PRIMARY OBJECTIVE:
I. To evaluate the safety, tolerability, maximum tolerated dose (MTD) and/or recommended
phase 2 dose, gemcitabine and cisplatin in combination with either ivosidenib or pemigatinib.
SECONDARY OBJECTIVES:
I. To evaluate median and progression free survival (PFS) for 6 months per investigator
assessment.
II. To evaluate the rate of overall survival (OS) in patients treated with gemcitabine and
cisplatin in combination with either ivosidenib or pemigatinib.
III. To describe the overall toxicity and adverse events profile associated with gemcitabine
and cisplatin in combination with either ivosidenib or pemigatinib.
IV. To determine the best response profile per Response Evaluation Criteria in Solid Tumors
(RECIST) 1.1 criteria in patients treated with gemcitabine and cisplatin in combination with
either ivosidenib or pemigatinib.
CORRELATIVE RESEARCH OBJECTIVE:
I. To measure plasma 2-hydroxglutarate (2-HG) levels =< 21 days prior to registration and at
cycle 4 day 1 (+/- 2 days).
OUTLINE: This is a dose de-escalation study. Patients are assigned to 1 of 2 arms.
ARM A (IDH1 GENE MUTATION): Patients receive ivosidenib orally (PO) on days 1-21, cisplatin
intravenously (IV) on days 1 and 8, and gemcitabine IV on days 1 and 8. Cycles repeat every
21 days in the absence of disease progression or unacceptable toxicity.
ARM B (FGFR2 GENE ALTERATION): Patients receive pemigatinib PO on days 1-21, cisplatin IV on
days 1 and 8, and gemcitabine IV on days 1 and 8. Cycles repeat every 21 days in the absence
of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 6
months for up to 3 years.
Inclusion Criteria:
- Histopathological diagnosis (fresh) or banked tumor biopsy sample collected within the
last 3 years from the registration date consistent with nonresectable or metastatic
cholangiocarcinoma and are not eligible for curative resection, transplantation, or
ablative therapies
- Documented disease without any evidence of progression following at least 3 cycles of
standard-of-care chemotherapy including gemcitabine and cisplatin as part of
first-line systemic therapy; NOTE: Only patients receiving standard-of-care
chemotherapy including gemcitabine and cisplatin as first-line therapy for
unresectable or metastatic cholangiocarcinoma will be permitted to enroll in this
trial. Prior systemic adjuvant chemotherapy is allowed as long as there was no
evidence of recurrence within 6 months of completing the adjuvant therapy
- Molecular testing result from Clinical Laboratory Improvement Amendments
(CLIA)-certified laboratory (using fresh tumor biopsy or most recent banked tumor
tissue available) confirming that the tumor tissue has at least one of the following:
- IDH1 gene mutation (R132C/L/G/H/S mutation)
- FGFR2 gene alteration
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
- Life expectancy >= 3 months
- At least one evaluable and measurable lesion by RECIST criteria prior to beginning
chemotherapy with gemcitabine and cisplatin
- NOTE: Subjects who have received prior local therapy (including but not limited
to embolization, chemoembolization, radiofrequency ablation, hepatic arterial
infusion, or radiation therapy) are eligible provided measurable disease falls
outside of the treatment
- Recovered from toxicities associated with prior anticancer therapy to baseline unless
stabilized under medical management
- Absolute neutrophil count >= 1,500/mm^3 (obtained =< 21 days prior to registration)
- Platelet count >= 100,000/mm^3 (obtained =< 21 days prior to registration)
- Hemoglobin >= 8 g/dL (obtained =< 21 days prior to registration)
- Serum total bilirubin =< 2.0 x upper limit of normal (ULN), unless considered due to
Gilbert's disease. If Gilbert's disease or disease involving liver, serum total
bilirubin =< 2.5 x ULN (obtained =< 21 days prior to registration)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN or =<
5.0 x ULN in the presence of liver metastases (obtained =< 21 days prior to
registration)
- Serum creatinine < 1.5 x ULN OR creatinine clearance >= 50 mL/min based on the
Cockcroft-Gault glomerular filtration rate (GFR) estimation (obtained =< 21 days prior
to registration)
- Serum phosphate =< institutional ULN and potassium within institutional normal range
for Arm B only (obtained =< 21 days prior to registration)
- NOTE: Supplemental potassium may be used to correct potassium prior to
registration
- Negative serum pregnancy test done =< 7 days prior to registration for women of
childbearing potential only
- NOTE: Females of reproductive potential are defined as sexually mature women who
have not undergone a hysterectomy, bilateral oophorectomy, or tubal occlusion or
who have not been naturally postmenopausal (i.e., who have not menstruated) for
>= 24 consecutive months (i.e., have not had menses at any time in the preceding
24 consecutive months)
- Women of reproductive potential and fertile men must agree to use 2 effective forms of
contraception (including at least 1 barrier form) from the time of giving informed
consent throughout the study and for 90 days (both females and males) following the
last dose of study drug
- NOTE: Effective forms of contraception are defined as hormonal oral
contraceptives, injectables, patches, intrauterine devices, intrauterine
hormone-releasing systems, bilateral tubal ligation, condoms with spermicide, or
male partner sterilization
- Able to understand and willing to sign the informed consent form
- NOTE: A legally authorized representative may consent on behalf of a subject who
is otherwise unable to provide informed consent if acceptable to and approved by
the site's Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
- Able to comply with scheduled visits, treatment plans, procedures, and laboratory
tests, including serial peripheral blood sampling during the study
- Willing to provide blood samples for correlative research purposes
Exclusion Criteria:
- Prior therapy with either an IDH inhibitor or selective FGFR inhibitor
- IDH inhibitors: ivosidenib, FT-2012, etc.
