum phosphate level, increased on days 8 and 15 of cycle 1 (mean: 2.25 mg/dL, CV% [percent coefficient of variation]: 31.3%) and decreased to baseline post 1 week off. Three (25.0%) patients experienced grade ≥ 3 treatment-emergent adverse events. Partial response was confirmed in one patient with FGFR1-mutant esophageal carcinoma and one with FGFR2-mutant cholagiocarcinoma. Pemigatinib had similar PK/PD characteristics to Western population and demonstrated an acceptable safety profile and potential anti-cancer benefit in Chinese patients with FGF/FGFR1-3 altered, advanced, solid tumor. (ClinicalTrials.gov: NCT04258527 [prospectively registered February 6, 2020]).
Afatinib: a review of its use in the treatment of advanced non-small cell lung cancer. [2022]Afatinib (Gilotrif™, Giotrif(®)) is an orally administered, irreversible inhibitor of the ErbB family of tyrosine kinases. Afatinib downregulates ErbB signalling by covalently binding to the kinase domains of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER) 2 and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation; it also inhibits transphosphorylation of HER3. Afatinib is approved as monotherapy for the treatment of EGFR tyrosine kinase inhibitor (TKI)-naïve adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutations in the EU, and for the first-line treatment of patients with metastatic NSCLC whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test in the US. In two randomized, open-label, multinational phase III trials, progression-free survival was significantly prolonged with afatinib compared with pemetrexed plus cisplatin (LUX-Lung 3) or gemcitabine plus cisplatin (LUX-Lung 6) in treatment-naïve patients with advanced NSCLC with activating EGFR mutations. The objective response rate was significantly higher with afatinib than with pemetrexed plus cisplatin or gemcitabine plus cisplatin, and patient-reported outcomes for symptoms such as cough and dyspnoea and certain health-related quality of life measures significantly favoured afatinib versus pemetrexed plus cisplatin or gemcitabine plus cisplatin. Afatinib also showed efficacy in EGFR TKI-naïve patients with advanced lung adenocarcinoma and activating EGFR mutations who had received no more than one prior chemotherapy regimen for advanced disease, according to the results of the noncomparative, multinational, phase II LUX-Lung 2 trial. Oral afatinib had a manageable tolerability profile. EGFR-mediated adverse events (e.g. diarrhoea, rash/acne) were generally managed using dose reduction and delays. In conclusion, afatinib is a valuable new option for use in treatment-naïve or EGFR TKI-naïve patients with advanced lung adenocarcinoma and activating EGFR mutations.