Clinical Trials /

Gemcitabine and Cisplatin With Ivosidenib or Pemigatinib for the Treatment of Unresectable or Metastatic Cholangiocarcinoma

NCT04088188

Description:

This phase I trial studies the side effects and best dose of gemcitabine and cisplatin when given together with ivosidenib or pemigatinib in treating patients with cholangiocarcinoma that cannot be removed with surgery (unresectable) or has spread to other places in the body (metastatic). Chemotherapy drugs, such as gemcitabine and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Ivosidenib and pemigatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving gemcitabine and cisplatin with ivosidenib or pemigatinib may work better in treating patients with cholangiocarcinoma compared to gemcitabine and cisplatin alone.

Related Conditions:
  • Cholangiocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Gemcitabine and Cisplatin With Ivosidenib or Pemigatinib for the Treatment of Unresectable or Metastatic Cholangiocarcinoma
  • Official Title: A Phase I, Multi-Center, Open Label, Dose De-Escalation and Expansion Study of Gemcitabine and Cisplatin With AG120 or Pemigatinib for Advanced Cholangiocarcinoma

Clinical Trial IDs

  • ORG STUDY ID: ACCRU-ICRN-1701
  • SECONDARY ID: NCI-2019-05811
  • SECONDARY ID: ACCRU-ICRN-1701
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT04088188

Conditions

  • Advanced Cholangiocarcinoma
  • FGFR1 Gene Alteration Positive
  • FGFR2 Gene Alteration Positive
  • FGFR3 Gene Alteration Positive
  • IDH1 Gene Mutation
  • IDH1 NP_005887.2:p.R132C
  • IDH1 NP_005887.2:p.R132G
  • IDH1 NP_005887.2:p.R132H
  • IDH1 NP_005887.2:p.R132L
  • IDH1 NP_005887.2:p.R132S
  • Metastatic Cholangiocarcinoma
  • Unresectable Cholangiocarcinoma

Interventions

DrugSynonymsArms
CisplatinAbiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone''s Chloride, Peyrone''s Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, PlatosinArm A (ivosidenib, cisplatin, gemcitabine)
GemcitabinedFdC, dFdCyd, DifluorodeoxycytidineArm A (ivosidenib, cisplatin, gemcitabine)
Gemcitabine HydrochloridedFdCyd, Difluorodeoxycytidine Hydrochloride, FF 10832, FF-10832, FF10832, Gemcitabine HCI, Gemzar, LY-188011, LY188011Arm A (ivosidenib, cisplatin, gemcitabine)
IvosidenibAG-120, TibsovoArm A (ivosidenib, cisplatin, gemcitabine)
PemigatinibINCB054828Arm B (pemigatinib, cisplatin, gemcitabine)

Purpose

This trial studies the side effects and best dose of gemcitabine and cisplatin when given together with ivosidenib or pemigatinib in treating patients with cholangiocarcinoma that cannot be removed with surgery (unresectable) or has spread to other places in the body (metastatic). Drugs used in chemotherapy, such as gemcitabine and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Ivosidenib and pemigatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving gemcitabine and cisplatin with ivosidenib or pemigatinib may work better in treating patients with cholangiocarcinoma compared to gemcitabine and cisplatin alone.

Detailed Description

      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 at baseline and after multiple doses of
      ivosidenib study.

      OUTLINE: This is a dose de-escalation study. Patients are assigned to 1 of 2 arms.

      ARM A (IDH1 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 (FGFR/FGF MUTATION): 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (ivosidenib, cisplatin, gemcitabine)ExperimentalPatients receive ivosidenib 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.
  • Cisplatin
  • Gemcitabine
  • Gemcitabine Hydrochloride
  • Ivosidenib
Arm B (pemigatinib, cisplatin, gemcitabine)ExperimentalPatients 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.
  • Cisplatin
  • Gemcitabine
  • Gemcitabine Hydrochloride
  • Pemigatinib

Eligibility Criteria

        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)

               -  FGFR1, FGFR2, or FGFR3 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: AG-120, 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

          -  Received 3 cycles of standard-of-care chemotherapy including gemcitabine and cisplatin
             prior to registration

          -  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

          -  Use of strong CYP3A4 inducers or 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 as well as potent inhibitors
             and moderate inducers

          -  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

          -  Left ventricular ejection fraction (LVEF) < 40% by echocardiography (ECHO) scan (or by
             other methods according to institutional practice) obtained =< 28 days prior to
             registration

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of significant toxicities
Time Frame:At 27 weeks
Safety Issue:
Description:A significant toxicity is defined as a dose limiting toxicity that is possibly, probably, or definitely related to treatment (ivosidenib or pemigatinib in combination with cisplatin and gemcitabine). Toxicities will be assessed using Common Terminology Criteria for Adverse Events.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:From start of study therapy to death due to any cause, assessed up to 3 years
Safety Issue:
Description:Overall survival is defined as the length of time from start of study therapy to death due to any cause. The distribution of overall survival for both arms of the study will be estimated separately using the Kaplan-Meier method.
Measure:Progression free survival
Time Frame:From the start of study therapy to documentation of disease progression, assessed up to 3 years
Safety Issue:
Description:Progression free survival time is defined as the time from the start of study therapy to documentation of disease progression. Patients who die without documentation of progression will be considered to have had tumor progression at the time of death. Patients who are still alive and have not progressed will be censored for progression at the time of the last disease evaluation. The time-to-progression distribution will be estimated separately for both arms, using the Kaplan-Meier method.
Measure:Incidence of adverse events
Time Frame:Up to 3 years
Safety Issue:
Description:The number and severity of all adverse events (overall, by dose-level, and by tumor group) will be tabulated and summarized in this patient population. The grade 3+ adverse events will also be described and summarized in a similar fashion.
Measure:Incidence of toxicities
Time Frame:Up to 3 years
Safety Issue:
Description:The term toxicity is defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment. Non-hematologic toxicities will be evaluated via the ordinal Common Terminology Criteria (CTC) standard toxicity grading. Hematologic toxicity measures of thrombocytopenia, neutropenia, and leukopenia will be assessed using continuous variables as the outcome measures (primarily nadir) as well as categorization via CTC standard toxicity grading. Overall toxicity incidence as well as toxicity profiles by dose level, patient and tumor site will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses.
Measure:Best response
Time Frame:From the start of the treatment until disease progression/recurrence, assessed up to 3 years
Safety Issue:
Description:Best Response is defined to be the best objective status recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient?s best response assignment will depend on the achievement of both measurement and confirmation criteria. Response Evaluation Criteria in Solid Tumors 1.1 criteria will be used for tumor evaluation and patients will be re-evaluated every prior to treatment in cycle 3 and then in odd subsequent cycles. Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population (overall and by tumor group).

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Academic and Community Cancer Research United

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