- FGFR inhibitors: pemigatinib, BGJ-398, TAS-120, ARQ 087, or derazantinib, etc.
- Progressive disease as best response on current standard-of-care chemotherapy
including gemcitabine and cisplatin
- Known toxicity to standard-of-care chemotherapy including gemcitabine and cisplatin
requiring cessation of this therapy
- Received radiotherapy to metastatic sites of disease =< 2 weeks prior to registration
- Underwent hepatic radiation, chemoembolization, or radiofrequency ablation =< 4 weeks
prior to registration
- Known symptomatic brain metastases requiring steroids
- NOTE: Subjects with previously diagnosed brain metastases are eligible if they
have completed their treatment and have recovered from the acute effects of
radiation therapy or surgery prior to study entry, have discontinued
corticosteroid treatment for these metastases for at least 4 weeks and have
radiographically stable disease for at least 3 months prior to registration
- NOTE: Up to 10 mg per day of prednisone equivalent will be allowed
- Other active malignancy =< 5 years prior to registration. EXCEPTIONS:
- Non- melanoma skin cancer unless stage 1a or carcinoma-in-situ of the cervix
- Breast cancer with ongoing hormone therapy being administered as adjuvant therapy
- NOTE: If there is a history or prior malignancy, they must not be receiving
other specific treatment
- Major surgery =< 4 weeks prior to registration or have not recovered from post-surgery
toxicities
- Any of the following because this study involves investigational agents whose
genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn are
unknown:
- Pregnant women
- Nursing women
- Men or women of childbearing potential who are unwilling to employ adequate
contraception
- Arm A: Use of strong CYP3A4 inducers or strong or moderate CYP3A4 inhibitors. In
addition, sensitive CYP3A4 substrate medications with a narrow therapeutic window,
unless they can be transferred to other medications =< 4 days or 5 half-lives
(whichever is shorter) prior to registration
- Arm B: Use of strong CYP3A4 inducers or inhibitors or moderate CYP3A4 inducers
- NOTE: Study principal investigator (PI) approval is needed if continued use of CYP3A4
inducers or inhibitors. Approval can be obtained via email (documentation of
approval/eligibility needed)
- For Arm B only: Current evidence of clinically significant corneal (including but not
limited to bullous/band keratopathy, corneal abrasion, inflammation/ulceration, and
keratoconjunctivitis) or retinal disorder (including but not limited to central serous
retinopathy, macular/retinal degeneration, diabetic retinopathy, retinal detachment)
as confirmed by ophthalmologic examination
- Known history and/or current evidence of ectopic mineralization/ calcification,
including but not limited to soft tissue, kidneys, intestine, myocardia, or lung,
excepting calcified lymph nodes and asymptomatic arterial or cartilage/tendon
calcification for Arm B only
- Known history of hypovitaminosis D requiring supraphysiologic doses to replenish the
deficiency for Arm B only
- NOTE: Subjects receiving vitamin D food supplements are allowed
- Active infection requiring systemic anti-infective therapy or with an unexplained
fever > 38.5 degrees Celsius (C) =< 7 days of registration
- NOTE: At the discretion of the investigator, subjects with tumor fever may be
enrolled
- Any known hypersensitivity to any of the components of ivosidenib or pemigatinib
- Significant, active cardiac disease =< 6 months prior to registration, including
- New York Heart Association (NYHA) class III or IV congestive heart failure
- Myocardial infarction
- Unstable angina
- Stroke
- Have a heart-rate corrected QT interval (using Fridericia's formula) (QTcF) >= 450
msec or other factors that increase the risk of QT prolongation or arrhythmic events
(e.g., heart failure, hypokalemia, family history of long QT interval syndrome)
- Note: Bundle branch block and prolonged QTcF interval are permitted with approval
of the medical monitor
- Taking medications that are known to prolong the QT interval, unless they can be
transferred to other medications >= 5 half-lives prior to registration or unless the
medications can be properly monitored during the study
- Note: If equivalent medication is not available, QTcF should be closely monitored
- Known active hepatitis B (hepatitis B virus [HBV]) or hepatitis C (hepatitis C virus
[HCV]) infections, known positive human immunodeficiency virus (HIV) antibody results,
or acquired immunodeficiency syndrome (AIDS) related illness
- NOTE: Subjects with a sustained viral response to HCV or immunity to prior HBV
infection will be permitted. Subjects with chronic HBV that is adequately
suppressed per institutional practice will be permitted
- NOTE: HBV, HCV, and/or HIV testing is not required prior to trial registration
- Any other acute or chronic medical or psychiatric condition, including recent (=< 12
months of registration) or active suicidal ideation or behavior, or a laboratory
abnormality that may increase the risk associated with study participation or
investigational product administration or may interfere with the interpretation of
study results and, in the judgment of the investigator, would make the subject
inappropriate for entry into this study
- Inability or unwillingness to swallow ivosidenib or pemigatinib or have significant
gastrointestinal (GI) disorder(s) that could interfere with absorption, metabolism, or
excretion
- NOTE: Gastroesophageal reflux disease under medical treatment is allowed
(assuming no drug interaction potential)
- Have been committed to an institution by virtue of an order issued either by the
judicial or administrative authorities
- Receiving any other investigational agent which would be considered as a treatment for
the primary neoplasm
