Overview
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.
Description
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.
Eligibility
Inclusion Criteria:
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) 0-1.
- 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.
- Measurable or non-measurable disease as determined by RECIST 1.1.
- Adequate organ function defined as:
- ALT or AST ≤ 3 × the ULN in the absence of liver metastases, OR ≤ 5 × ULN with documented liver metastases
- Total bilirubin ≤ 2.0 × ULN in the absence of Gilbert's Disease, OR ≤ 3 × ULN with Gilbert's Disease provided direct bilirubin is ≤ ULN
- Serum Creatinine ≤ 1.5 × ULN OR calculated creatinine clearance ≥ 60ml/min
- Hemoglobin ≥ 9 g/dL (≥ 90 g/L)
- Absolute Neutrophil Count ≥ 1.5 x 109/L
- Platelets ≥ 75 x 109/L
- INR or PT, aPTT or PTT ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy
- NOTE: Transfusions to increase a patient's hemoglobin level or initiation of erythropoietin or G-CSF therapy to meet enrollment criteria are not allowed in the 14 days preceding the first dose of study drug. If a patient receives transfusions, erythropoietin, or G-CSF therapy ≥ 14 days prior to the first dose, the hematologic criteria listed above must be met following the 14-day window and prior to the first dose of study therapy
Dose expansion cohort 1: Patients should fulfill the eligibility criteria above for all
patients in addition to the following:
- Histologically or cytologically confirmed diagnosis of advanced or metastatic
cholangiocarcinoma
- No prior treatment with a selective FGFR inhibitor treatment
- FGFR2 fusion, in-frame rearrangement, or extracellular domain in-frame deletion on
tumor profiling in tumor tissue as determined by testing routinely performed on tumor
biopsy at a CLIA or other similarly certified laboratory. If the FGFR alteration is
present on ctDNA analysis alone, the patient may be eligible with principal
investigator approval.
- An archived tumor tissue sample is available in patients not undergoing fresh tumor
biopsy. Patients who do not have adequate archival tumor tissue available are required
to undergo a fresh tumor biopsy. If a fresh biopsy cannot be safely performed, the
patient may be eligible with principal investigator approval.
Dose expansion cohort 2: Patients should fulfill the eligibility criteria above for all
patients in addition to the following:
- Histologically or cytologically confirmed diagnosis of advanced or metastatic
cholangiocarcinoma
- Prior FGFR inhibitor treatment at any time prior to treatment start is required
- FGFR2 fusion, in-frame rearrangement, or extracellular domain in-frame deletion for
which they derived clinical benefit (objective response of any duration or stable
disease for at least 6 months) from prior FGFR inhibitor therapy, as determined by
testing routinely performed on tumor biopsy at a CLIA or other similarly certified
laboratory. If the FGFR alteration is present on ctDNA analysis alone, the patient may
be eligible with principal investigator approval
- An archived tumor tissue sample after progression on or intolerance of prior FGFR
inhibitor available in patients not undergoing fresh tumor biopsy. Patients who do not
have adequate archival tumor tissue available are required to undergo a fresh tumor
biopsy. If a fresh biopsy cannot be safely performed, the patient may be eligible with
principal investigator approval.
Exclusion Criteria:
- 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
- Child-Pugh B and C cirrhosis
- Chronic nausea, vomiting, or diarrhea considered to be clinically significant in the
opinion of the investigator. This includes significant or recent gastrointestinal
disorders with diarrhea as a major symptom
- Clinically significant active malabsorption syndrome or other condition likely to
affect gastrointestinal absorption of the study drug.
- Patients with a history of another primary malignancy that is currently clinically
significant, and has potential for metastases or currently requires active
intervention (except for gonadotropin-releasing hormone (GnRH) or luteinizing
hormone-releasing hormone (LH-RH) agonists in prostate cancer or hormonal therapy in
breast cancer
- Have history of hepatic encephalopathy of any grade
- Patients with ascites requiring serial paracenteses
- Active central nervous system (CNS) metastases are not eligible. Patients with
asymptomatic and treated brain metastases may participate provided that they are
stable for ≥ 2 months. Patients with suspected or confirmed leptomeningeal disease are
not eligible even if treated. Patients with glioblastoma multiforme (GBM) are not
eligible.
- Clinically significant, active cardiovascular disease such as uncontrolled
hypertension, congestive heart failure New York Heart Association (NYHA)
classification of 3, unstable angina or poorly controlled arrhythmia, or history of
myocardial infarction within 6 months prior to planned start of pemigatinib and
afatinib
- Fridericia's corrected QT interval (QTcF) > 480 ms on ECG conducted during Screening,
or history of torsades de pointes or personal or family history of prolonged QT
syndrome.Correction of suspected drug-induced QTcF prolongation can be attempted at
the investigator's discretion and only if clinically safe to do so with either
discontinuation of the offending drug or switch to another drug not known to be
associated with QTcF prolongation.
- Active uncontrolled systemic bacterial, viral, fungal or parasitic infection (except
for fungal nail infection), or other clinically significant active disease process
which in the opinion of the investigator and the sponsor-investigator makes it
undesirable for the patient to participate in the trial. Screening for chronic
conditions is not required.
- Active hepatitis B virus (HBV)
-- Note: Controlled (treated) hepatitis will be allowed if they meet the following
criteria: antiviral therapy for HBV must be given for at least 1 month prior to first
dose of study drug, and HBV viral load must be less than 2000 IU/ml (104 copies/ml)
prior to the first dose of study drug. Those on active HBV therapy with viral loads
under 2000 IU/ml (104 copies/ml) should stay on antiviral therapy throughout the study
treatment.
- Known human immunodeficiency virus (HIV) and on anti-retroviral therapy for
HIV(excluded due to potential drug-drug interactions between anti-retroviral
medications and study treatment but HIV itself is not an exclusion).
- Known or suspected active drug or alcohol use
- Concomitant treatment with known strong p-gp inhibitor.
- Use of any potent CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers within 14
days or 5 half-lives (whichever is longer) before the first dose of study treatment.
-- Note: Moderate CYP3A4 inhibitors are not prohibited
- Pregnancy during the study or within 30 days of the last dose of study intervention.
Also excluded are any persons of childbearing potential, including men who are able to
father a child, who are unwilling to use a medically acceptable method of
contraception during the trial (see below section 3.3). Lactation and breastfeeding
during the study or within 30 days of the last dose of study intervention is also not
allowed. Female patients must have a negative pregnancy test (B-HCG test in urine or
serum) prior to commencing study treatment.
- Unable to swallow pills
- Any other concomitant serious illness or organ system dysfunction which in the opinion
of the investigator would either compromise patient safety or interfere with the
evaluation of the safety of the study drug. Patients unable or deemed by the
investigator as unlikely to comply with the protocol are also excluded.